WOMEN HEALTH CONTRACEPTIONS
Item
- Title
- WOMEN HEALTH CONTRACEPTIONS
- extracted text
-
RF_WH_3_PART_1_SUDHA
IMPORTANT INFORMATION FDR WOMEN ON NEW CONTRACEPTIVES
< £ ;• rt . j cut a r 1. y. 1 on q-act i ngj_ hormonal,
j* JI t s and. in j_i: • • ,t a b.L£iS)
Have- you or other women you know been told about some
marvellous
new
contraceptives which will keep you free from
pregnancy
for
three months or five years?
about to
planning
methods
on human beings.
Madras
1-W
litthe
prospect
of
not constantly
having
to
worry
about
gutting pregnant appeal to you?
Would you consider am.opting oiie
of theses new, long-acting contraceptives so that you can delay or
prevent
pru-ju'ancy,
in order to have time -to
recover
from
unit
i
i v.iiii.iiicy
bciiiiv having to cope with another one, to
h.-.ivi.'
/.oiiii'
hew
them.
These new contraceptives cone in two forms: as an injection or as
an implant (six matchstick-like rods which the doctor' will
pi
cinder
the
skin of your arm through a
small
opera! ion) .
l.t<»l.h,
i ontain
similar
substances:
arti ficial versions of
the
human
hormone, progesterone.
The injection likely to be usml in
India
mon
is
Depo-Proveraj
its.contraceptive effect will
I act
tor
three
months.
The
implant already being tested
in
India' is
i ..lied Norplant;
it prevents pregnancy for five years.
I
flk:.
people
■suitable
for
believe
the
that
these
majority of
new
Indian
contraceptives
women.
Hero
ar
*
.not
are ' their
Thesiare
some
of
the
side-effects
of
hormonal
r. I i
p t i .1 ■
like theses
heavy and continuous bleeding
and/or
..•me
of
periods,
cardiac
problems,
liver
trouble,
blood
.11 tug disorders,
headache, depression, nervousness, change in
I ite, nausea and weight gain.
Const flor i.ng the
If Norplant stays in your body For longer than five years,
raiic.i' ectopic pregnancy (when the? foetus begins to
grow
you -iUlLU y.'Jli HULL
tfl Ut'.L 1.1. r£HlQY£il
No studies have clearly established that
again after using Norplant.
-
dlLit.
you can have
they have no right to force or threaten you in any way
the contraceptive.
before
enrolling you in the trial,
it
in
it's their duty to-
to
get
informed consent on a. form which must be in a language
you
understand (if- you cannot read, you must get a ^rusted person
i i.-ad
out to you before you sign or put your thumb impression
conduct
thorough
After obtaining your consent, they must
medical
tests to rule out the conditions with which
you
should
nut use such contraceptives.
I-, ke
sure
that
responsibilities.
J . 'i i im, r /o
•ti’^SOA/
*/
Tbi-J
,
they
respect
your
rights
and
fulfil
thu-ir
For more details, contact the Women's
Health
CoMM
hdms ,
p.g. H-610 . 69, muxca's
,
?60o^6.
*
J?
TOE EflSTO
oral contraception
THIRTY YEARS OF ORAL CONTRACEPTIVES
A brief history of the Pill
* 1960: Following trials in the USA, Puerto Rico and Mexico, America’s Food
and Drug Administration approves the Pill for use in the USA. The rest of the
world follows. For example:
Argentina
Australia
Britain
Indonesia
The Netherlands
Germany
Brazil
Denmark
New Zealand
Spain
Italy
France
Norway
India
Greece
Czechoslovakia
Morocco
Japan
1961
1961
1961
1961
1961
1962
1963
1964
1964
1964
1965
1966
1966
1967
1968
1972
1973
1991 (?)
* 1967: Following isolated and unexpected reports in British medical
journals, Britain's Royal College of General Practitioners links the high dose of
estrogen in the Pill to risk of thrombo-embolic disease.
* 1968: To monitor the effect of the Pill, three prospective studies involving
many thousands of women are set up: two in Britain under the control of the
Royal College of General Practitioners (RCGP) and the Oxford/Family
Planning Association (Oxford/FPA): and one in the USA, the Walnut Creek
Study. The British studies continue today.
* 1969: Britain's drug authority, the Committee on Safety of Medicines
(CSM), recommends a top dose of 50 micrograms estrogen in the Pill. The
recommendation is accepted world-wide. Enovid, the USA's first licensed Pill,
contained 150 micrograms estrogen. Five years later, in 1974, a RCGP study
report shows that the reduction in estrogen dose has caused a significant fall
in the incidence of deep vein thrombosis.
* 1975: The first of the "low dose’ Pills appears; it contains 30 micrograms
estrogen and a potent new progestogen called levonorgestrel.
* 1977: The RCGP study finds an association between risk of cardiovascular
disease and the progestogen in the Pill. Only now in the 1970s does
attention shift from estrogen to progestogen. The risk is seen to be greater in
women over 35, who smoke, and who have used the Pill for more than five
3
years. The RCGP report is a major event in the Pill's history, and at the time
prompts a joint statement from the Presidents of the RCGP and Royal College
of Obstetricians and Gynaecologists.
* 1978: Bradley reports from the USA’s Walnut Creek study a connection
between the Pill and lipid metabolism. Later, a 1980 report from the RCGP
shows that incidence of cardiovascular disease (such as heart attack and
stroke) correlates with the extent to which Pills decrease levels of the
protective blood lipid known as high density lipoprotein cholesterol, or HDL-C.
The smaller the decrease in HDL-C, the lower the incidence of disease.
* 1981: The first of the new generation Pills appears; it contains a new
progestogen called desogestrel which appears to have minimal impact on
lipid metabolism - and thus on risk factors for cardiovascular disease. This
new Pill - known as Marvelon - is shown to increase levels of HDL-C.
Meanwhile, a RCGP report is reassuring and instrumental in changing
attitudes to the Pill. It shows virtually no risks from the Pill in the 15-35 age
range - except in smokers. The report makes way for extending the age limits
on Pill use to 45 for non-smokers.
* 1983: A world Pill scare when Dr Malcolm Pike’s results from California link
use of the Pill to an increased risk of breast cancer. The link is later rejected.
* 1986: Results from the Cancer and Steroid Hormone (CASH) study in the
USA involving 9000 women fail to show any link between breast cancer and
the Pill.
* 1987: The CASH report confirms the results of other studies over the past
decade that the Pill protects against endometrial and ovarian cancer. Risk is
roughly halved, and the protection lasts after stopping the Pill.
* 1988: London's Cavendish Clinic reports results from the world's largestever study of the metabolic 'effects of the Pill. Nine brands are examined over
two years. The study, commissioned by the US government's National
institutes of Health, confirms that Marvelon does not produce the unwanted
effects on lipids seen with Pills containing the progestogen levonorgestrel.
Moreover, Marvelon has a positive effect on levels of HDL-C.
* 1989: Following the published results of four studies which show a slightly
raised risk of breast cancer in different sub-groups in each study, a committee
of the USA’s Food and Drug Administration recommends no changes in the
use of the Pill or in the wording of Pill package instructions. The studies are
"conflicting and inconsistent”, says the expert committee.
In a later meeting at the Royal College of Medicine in the UK, Oxford FDA’s
principle investigator Professor Martin Vessey presents data that show that
health benefits of the Pill outweigh its risks.
4
WHO'S USING THE PILL IN 1990?
Consumers’ wider choice
The Pill picture world-wide
* According to a Population Report (November 1988), 63 million women
throughout the world were using oral contraceptives in 1988, 24 million in
developed countries, and 39 million in developing. The Pill is thus one of the
world’s preferred contraceptive methods. However, all users together do not
exceed 10 per cent of the world's eligible population.
* In Western Europe, Australia and New Zealand, about 30 per cent of
women of reproductive age use the Pill
* in North Europe (Scandinavia) 21 per cent
* in East Europe (including USSR) 6 per cent
* in South Europe 14 per cent
* in North America 18 per cent
* in China 5 percent
* in India 2 percent
* in Far Eastern Asia 13 per cent
* in Latin America 5 per cent
The greatest growth in use of the Pill is currently seen in developing countries
where in the past decade use has risen by about 6.4 per cent per year. In
1990 the Pill remains unavailable as a contraceptive in Japan.
In other developed countries use increased by about 2.5 per cent per year
during the 1980s.
The Pill picture in continental Europe
* From surveys conducted in the mid-1980s the Brussels-based International
Health Foundation (1HF) found that contraceptive practice in seven European
countries - Austria, Britain, France, Italy, Spain, Sweden and West Germanyvaried quite distinctly.
However, in five of the seven countries more than half the women surveyed
had either past or present experience of the Pill. And, with the exception of
Spain and Italy, the Pill was the most frequently used contraceptive method.
Among "exposed" women - that is, women aged between 15 and 44 who
need contraception - the IHF found the following percentage rates of Pill use:
Austria
Britain
Sweden
West Germany
France
Spain
Italy
42 per cent
38 per cent
37 per cent
33 per cent
31 percent
19 per cent
6 per cent
5
In Italy, natural or no methods (abstinence, coitus interrupts) are practised
by more than half of the exposed women. Barrier methods, as in Spain, are
the favoured method of birth control, relied on by 23 per cent of women.
Sterilisation, relied upon by about one quarter of Britain's couples, is very
little used in France, Italy, Spain and West Germany, according to the IHF.
The IHF surveys further show that the age group most favouring the Pill is
between 20 and 24 years - 72 per cent using the Pill in Britain and 56 per
cent in France, for example.
* The same survey shows that women have two principal motives for using or
changing their contraceptive method - reliability and effect on their health.
The IHF reported: "It was astonishing to discover how many women in each
country thought the Pill caused infertility or increased the risk of
cardiovascular disease and cancer. These impressions appear to be entirely
out of step with the facts."
Pill use in older women
* Commenting in 1986 on a 4 per cent use of the Pill among UK women aged
40
to 44, the British Journal of Family Planning noted: "Until recently the
combined Pill was only advised for women under the age of 35; only within
the last two years has this upper limit been extended for non-smoking women
with no medical problems."
Thus, the current advice on Pill use and age by experts all over the world is
that only women who smoke, are overweight or who have risk factors for
cardiovascular disease should be advised to stop the Pill at age 35.
Otherwise, healthy women can continue the Pill till at least 45.
The relaxation in age limit rules follows increasing evidence that the beneficial
effects of modem low dose Pills outweigh any possible adverse effects in
healthy women, whatever their age.
In particular, smoking and not age has been shown to be the single most
important factor predisposing to any risk from the Pill. For example, an
investigation conducted by Dr Margaret Thorogood from Oxford, UK, and
presented at the 1,989 world congress of the International Federation of
Fertility Societies, showed that women who smoked while on the Pill were 11
times more likely to suffer a fatal heart attack than women who don't.
* Despite the reassuring news about Pill use beyond the age of 35, as many
as 30 per cent of West European women of that age-group do not practise
any contraception and are at risk of an unwanted pregnancy, according to the
IHF's analysis. These high figures are observed in Italy and Spain; in countries
recording the "safest" habits in the survey - Britain and Sweden - one in ten is
at risk. Exposed older couples use the following reliable methods (%):
6
Pill
Barrier
IUD
Italy
35-39
40-44
1
0
19
12
20
4
0
0
0
0
France
35-39
40-44
23
10
10
9
25
23
7
10
2
2
Britain
35-39
40-44
28
3
15
23
13
7
13
26
14
28
Spain
35-39
40-44
19
8
29
23
8
7
3
2
1
1
West Germany
35-39
40-44
22
19
3
13
1 1
7
10
15
13
21
Austria
35-39
40-44
31
21
15
11
12
8
2.5
2
7.5
5
Sweden
35-39
40-44
20
5
27
35
31
26
7.5
10
2.5
3
Female
Male
sterilis ation
The Pill was perceived as reliable by most of the older women questioned, as
good for their sex life by more than half of them (86 per cent in Britain, 46
per cent in Spain) but, against current scientific evidence, as "unsafe for
health" by about 80 per cent.
The 1HF noted: 'Heart disease and cancer were frequently mentioned in
France, Great Britain and Sweden." This showed, according to the IHF, that
older women have an equally or more negative opinion of the Pill than
younger ones. And for these reasons, oral contraception might unjustifiably
be disregarded by older couples.
7
REACHING NEW LEVELS OF CONFIDENCE
Health issues for the 1990s
Background
* At the end of 1989 Prof Martin Vessey and colleagues reported their latest
findings in the follow-up of 17,032 women from the Oxford/FPA study in
Britain. The overall relative risk
*
of death among the Pill user group was 0.9,
so indicating that use of the Pill exerted no increased risk of death (in fact,
slightly decreased the risk).
In their conclusion, the Oxford investigators said: “The results of this analysis
of all 17,032 women recruited to the Oxford-Family Planning Association
study give no cause for concern, in that death rate was slightly lower in the
oral contraceptive entry cohort than in the diaphragm and intrauterine device
entry cohort.”
Cardiovascular disease
* An earlier report (May 1989) from the Oxford/FPA study suggests that
risks of heart disease have been reduced by the introduction of low dose Pills.
Pill users are now one third less likely to suffer a fatal heart attack than they
were in the 1960s, according to Prof Vessey and his colleagues. Again, the
risk to emerge from this analysis is smoking - three-quarters of the 130
women who died from a heart attack in the Oxford/FPA study were smokers.
* The Cavendish Clinic study, whose results were announced at the FIGO
world congress in Rio de Janeiro in 1988, confirmed that the type of
progestogen used in the Pill is crucial to its effect on the body’s metabolism
and thus on cardiovascular risk factors. Nearly 1500 women took part in the
study, which was commissioned by the US government's National Institutes
of Health, and seven different combination Pills were involved, each
containing one of three progestogens - desogestrel, norethisterone, and
levenorgestrel. It was by far the biggest study of its type ever undertaken.
From some 1478 measurements of blood lipids the investigators concluded
that Pills containing the progestogen levonorgestrel had a strong impact on
lipid metabolism and reduced levels of HDL cholesterol, the blood chemical
known to protect against heart disease. Pills containing desogestrel did not
produce any of these unwanted effects - indeed, Marvelon increased levels of
HDL cholesterol. One of the Cavendish investigators said: “For the present
time it would seem advisable to favour those formulations which have the
least metabolic impact.”
Thrombosis
* it was an increase in risk of thrombosis (blood clots in the veins) which
caused concerns over the first high estrogen dose Pills. Subsequent studies
alerted investigators that risk of thrombosis was related to the dose of
estrogen, and made way for a reduction in the estrogen dose of the Pill.
The Puget Sound study in the USA followed 65,000 women from 1977 to
1982, a period in which their use of low-dose Pills increased from 16 to 39
8
' "relative risk" is the risk faced by an exposed population in relation to the risk faced by an
unexposed control population. Numerically, it is the exposed risk divided by the control risk.
A relative risk of 1 means there is no difference.
per cent. Throughout the study, the relative risk of thrombosis in Pill users fell
from 8.5 to 2.9 compared with that of non-Pill users.
This trend was confirmed by the Oxford/FPA study in 1986.
Stroke
* Again, early reports in the 1960s and 1970s suggested Pill users were at
an increased risk of stroke {cerebrovascular disease). The risks were
particularly high in Pill users who smoked cigarettes, and the risks increased
with age.
More recently, studies have not found an elevated risk of stroke in Pill users.
The Puget Sound study, for example, found no increased risk from Pill use
alone.
In Britain, the Oxford/FPA study in 1984 noted that there had been no cases
of stroke in 9100 "woman-years” of Pill use in those women using Pills with
less than 50 micrograms estrogen. However, among those using the old highdose Pills of more than 50 micrograms estrogen, there were 13 cases of
stroke in 39,400 woman-years of use.
Cancers
1.
Breast cancer. In 1989 a reassuring conclusion was reached by the health
authorities of the USA and the UK on the relation between the Pill and breast
cancer. They analysed new studies published since December 1988 which
showed a slight increased risk of breast cancer associated with Pill use in
different sub-groups of women in each study.
Faced with these conflicting results, regulatory agencies like the Food and
Drug Administration of the USA and Committee on the Safety of Medicines in
Britain have reassured doctors and their patients that they should not alter
prescribing practice or use of the Pill.
In the latest revision to the Food and Drug Administration's leaflet inserted in
all American Pill packs, the FDA says: “The overwhelming evidence in the
literature suggests that use of oral contraceptives is not associated with an
increase in the risk of developing breast cancer, regardless of the age and
parity of first use or with most of the marketed brands and doses."
In 1986 the results of the Cancer and Steroid Hormone (CASH) study were
published in the New England Journal of Medicine. This largest case control
study on the Pill and cancer risk, which involved more than 4000 women with
breast cancer and 4000 controls drawn from eight American states, found no
overall link between the Pill and breast cancer. Moreover, no association with
early use - or with the type of progestogen - was found. The CASH study has
since set the benchmark for all studies examining the relationship between
the Pill and breast cancer.
2.
Ovarian cancer. It was in 1977 that the first hint of the Pill’s protective
effect against ovarian cancer was made. This has now been confirmed in at
least ten studies, which demonstrate a risk reduced by about 50 per cent
9
(ie, halved) in Pill users. Moreover, most of the studies show that the
protective effect continues for several years after stopping the Pill. One study
showed the risk of ovarian cancer halved after four years of Pill use, and cut
by 60-80 per cent after seven or more years. The benefit was seen to last for
up to 15 years after stopping the Pill.
It was suggested that as little as three months use of the Pill could offer this
protection.
In a 1989 report published in the British Journal of Obstetrics and
Gynaecology, Prof Vessey estimated that the Pill had reduced by 25% the
number of deaths from ovarian cancer in women under 55 since widespread
Pill use began over 20 years ago. Prof Vessey described a trend in Britain of
falling deaths from ovarian cancer in young women "compatible with patterns
of use of oral contraceptives."
3.
Endometrial cancer. Similarly, the Pill's protective role in endometrial
cancer has now been confirmed beyond dispute. The CASH study in the USA
(which also confirmed protection against ovarian cancer) found the risk
reduced by about 40 per cent after two years of Pill use. Again, the protective
effect increased with longer duration of Pill use, and persisted after stopping
the Pill. These results have been confirmed in at least ten different studies.
4.
Cervical cancer. Studies attempting to show an association between the
Pill and cervical cancer have so far been inconclusive, not least because
cancer of the cervix is now known to be caused by a sexually transmitted
virus (human papilloma virus). Thus, sexual behaviour presents investigators
with a statistical variable which removes much confidence from the study. The
FDA’s new packet insert says confidently: "A cause-and-effect relationship has
not been established."
The risks in perspective
* The FDA has stressed that the risk of any form of contraception is less than
the risk of pregnancy. Citing a study of Ory the FDA’s packet insert says that,
with the exception of Pill users who smoke, ‘mortality associated with all
methods of birth control is low and below that associated with childbirth."
Smokers on the Pill, says the FDA, have a mortality risk higher than those
using other methods.
* John Guillebaud, a British family planning expert, says that women must be
reminded that there are other risks in life greater than using the Pill which are
all tolerated. To help physicians, he has established his own risk activity table:
10
Annual deaths per 100,000 exposed
under 35
35-44
Fertility after stopping the Pill
* As surveys of attitudes towards contraception show, one of the myths
about the Pill is that it delays a return to fertility after stopping. The evidence
does not support this view. In 1986 Professor Martin Vessey and colleagues
from the Oxford/FPA cohort study of nearly 20,000 women in Britain
reported that the Pill had no effect on fertility in women who had already had
at least one child. ’Our findings are entirely reassuring,’ said Professor
Vessey. Nulliparous women - that's women who have not had any children experienced a slight delay in returning to fertility, but only among older
women. Professor Vessey stressed that there was no evidence at all that the
Pill caused any permanent infertility.
11
RELIABILITY OF THE PILL
The most effective contraceptive
* Experts assess the reliability of a contraceptive by the 'Pearl Index’, a
numerical factor expressed as the failure rate per 100 woman-years of
exposure. This is calculated according to the formula:
Total accidental pregnancies x 1200
Pearl index - ---------------------------------------------------Total months of exposure
* The Pill is consistently found to be the most reliable reversible
contraceptive available. (Irreversible methods like tubal sterilisation are
equally effective, but fertility cannot be simply restored.)
Indeed, surveys of attitudes to birth control suggest that the reliability of the
Pill is now taken for granted and is no longer a major factor in determining'
choice of method - unlike attitudes of 20 years ago when reliability was a
major concern in choice of method.
The table below indicates Pearl index failure rates (per 100 woman-years) of
different contraceptive methods according to the Oxford/FPA study in Britain
(reported in 1982 in which all women were married and over 25) and a range
from other studies:
Oxford
Sterilisation
Male
Female
Combined Pill
High dose
Low dose
JUD
Lippes loop
Modem copper
Diaphragm
Condom
Coitus interruptus
Spermicide alone
Contraceptive sponge
Others
0.02
0.13
0
0
-
0.02
0.15
0.16
0.27
0.1 0.2-
1.0
1.0
1.4
1.5
1.9
3.6
6.7
11.9
0.3-• 4.0
0.3-■ 4.0
2.0-• 15.0
2.0-•15.0
8.0-• 17.0
4.0-■25.0
9.0-■25.0
Gynaecologist John Guillebaud has further estimated that the likelihood of
pregnancy from using no contraception during one year is about 40 per cent.
This corresponds to about 10-12 live-born children in 25 years of marriage.”
* Other studies have assessed the contraceptive reliability of different Pills.
For example, the aggregate Peart index from seven studies of low dose Pills
12
produced the following results, and showed Marvelon (30 micrograms
ethinylestradiol (EE) and 150 micrograms desogestrei) to be today’s most
reliable low dose Pill:
Cycles
Pill
failures
Patient
failures
Peart
Index
23,258
16,345
36,771
11,064
0
0
2
1
1
3
5
2
0.05
0.22
0.23
0.33
0.86
?
7
0.17'
0.31
Monophaslc OCs
Marvelon
Norethisterone/EE
Gestodene/EE
Levonorgestrel/EE
Norgestimate/EE
16
Triphasic OCs
Norethisterone/EE
Levonorgestrel/EE
14,222
35,036
2
2
’ Pill failures only
13
HOW CAN THE PILL BE GOOD FOR YOU?
The non-contraceptive benefits
* In developing countries especially, regular use of a reliable contraceptive
has enormous benefits on the quality of maternal and child health. Indeed,
the benefits are such that in many developing countries the very future of
their economy depends on wide and continued use of reliable contraception.
According to a Population Report {November 1988), an estimated half
million women die in pregnancy and child birth each year. Almost all these
deaths occur in developing countries, where - with the exception of China - on
average 550 women die for every 100,000 live births (or one for every 180
live births). As many as one in five babies die in parts of Africa and Asia.
It is now agreed that pregnancies are high risk because they occur too soon
(before the age of 18), too late (after 35), are too many (more than four), or
too close together (less than two years apart). Avoiding these high risk
pregnancies would prevent two in every five maternal deaths and some six
million infant deaths per year.
* The Pill is not only the most reliable reversible contraceptive; the USA's
cautious Food and Drug Administration has for the first time ever now
included non-contraceptive health benefits on its detailed Pill packet inserts.
The FDA groups the benefits into three categories: effects on menstruation;
effects related to inhibition of ovulation; and effects from long-term use.
Menstrual benefits
1.
Better cycle regularity. The effect of the Pill on cycle regularity is to
produce a regular four-week cycle and reduce prolonged and excessive
bleeding. One consequence of the last effect is that women on the Pill are less
likely to suffer iron-deficiency anemia (at menstruation Pill users lose only half
the body's blood iron which non-Pill users lose). A 1974 report of the RCGP
showed that Pill users had 45 per cent less iron-deficiency anemia than non
users. This finding is especially important in countries where nutrition is poor.
In an Italian study of Marvelon reported in 1988 a regular cycle was
experienced by 95 per cent of 11,605 users by the sixth cycle of use. The
proportion of women experiencing prolonged bleeding fell from 8 to 0.6 per
cent, and excessive bleeding from 21 to 3 per cent.
2.
Less dysmenorrhea. Studies show that about one half of all women suffer
pelvic pain during menstruation. The RCGP study showed that dysmenorrhea
was 63 per cent less common among Pill users than among non-Pill users. In
fact, the Pill is usually prescribed by doctors as a treatment for women (about
one in ten) whose dysmenorrhea interferes with their everyday lives.
Benefits from inhibited ovulation
1. Reduction in ectopic pregnancy. Ectopic pregnancy, which occurs when
the embryo develops outside the uterus, is a life-threatening disorder
requiring major surgery.
74
2. Reduction in functional ovarian cysts. This finding was first reported in
1974 and has since been confirmed in other studies. A reduction in cysts is
thought to occur because the Pill suppresses the cyclical activity of the ovary.
Benefits from long-term use
1. Less benign breast disease (fibroadenoma and fibrocystic disease). It is
estimated that between half and three-quarters of all benign breast disease
which would occur in Pill users is prevented because of the Pill. It is thought
that in the USA the Pill prevented more than 23,000 surgical procedures for
benign breast disease in the 1970s. The Oxford/FPA study suggested that
the progestogen in the Pill could be the reason.
2. Less pelvic inflammatory disease. Women who use the Pill appear to
halve their risk of developing pelvic inflammatory disease (PID). This finding
emerged after 11 studies had been analysed in the early 1980s. This is an
important finding in itself, but especially important as PID - an infection which
begins in the cervix and climbs to the upper reproductive tract - is a major
cause of blockage in the fallopian tube, and hence of infertility. At the 1989
world congress of the IFFS, WHO experts spoke of a world epidemic of
infertility as a result of PID. PID is also a major
cause of ectopic pregnancies. An American analysis indicated that 600 of
every 100,000 Pill users would be prevented from suffering a first episode of
PID because of the Pill.
3.
Reduced endometrial and ovarian cancer. The protection given by the Pill
against both these cancers has now been proved beyond dispute. The risks
are approximately halved, and are prolonged beyond stopping the Pill.
* Howard Ory, of the Centres for Disease Control, Atlanta, USA, has written:
"The magnitude of these preventive effects, particularly against pelvic
inflammatory disease and benign breast disease is substantial... In addition,
by limiting oral contraceptive use to younger women who do not smoke, one
can tilt the balance toward the protective effect by largely eliminating the risk
of cardiovascular disease.’
Thus, the Pill becomes of positive health benefit - and can be good for you!
Further advantages described by Pill users
1. Postponing withdrawal bleeds. Who wants her period on holiday; or on
her honeymoon; or during exams; or during the season’s top games final?
Because the menstrual cycle of women on the Pill is controlled by the Pill
itself, postponing a bleed for a few days or even weeks presents no problems,
by simply skipping the seven tablet-free days between packets. The
procedure is much simpler for ’monophasic’ single<iose Pills than for phasic
Pills.
2. Cosmetic benefits. Hormones, and particularly those known as androgens,
are partly responsible for acne and unwanted hair (hirsutism). In the past,
older Pills contained hormones (like levonorgestrel) which are rather
androgenic, so girls could find their acne worsening when they went on the
Pill. Modem Pills contain progestogens like desogestrel which are not
androgenic, and thus have no adverse effect on acne. Indeed, studies on
Marvelon have shown that the numbers of spots can even be reduced. One
15
study described at the world obstetrics and gynaecology congress in Rio de
Janeiro in 1988 showed that average numbers of facial spots were reduced
from 15 to 6 after six cycles use of Marvelon. This was an improvement
comparable with specific anti-acne therapies. Another study from Italy found
that of 1021 women with acne it disappeared in 754 after six months on
Marvelon.
16
HOW THE PILL WORKS
Preventing ovulation
The normal menstrual cycle
* The human female’s store of eggs lies in the ovaries. One egg is released
once a month when chemical messengers from the pituitary gland in the brain
stimulate development of some eggs and the release of one of them. The
release is known as ovulation, and takes place roughly midway in the
menstrual cycle.
The messenger which stimulates the development of an egg is a hormone,
called follicle stimulating hormone (FSH). However, two other important
hormones are at work during the cycle which act together to prepare the
womb and body cells for pregnancy. They are called estrogen and
progesterone.
However, pregnancy only occurs when an egg released from the ovaries is
fertilised by a sperm swimming along the fallopian tubes to meet it. Just one
sperm is enough to complete the fertilisation. The fertilised egg (embryo)
embeds in the wall of the womb. Once the embryo has implanted in the
womb, pregnancy has begun. Levels of estrogen and progesterone continue
to rise throughout pregnancy, and the production of eggs in the ovaries
stops.
The oral contraceptive
* The Pill works by mimicking this hormone production seen in pregnancy.
For most of today's Pills contain a combination of these two hormones active
during pregnancy - estrogen and progestogen. So a raised level of these
hormones in the blood stops the messages of the pituitary gland by blocking
FSH production, so preventing the development of eggs. In this way, ovulation
is prevented, so no fertilisation can take place.
* The hormones used in the Pill are man-made, but throughout the Pill’s 30
year history efforts have been made to produce compounds which act as
closely to nature as possible. The latest generation of progestogens, like
desogestrel is very close to natural progesterone and - according to many
experts - unlikely to be improved upon in the foreseeable future. (Which is
why in the West - despite interest in such new contraceptive methods as
vaginal rings, transdermal implants or male vaccines - the Pill is likely to
remain the favoured and most successful method of birth control.)
* In most cases a Pill is taken for 21 consecutive days. This period is followed
by seven Pill-free days during which levels of estrogen and progestogen in the
blood go down. As a result, the mucous lining of the womb - which has
apparently been preparing to receive an embryo - is shed, and a monthly
bleeding occurs just as in normal menstruation.
17
Population Reports
Series K
Number 3
March-April 1987
INJECTABLES AND IMPLANTS
Population Information Program, The Johns Hopkins University, Hampton House, 624 North Broadway, Baltimore, Maryland 21205, USA
Hormonal Contraception: New Long-Acting Methods
Editors' Summary. Before the year 2000 women
around the world may have up to five new family
planning methods to choose from. All will be very
effective, convenient to use, and long-acting—from
one month to five years. All use a progestin, a type
of female hormone that is also used in birth control
pills. One new method, Norplant, has already been
approved in seven countries. Other new methods
are in various stages of development and testing.
The new methods share one obvious disadvantage.
To varying degrees, all change or disrupt menstrual
patterns. If women expect this and know it is not
harmful, many are willing to accept it.
Norplant implants have been approved in Finland,
Sweden, Ecuador, the Dominican Republic, Indo
nesia, Thailand, and Colombia, and applications are
pending elsewhere. Already about 75,000 Indonesian
women have used Norplant. Placed just under the
skin on the inside of a woman's arm, six capsules
release the progestin levonorgestrel at a slow, steady
rate. For five years they prevent nearly all pregnan
cies. Then they must be replaced. Similar products,
*using different progestins and/or fewer implants, are
being developed. Norplant-2, a 2-rod system that,
lasts at least three years, has been approved in Fin
land. Application for US approval will be filed in 1987.
Biodegradable implants also are placed under the
skin, but they eventually dissolve and disappear.
There are two types—(1) Capronor, a single capsule
containing levonorgestrel, and (2) three or four pel
lets of the hormone norethindrone/:ombined with
small amounts of cholesterol. Capronor is expected
to prevent pregnancy for at least 18 months; the
pellets, for at least 12 months. They may be available
by the mid-1990s.
injectable microspheres and microcapsules, sus
pended in a solution, are given with a hypodermic
needle. The tiny particles of different sizes, consist
ing of hormone in a polymer carrier, dissolve and
release hormone at various rates, providing a nearly
constant dose that prevents pregnancy for one to six
months. The first microsphere contraceptive may be
available in some countries in the early 1990s.
women in China and Latin America already use
monthly injectables. Two new monthly injectables
may be available as early as 1988.
The vaginal ring is placed by the woman in her
vagina, where it gradually releases hormone. A
3-month levonorgestrel ring may be available in
some countries by 1988. A 3-month progesterone
ring is being developed for breast-feeding women.
The precursors of these new methods are the longacting injectable contraceptives—the 3-month
Depo-Provera and the 2-3 month Noristerat. They
have been available for over a decade. Depo-Provera
is approved for contraception in at least 90 coun
tries; Noristerat, in more than 40. Some five million
women use them. Animal studies raised fears that
long-acting injectables might cause cancer. Prelimi
nary results from new studies of women are reassur
ing for the most part, but some questions remain.
When new long-acting methods become available,
marketing and program development are essential.
Production must be arranged; providers trained; lo
gistics systems in place; and supplies available. The
media, the health care professions, and other opin
ion leaders must be thoroughly briefed in advance.
Couples must learn about the new methods. If these
are properly introduced and made continuously
available, there will soon be a much broader choice
of contraceptives for women. Effective, reversible,
long-acting hormonal contraception will be available
for nearly every couple, whatever their plans and
needs.
End of Editors' Summary.
CONTENTS
Norplant Implants............................................ K-58
Biodegradable Implants ................ .............. K-65
Injectable Microspheres and Microcapsules .. K-66
Vaginal Rings ................................................... K-68
Long-Acting Injectables................................... K'69
Monthly Injectables ......................................... K-75
Use of Injectables............................................. K-77
Introducing^ New Contraceptive Method ... K-79
Monthly injectables add an estrogen to a progestin
to minimize menstrual changes. Some 1.5 million
Volume XV, Number 1
NORPLANT IMPLANTS
Norplant’ implants consist of flexible, nonbiodegradable
tubes filled with levonorgestrel, a synthetic hormone of
the progestin family. The implants are placed under the
skin on the inside of a woman's upper or lower arm. The
hormone is slowly released at an almost constant rate for
several years. Developed by the Population Council, Nor
plant has been tested in more than 44,000 women in 31
countries (189). It has proved to be highly effective, safe,
and well-liked by its users. By 1987, a 6-capsule Norplant
system had been approved for marketing in seven coun
tries—Finland, Sweden, Indonesia, Thailand, Ecuador, the
Dominican Republic, and Colombia (85). Applications for
approval have been filed in many other countries.
Norplant implants come in two forms. The first, called
simply Norplant, consists of six hollow Silastic (silicone
rubber) capsules. Each capsule is 34 mm long, with a
diameter of 2.4 mm, and contains 36 mg levonorgestrel.
The ends of the capsules are sealed shut with Silastic
• NORPLANT is the registered trademark of the Population Council for
contraceptive subdermal implants.
This issue of Population Reports was prepared by
Laurie Liskin, Sc.M., and Richard Blackburn, M.S.,
with the assistance of Rula Ghani, M.S., on the basis
of published and unpublished materials, correspon
dence, and interviews. Comments and additional
material are welcome.
The assistance of the following revii >-.ers is appreci
ated: Semiramis Aydinlik, Lee Beck, Gabriel Bialy,
Lynda Cole, Laneta Dorflinger, Gordon Duncan,
Hanni Ellis, Larry L. Ewing, Izhar Fihir, Henry Gabel
nick, Alfredo Goldsmith, Ronald H. Gray, Forrest
Greenslade, A.T. Gregoire, Gary Grubb, Peter Hall,
Robert A. Hatcher, Soile Jarvela, Sandra Kelly, Danny
Lewis, James McCarthy, Kee Kee Minor, Harold Nash,
Mark W. Oberle, Malcolm Potts, Michael Rosenberg,
Patrick J. Rowe, Pramilia Senanayake, James Shelton,
Irving Sivin, J. Joseph Speidel, Joanne Spicehandler,
Sandra Waldman, and Beverly Winikoff. Some re
viewers read portions of the manuscript; others, all.
Population Reports (USPS 063-150) is published five times a year
(March, May, July, September, November) at 624 North Broadway,
Baltimore, Maryland 21205, USA, by the Population Information
Program of The Johns Hopkins University and is supported by the
United States Agency for International Development. Second-class
postage paid at Baltimore, MarylAid. Pdstmaster to send address
changes to Population Reports, Population Information Program,
The Johns Hopkins University, 624 North Broadway, Baltimore,
Maryland 21205, USA.
Population Reports is designed to provide an accurate and au
thoritative overview of important developments in the population
field. It does not represent official statements of policy by The Johns
Hopkins University or the United States Agency for International
Development.
Population Information Program
The Johns Hopkins School of Hygiene and Public Health
Phyllis T. Piotrow, Ph.D., Director, Population Information Program
Ward Rinehart, Deputy Director and Editor, Population Reports
Anne W. Compton, Associate Director for POPLINE computerized
bibliographic services
Patrick L. Coleman, Associate Director and Project Director, Popula
tion Communication Services, developing family planning commu
nication strategies and materials •
K-58
adhesive. This is cur--:>tly the more widely used of the two
systems. Il is highly ellective in preventing pregnancy for ,
five years. The newer system, called Norplant-2, consists
of two solid Silastic rods, each 44 mm long. A total of 70
mg levonorgestrel is dispersed in the matrix of eacK rod.
Norplant-2 is .highly effective for at least three years. This
system was approved tn Finland7rH987:-An application for
approval in the OS will TxTfiled in 1987? The materials in
Norplant and Norplant-2—Silastic rubber, Silastic ad
hesive, and levonorgestrel—have been used safely for
years in a variety of medical applications (192). Levonor
gestrel is the progestin in several popular brands of oral
contraceptives.
Preintroductory trials of Norplant have taken place all over
the world. Over 40 percent of participants are in Asia and
the Pacific, primarily in China, Indonesia, and Thailand.
Another 30 percent are in Latin America, primarily in Bra
zil, the Dominican Republic, and Ecuador. About 2,500
Egyptian women and more than 1,000 women in sub-Sa
haran Africa also have participated. Preintroductory trials
of Norplant-2, involving more than 4,500 women, are in
progress in Chile, Colombia, China, the Dominican Re
public, Ecuador, India, Mexico, Thailand, and the US (^O).
With both Norplant and Norplant-2, levonorgestre^oiffuses through the Silastic membrane at a steady, slow rate.
Within 24 hours after insertion, levels of levonorgestrel in
blood plasma are high enough to prevent ovulation (18).
The daily release averages 50 to 80 pgs in the first year of
use, then declines to about 30 to 35 pgs per day over the
next five years (18, 56, 208). In the first year, this is about
the same as the daily dose of levonorgestrel in progestinonly oral contraceptives and one-fourth to one-half the
dose in combined estrogen-progestin oral contraceptives.
Insertion and Removal
Inserting and removing Norplant implants are usually
minor surgical procedures that require local anesthetic
and a small incision (see box, p. K-62).'Removal isTnofe
difficult and takes longer than insertion. If health workers
are adequately trained and maintain sterile conditions,
however, complications are unlikely to occur with either
procedure.
The best time to insert Norplant implants is wnff a
woman is menstruating or no later than five to seven days
from the start of menstrual bleeding. This ensures that she
is not pregnant. At, other times, the woman should be
given another contraceptive method for the rest of her
cycle and asked to return to the clinic when she is men
struating (180).
Norplant capsules and rods are inserted just under the
skin usually in the inside of the upper or lower arm. An
experienced practitioner can insert the six capsules in 5 to
10 minutes. The two rods in Norplant-2 are easier to insert
and remove than the six capsules in Norplant (6,115,191).
In multicenter clinical-trials infection and other complica
tions after insertion have been rare; only 3 women in
every 1,000 ever developed infections (235). In an Indone- .
sian study, however, there were 12 infections treated with
antibiotics in 828 insertions, or 14 per 1,000 (6). With the
exception of one trial in India (115), studies show that the
capsules or rods are rarely expelled. Expulsion may occur
if the insertion site becomes infected (269) or if the im
POPULATION REPORTS
plants an
* plated loo close Io the iiu ision (232). Bruising
often occurs during insertion. Rare complications are mild
itching and formation ol sc ar (issue
*
(137. 269).
around lhe incision
Insertion causes little or no immediate pain for most
women, although the area may be bruised and sore lor
sever ,1 days. Among 700 Thai women, for example, 69
percent reported feeling no pain during insertion, 28 per
cent tell slight discomfort, and only 3 percent reported
moderate to severe discomfort (211). The capsules and
rods are flexible and fairly soft. Once inserted, they do not
cause any pain or interfere with a woman's activities (191).
Removing 6-capsule Norplant usually takes about 15 to 20
minutes and usually requires only one small incision. In
one US trial about 20 percent of 106 removals took more
than 30 minutes, however. Ordinarily, only one incision
was needed, but in about 5 percent a second incision was
needed. As the nurse-practitioner performing removals
became more experienced, however, problems were
much less frequent (52). Generally, implants are relatively
easy to remove if they were inserted properly—that is, jus^
under lhe skin. They are harder to remove if they were
inserted deeply (6,132). Sometimes one or more implants,
or a piece of an implant, cannot be removed easily. Occa
sionally, the implants cannot be removed on the first at
tempt. How often these problems or ur has not yet been,
determined.
When the implants are removed, a new set can be inserted
immediately. If the original implants have been removed
easily and the insertion site is not swollen, the new im
plants can be inserted in exactly the same place. If the
removal causes swelling or trauma, however, the implants
should be inserted either in the other arm or through the
original incision but facing the opposite direction (191).
How often do complications occur after removal of the
implants? In two US trials no infection or other complica-
An Indonesian woman tells a friend about Norplant in this
drawing from a pamphlet prepared lor the Indonesian National
Family Planning Coordinating Board (BKKBN) by PATH/PIACT.
tions have occurred after a total of about 150 removals (52,
132). In 122 removals at an Indonesian clinic, 11 hema
tomas (bleeding under the skin) and two infections oc
curred in the week after removal (6). No treatment was
needed for the hematomas. The infections wen treated
with antibiotics (275). Information is not available from
other countries. As implants become more widely avail
able and as less expet., need doctors perform insertions
Table I. Characteristics and Status of Nonbiodegradable Implants as of March 1987
Delivery
System
Development
& Testing
Hormone
Duration
of Action
Status of
Animal
Trials
_______ Status of Human Trials_____
Phase II
Phase III
Phase 1
Norplant
Population
(6 capsules) Council
Levonorgestrel 5 years
Completed
Completed
Completed
Completed or
underway in 31
countries in
over 44,000
*
women
Norplant-2
(2 rods)
Levonorgestrel At least
3 years
Completed
Completed
Completed
Underway in 9
countries in
4,500 women
Population
Council
Estimated
Availability
Approved in Co
lombia, Dominican
Republic, Ecuador,
Finland, Indonesia,
Sweden & Thai
land. Widespread
availability by early
1990s.
Approved in Fin
land. More ap
provals in late
1980s.
Mid-1990s
Completed Completed4 Planned
Partially
Population
ST-1435
2 years
completed’
Council
Early 1990s
Planned
Population
2'Ze-4 years Completed Completed Underway
3-keto
in 3 coun
desogestrel
Council,
tries
Organon
International
Note: Phase I trials are conducted in small numbers ol volunteers Io determine how a drug is absorbed, metabolized, and excreted from lhe body and to
determine tentatively delivery method and safe dosage. Phase II Inals usually involve 20 to 50 volunteers for three months to assess safely and efficacy and to
evaluate delivery method further. Phase III trials involve al least several hundred volunteers—and often thousands— for two years or more to confirm safely
and efticacy.
(Trials ongoing in some animal spur les
‘Some of these trials were not intended Io meet requirements lor regu
'Phase II trials being repealed with modified delivery system
latory approval.
-Trade name not yet chosen
1 rod-’
1 rod-’
POPULATION REPORTS
K-59
Norplant implants release the progestin levonorgestrel. They are inserted just under the skin in the arm. The 6-capsule system (left)
provides almost complete protection from pregnancy for five years. Norplant-2 (right), using two rods, is effective for at least three years.
and removals, training programs must emphasize the im
portance of sterile technique to prevent infection.
There are few contraindications to Norplant use. The im
plants are not recommended for women using medication
to prevent blood clots or for women with active liver
ildisease, jaundice, undiagnosed abnormal genital bleedtjing, or bleeding disorders (269). Norplant also is not curIjrently recommended for breast-feeding women because
'Jew studies have looked at potential risks to nursing in
fants (191).
Effectiveness
Norplant provides almost complete protection against
pregnancy. In the first five years of use of the Norplant 6capsule system, the chances of pregnancy are less than
one per 100 women per year (see Table 2). This rale is ,
lower than for oral contraceptives, intrauterine devices, .
and barrier methods. Effectiveness decreases slightly after;
five years, and in the sixth year 2.5 to 3 percent of users
conceive (IB). Thus replacement after five years is recom
mended. A slight and gradual decrease in the daily release
of levonorgestrel over time probably accounts for the in
crease in pregnancies after five years (lt>8).
Ongoing international trials show that Norplant-2, the 2rod system, is as effective as the 6-capsule system for the
first three years of use (I9, 115). It was expected that
Norplant-2, like Norplant, would be effective for five
years. After three years, however, an unexpectedly high
number of pregnancies occurred in a large 5-country trial.
The cumulative failure rates ranged between 5 and 6 per
cent al the various centers. As a result, the Population
Council has asked < linical investigators in this studio
remove Norplant-2 after three years (232). Other stu^PL
have reported few pregnancies so far, and most are con
tinuing into the fourth year (232).
Il
is not vet dear why the pregnancy rate with Norplant-2
increased in the 5-counlry trial. Presumably, the release
rale ol progestin dedined. The Population Council is con
ducting extensive laboratory tests to find the reasons for
this.
Prerisely how Norpl,ml prevents pregnancy is not fully
„uTiderstood. Like other progestin-only contraceptives ,
Norplant implants appear to prevent pregnancy in several
ways. Norplant suppresses ovulation in at least half of
menstrual cycles (18). Hormonal indicators of ovarian ac
tivity suggest that ovulation may occur in some of the
remaining cycles (49). Even if ovulation does occur, levo
norgestrel makes cervical mucus thick and scanty, and
sperm cannot easily pass through it into the uterus to
fertilize ova (18, 269). Levonorgestrel also suppresses the
Advantages and Disadvantages of Norplant Implants
Advantages
• Norplant is highly effective.
• Once in rlace, the implants require no further
action until removal.
• The 6-capsule system provides continuous protec
tion for five years.
• The implants have no estrogen and thus no es
trogen side effects.
• The contraceptive effect of the implants ends soon
after they are removed.
• The implants release progestin at a fairly constant,
low rate, avoiding the high initial dose typical of
injectables and the daily surge of hormones with
oral contraceptives.
• Norplant may help to prevent anemia.
K-60
Disadvantages
• Norplant must be inserted and removed by health
professionals.
• Health workers need special training and practice
to insert and remove implants.
• Norplant implants are initially more expensive than
oral contraceptives and other short-term methods.
• Norplant often changes bleeding patterns.
• Women cannot discontinue use on their own.
• Some women may be reluctant to use an unfamiliar
method.
• Implants may be visible.
POPULATION REPORTS
Table 2. Performance of Norplant Implants, Selecled Trials, tin hiding < omp,iiisons with IUDs, IMII2 19116
Length of Follow-Up,
Author, Dale
(Ref. No.)
12 Months
Lopez et al. I98G
Lubis et al. 1983 (155)
Marangoni et al.
1983 (158)
Salayapan 1983 (211)
Shaaban el al. 1983
(22l)‘
24 Months
Affandi et al. 1984 (5)
Indian Council of
Medical Research
1986 (115)’Lopez et al. 1986
(154)
Shaaban & Salah
1984 (217)
nancy
Norplant
389
0
Norplant
Norplant
TCu 200
Norplant
Norplant
TCu 380A
813
283
283
704
250
100
i
■>
0
z
• 0.5
lJ
1
7"
■).t.Li
I
6*>
0
0
1
i
1
I
1
1
Norplant
Norplant
Norplant-2
451
88
84
<0.5
0
0
15
20
<0.5
NA
NA
Device
Colombia
Indonesia
Ecuador
Thai Lind
Igypt
Indonesia
India
Non
medical
Conlinuualion
Rate
0.5
l
<i>
NA
0
.1
1
95
87
88
88
90
87
Menstrual
Problems
0.5
• 0.5
1
1
NA
0
)
)
3
NA
NA
NA
.1
6*
1-2H
92
77
66
•>
•>
Colombia
Norplant
389
0
14
<0.5
<0.5
0
j
77
Egypt
Norplant
TCu 380A
250
100
pi
16
2 lh
0
0
9
0
3
9
13
68
52
Norplant
Norplant-2
300
750
16
I6
NA
NA
I|
10
NA
NA
10
61
61
10
19
14
NA
NA
NA
<0.5
36 Months
Bardin el al. 1986 (19) NA
60 Months
Affandi et al. 1987 (7)
Diaz et al. 1982 (56)
Shaaban 1987 (216)
Sivin 1984 (228)
Norplant
Indonesia
Norplant
Chile
Norplant
Egypt
Finland,
Norplant
Chile,
Dominican
Republic
Note: Rates may not add to 100 dde to rounding.
'Difference statistically significant
“Includes pelvic pain
‘Rates calculated for nine tv nits of use
101
250
324
0
2
1
cyclic development of the endometrium in over 50 percent
of Norplant users (51).
I
Cumulative Nel termination Rates
per 180 Women lor
InletExpul
Ollier
lion
Medical
sion
No. of
Women
Place
14
14
0
NA
0
NA
14
29
78
54
58
42
•■All pregnant ies probably tout rived 1) ciorc Norp
“Gross termination rales
'local inflammation reported in 2 nt 3 cases ol expulsion
"Includes some medical
mia (94,139, 221, 233). In three other studies average levels
remained the same (155, 169, 210).
Menstrual Changes
Reproductive Effects
Irregular menstrual bleeding is the most common side
effect of Norplant. About 60 percent of women notice
changes in their menstrual patterns in the first year after
Norplant insertion (211, 233, 269). Most common are an
increase in the number of days of bleeding and/or spotting
per cycle and a decrease in the length of the menstrual
cycle. For many women irregular bleeding decreases over
lime, however. Among 116 womep who used the 6-capsule
system for five years, the average number of days of bleed
ing and spotting per year gradually dropped from 92 in the
first year of use (an average of seven days per cycle) Io 70
in the fifth year (five per cycle) (19). Amenorrhea (absence
of menstrual bleeding) is less common that? prolonged
bleeding or spotting, but in one multicenter study 25 per
cent of users did not menstruate for at least 90 days during
the first year of use (233).
No serious reproductive side effects have been reported
•"among Norplant users. Transient ovarian cysts have been
found in as many as 10 percent of users (56, 139). Some of'
these cysts have grown to 10 cm. Surgery to remove the.
cysts, removal of the implants, or other treatment is usu-
These menstrual changes have no apparent harmful ef
fects. Although many women bleed more often than be
fore, the volume of blood lost does not change (169).
Heavy bleeding is quite rare.(269). In fact, in four studies
average hemoglobin levels increased significantly after
Norplant insertion—a change that may help prevent anePOPULATION REPORTS
Implants should be gently inserted just beneath the surface of
the skin. Inserting them too deeply makes removal difficult.
(Courtesy of Kee Kee Minot, z\Vs< )
K-61
Inserting and Removing Norpiunt Implants
Inserting Norplant implants is a simple procedure. Re
moval is mule difficult. With careful training and the
supervision of an experienced piac lilionei, howevei,
doctors, nurses, and other health workers can perform
both procedures.
Insertion
Implants are inserted on the inside of the upper or
lower arm 6 to 8 cm above or below the elbow. Inserted
through a single incision, the six Norplant capsules
form a fan shape, with its base toward the incision.
Special care must be taken during insertion to place the
implants just under the skin. If the implants are in
serted too deeply, locating and removing them can be
difficult. Maintaining sterile technique throughout the
procedure is essential to prevent infection.
For the most part, only basic surgical equipment is
needed: a table for the woman to lie on and a support
for her arm, sterilised surgical cloths, sterile gloves
without talc, soap, an antiseptic solution such as be- I
tadine, local anesthetic, a 4 to 4.5 cm anesthetic needle S
and syringe, scalpel, tweezers or mosquito forceps,
butterfly skin closures, and sterile gauze and com-1
presses In addition, a spectally marked #10 trocar is '
needed.
To insert Norplant implants:
1.
Wash the insertion area, apply antiseptic solution,
and, if possible, cover the area below the1 arm with a
sterile cloth.
2.
Anesthetize the insertion area with local anesthetic,
such as lidocaine 1%: inject a small amount into the
incision area, then turn the needle and anesthesize
the six or two areas, 4 to 4.5 cm long, where the
implants will be inserted. Apply the anesthetic just
beneath the skin. This raises the outer layer of skin
from underlying tissue and makes insertion easier.
3.
With the scalpel or the trocar, make a 2 mm incision
parallel to the bend in the elbow.
4.
Insert the tip of the trocar through the incision. The
trocar is marked in two places—near the top and
near the tip (see photo, p. K-63). Gently advance the
trocar into the incision to the mark near the top of
the trocar—about 4 to 4.5 cm. While advancing the
trocar, keep upward pressure on it without changing
the angle of insertion so that the implants will be
inserted just below the skin.
5.
Load the implant into the trocar. With the plunger,
gently push the implant towards the tip of the trocar
until you feel resistance. Then bring the trocar back,
keeping the plunger stationary, until the mark close
to the tip is visible in the incision and you feel the
implant pop out of the trocar. Leave about 0.5 cm
between the incision and the tips of the implants.
Do not remove the trocar from the incision. Feel the
arm to make sure the implant is in place.
6.
Load the second implant into the trocar. To place the
next implant, change the direction of the trocar so
that the next implant will be angled 15 degrees from
the first implant. Place your finger on top of the first
implant. Advance the trocar alongside your finger to
the mark near the top. Then release the implant
under the skin by pulling back the trocar. Repeal the
procedure until all implants are inserted.
Al lei all lhe implants ate inserted, apply pressure Io
the incision with sterile gauze to minimize bruising
and to stop I .-ding. Then press the edges of the
incision together and close it with a butterfly clos
ure. Sutures are not needed.
8. Cover the incision with a dry compress and wrap
gauze around the arm to prevent bleeding. Tell the
woman to keep lhe bandage clean and dry for four
days (132, 144, 182, 191).
Removal
Removing the implants is usually more difficult than
inserting them. Problems can occur if insertion was
done improperly—that is, if the implant was placed too
deep in the tissue—or when fibrous tissue has grown
around the implants, as often happens. Practitioners
should work gently, carefully, and patiently to avoid
injuring the skin of the arm. Along with equioment
used for insertion, mosquito and Crile forc^jl are
needed for removal.
To remove the implants:
I.
Wash the woman's arm and apply antiseptic. A
during insertion, sterile technique is essential.
2.
Locate the implants with your fingers. The location
of the implants can be marked with a pen.
3.
Apply a small amount of local anesthetic under th
hall of lhe implants nearer the elbow. Applying
anesthetic over lhe implants makes the skin swell
and blocks your view of the implants.
4.
Make one 4 mm inc ision as close as possible to th
ends ol all the implants, at the base of the "fan."
This incision is long enough to remove all implants.
A longer incision does not make removal easier.
5.
Remove first the implant that is closest to the inc
sion or closest to lhe surface.
6.
Gently push the implant toward the incision unt
the tip is visible. Grasp the tip with the mosquito
forceps. Scrape away the fibrous tissue around the
implant with gauze or, if necessary, cut Mdth a
scalpel. If you use a scalpel, be careful n^K> cut
the end ol the implant. Grasp the implant with the
Crile forceps and remove it.
If you cannot push the implant into the incision
insert closed forceps into the incision and gently
dissect the tissues around the implant. At the same
time push the implant toward the incision with
your other hand.
8.
Apply more anesthetic as needed to remove th
other implants.
9.
If the woman does not want a new set of implants
close and bandage the incision as you would after
insertion. If she does want a new set, it can be
inserted immediately (see p. K-59).
10.
If an implant cannot be removed, the woma
should return to the clinic in about two to four
weeks. Removing the remaining impG-u or im
plants is easier when the arm has healed (6, 14
*1,
182, 191). Of course, the woman should receive
another contraceptive method to prevent preg
nancy until she returns.
7.
POPULATION REPO'
rescan hers will look lor any long term diet Is (.’I?) In
Indonesia troth gloups ol inlants grew satr.lai (only In
weight and length over six months. In lad, tin- Not [riant
infants gained weight slightly but significantly taster (4).
Norplanl use during bn r.l feeding does not alter hor
mone levels in infants Seiuni levels ol immunoglobulins
and urinary levels of follicle-stimulating hormone (FSH),
luteinizing hormone (LH), and testosterone are the same
in breast-fed infants of women using Norplant and of
women using barrier methods or no contraception (1,
114).
Inserting Norplant requires only simple instruments, including
a specially marked trocar (see arrows). After a small incision is
made in the skin, the trocar is inserted just under the skin up to
one of the marks away from the tip—the middle mark for
Norplant, the upper mark for the longer Norplant-2. Then the
plunger is held in place and the sleeve withdrawn until the mark
near the tip shows and the implant pops out of the trocar. Ster
ile technique is essential throughout the insertion procedure.
ally not needed, however, since the cysts regress sponta
neously within six weeks (18, 19).
[Concerns have been raised about an increased risk of
ectopic pregnancy among Norplant psecSvIbese concerns
lari' because higher than expected rales of ectopic preg
nancy have been reported among women using progestinonly oral contraceptives (30, 32, 152, 238). As of January
1987, in studies of Norplant and Norplant-2 conducted by
the International Committee for Contraception Research,
10 ectopic pregnancies had been reported in 6,800
woman-years of use, for a rate of 1.5 per 1,000 womanyears (232). This is about the same as the rate among
women using copper and unmedicated intrauterine de
vices (IUDs), excluding the Daikon Shield, and probably
does not represent an increased risk for Norplant users.
The rate is lower than the rate among women using no
contraception (231, 256). Certainly, any pregnancy during
Norplant use is rare.
The contraceptive effect of Norplant wears off quickly
once the implants are removed. Former users of Norplant
conceive as rapidly as women who have not used con
traception. Among v5 women seeking to become preg
nant, 50 percent conceived by three months after discon
tinuation, and 86 percent, by one year (232).
Preliminary evidence suggests that the small amount of
levonorgestrel released by Norplant has no harmful ef
fects on infants exposed during pregnancy or breast-feed
ing. To. date, researchers have followed up 15 full-term
pregnancies conceived during Norplant use. All pregnan
cies were normal, and the children, healthy (232). This
I number would be too small to delect most birth defects,
of course and follow-up’is7do' shdrfrfi deletFany possible
llong-term effects.
<2
In Chile and Indonesia researchers have compared breast
feeding infants of mothers who used Norplant with infants
of mothers who used copper-T IUDS. In Chile there was
no difference between the two groups in the percentages
receiving supplementary bottle-feeding in the first six
months postpartum, in the percentages still breast-feed
ing at 12 months, or in average monthly weight gain. Infant
daughters of Norplant users, gained less weight than
daughters of IUD users, but weight gain for all children
was within the normal range (55). The sb ' is continuing;
POPULATION REPORTS
Other Side Effects
Norplant causes few side effects apart from menstrual
changes. Headache is the most common other complaint
(154, 221, 229, 235). In one study Norplant users reported
more headaches than IUD users (229). In another, how
ever, rates were the same (221).
Norplant causes few systemic changes. Lipid metabolism j
is especially important because of its link with cardiovas- |
cular disease. Six studies to date have reported conflicting .*
results (50, 94, 105, 210, 218, 279). Other clinical indicators
are reassuring. Only minor changes—all within the nor-,mal range—have been observed in liver function (48, 50, i
94, 210, 220), carbohydrate metabolism (50, 94, 269), blood
coagulation (219), blood pressure (139, 155, 210, 220), im
munoglobulins (1, 269), serum cortisol (21), urea nitrogen,!
uric acid, sodium, potassium, calcium, inorganic phos-'
phorous (48, 50, 269), and body weight (139, 155, 221, 235)-
Care of Equipment for
Norplant Insertion and
Removal
Special care should be taken with the equipment
used during Norplant insertion and removal. The
trocar should be washed with warm water and anti
septic solution immediately after each insertion and
then disinfected before reuse. The equipment can
be disinfected by several methods:
• autoclave for 20 minutes,
• immerse in boiling water for 5 to 10 minutes, or
• cold-sterilize with standard hospital-strength
germicide for at least one hour.
'Autoclaving is the most effective disinfection
method. All three methods will kill human immu
nodeficiency virus (HIV), the virus that causes AIDS
(68). Neither cold sterilization-nor boiling in water
for 5 to 10 minutes kills hepatitis B virus, however.
Where hepatitis is endemic, instruments should be
autoclaved or boiled in water for 15 to 30 minutes.
The tip of the trocar becomes blunt after repeated
use, and this makes it harder to advance the trocar
into the incision. Health workers should examine
the tip of the trocar after_eyery. 10..insertions and
sharpen it as needed (188). With proper care a trocar
can be used for about 50 insertions (124). If incisions
are madejyilh. the trocar, it may„need sharpening_
more often and may not be usable for 50 insertions.
K-63
Over two thirds of women ti .c Noipl.ml implants ioi .it
least two yeais. Aller one ycai> continuation idles range
from 87 to 95 percent, and after two years, from 66 to 92
percent (see Table
*
2). In a inulticenter Indonesian field
, study involving more than 8,600 women after 12 months
95 percent of the urban participants anu -M peccent of the
rural participants were still using Norplant; at 18 months,
92 and 98 percent (277). According to smaller studies in
Chile, the Dominican Republic, Egypt, Finland, and Indo
nesia, after five years 42 to 78 percent of users were still
relying on implants (56, 228). Bleeding irregularity is the
most frequent reason for discontinuation, causing 2 to 7
percent of women to stop using implants in the first year
(see Table 2). This is lower than discontinuation rates for
bleeding problems with long-acting injectables (see p.
K-72). The greater difficulty of discontinuing Norplant may
help account for the difference in discontinuation rates.
The long effectiveness and ease of use of Norplant are
among its most attractive features. In Thailand, for exam
ple, 31 percent of 700 women reported that five years of
effectiveness was the major reason that they chose Nor
plant over other methods (211). Focus-group discussions
among Norplant users in the Dominican Republic, Ec
uador, Indonesia, Kenya, the Philippines, Sri Lanka, and
Thailand identified other desirable features of the method
as well: not having to put anything into the vagina, not
having to do anything just before intercourse, reversibility,
and the possib., ty of slight weight gain (a much less com
mon side effect than menstrual irregularity), which most
women considered a sign of good health (184, 274).
Use of Norplant
Data on use of the 6-capsule Norplant system are available
for onlyJ.our.Qf the seven countries where it has been
approved;.the other three countries have granted ap
proval only recently. In Indonesia Norplant is available
through the Indonesian family planning program at more
than 150 locations, mostly in Java. The Indonesian National
Family Planning Coordinating Board (BKKBN) buys Nor
plant directly from the manufacturer using grant funds
y from the United Nations Fund for Population Activities
. (UNFPA) and loan funds from the World Bank (276). About
More Nunbiodegradable
Implants Being Developed
In addition to levonorgestrel, which is used in Nor
plant, at least 10 compounds have been tested in
nonbiodegradable implants (150). Most have proved
unsuitable lor contraception or lor delivery in im
plants. Several are promising, however, and clinical
trials are underway (see Table 1). As of March 1987,
no application had been filed with the US Food and
Drug Administration (US FDA) for testing or ap
proval for these products. The most advanced is an
implant containing desogestrel, a new progestin
used for several years in some oral contraceptives.
The pharmaceutical firm Organon International and
the Population Council are conducting clinical trials
with the main metabolite of desogestrel, 3-keto des
ogestrel. Different lengths of a single rod are being
tested in Chile and Sweden to determine release
rates and duration of action (168). In addition, trials
with single rods releasing about 15 pg or 30 pg per
day are being conducted in China (173). The rogBan
be inserted in the inside or outside of the up(^R>r
lower arm. Organon International plans to develop
implants with varying amounts of hormone so that a
single rod will prevent pregnancy fot two, three, or
four years (171).
Another progestin, ST-1435, also is being used in
implants (47). In recent clinical trials one capsule
with 20 to 40 mg ST-1435 suppressed ovulation and
prevented pregnancy in 28 women for six months
(140, 141). Like Norplant and other progestin-only
contraceptives, the ST-1435 implant causes irregular
bleeding. Amenorrhea occurs more often with
ST-1435 than with Norplant. Almost 60 percent of the
28 women did not menstruate for at least 90 days
over a 12-month period. Because ST-1435 diffuses
fairly rapidly through the implant membrane, a sin
gle capsule may have to be replaced every 6 to 12
months (140). The Population Council is developing
a single rod implant expected Io release hormones
at a constant rale for two years. The organization
plans to submit an application to US FDA for pe^^ssion to test this implant (168).
18,000 Indonesian women chose Norplant in preintroductory trials. Between approval in 1986 and January 1987 an
. additional 57,000 women adopted the method (85). In
I Thailand almost 7,000 women are using Norplant (85); in
I Finland about 9,000; in Sweden about 10,000 (124).
At a follow-up visit to a clinic in Brazil, a Norplant user lets
other clients see that implants hardly show. (Population Council)
K-64
UNFPA is the only donor agency currently supplying Nor
plant to developing countries. In 1985 UNFPA shipped
12,000 sets of Norplant implants, mainly to India and the
Dominican Republic. In 1986 about 38,000 sets were
shipped to four countries—India, Thailand, Tunisia, and
Nigeria. Shipments to India were the 2-rod Norplant-2
system for clinical trials. All other shipments were 6-capsule Norplant (245). the International Planned Parenthood
Federation (IPPF) has approved Norplant for distribution
to its 120 affiliated family ...ning associations if the coun
tries have granted regulatory approval and if health work
ers have been trained.
POPULATION REPORTS
■.hoilci th.in hclim- the thhit.c w.c. tiiscilcd No < h.ingcs
in blood pressure, lipids, or blood < hemistry were ob
BIODEGRADABLE IMPLANTS
served (174)
Capronor is inserted under the skin in the hip or upper
arm Ili<- area is liisl numbed with a local anesthetic. A
small incision is made in the skin, and the capsule is
inserted through a special inserter (see photo, p. K-66).
The polymer capsule does not cause inflammation al the
insertion site (174).
z
Biodegradable implants deliver progestins from a carrier
that gradually dissolves in body tissues. Ihus the <airier
never has to be removed, as with Norplant implants. Once
the carrier begins to dissolve, however, it cannot be re
moved.
Two implants now being tested in women are:
• a polymer capsule filled with the progestin levonor
gestrel and
• pellets consisting of the progestin norcthindrone and
small amounts of cholesterol.
Preliminary results indicate that both implants are safe and
effective. Both may be available by the mid-1990s.
Norethindrone Pellets
Small pellets are another type of biodegradable implant.
The pellets were developed by Gopi Gupta while working
at the Population Council (90). They are made of 15 percent
pure cholesterol and 85 percent norethindrone (NET).
Each pellet contains about 15 mg NET, which is released as
the pellets gradually biodegrade. The pellets are quite
small, each a little larger than a grain of rice. After inser
tion they are barely visible under the skin (226).
Capronor
Capronor, developed by the.Research Triangle Institute,
consists of a biodegradable capsule made of the polymer
poly(c-caprolactone) containing the progestin levonor
gestrel. Current trials involve capsules that are less than
0.24 cm in diameter and either 2.5 cm or 4 cm long (202,
260). The shorter capsule contains 16 mg levonorgestrel.
I he longer capsule contains 26 mg levonorgestrel. In both
capsules the levonorgestrel is suspended in an oily solu
tion of ethyl oleate (97). Studies in rabbits and monkeys
suggest that contraceptive protection will last at least 18
months and probably longer (260). The polymer carrier
remains largely intact for 18 to 24 months and can be
removed easily during that time. Then it begins to bio
degrade. It is not completely absorbed for several years
(260).
The first clinical trials of Capronor in women began in 1980
(202). A 2.5 cm long device releasing an average of 20 pg
levonorgestrel per day suppressed ovulation in 22 of 26
women during one menstrual cycle. A 4 cm device releas
ing 30 to 50 pg levonorgestrel daily prevented ovulation in
all 10 women using it (260). Recruiting for Phase II trials
(preliminary effectiveness trials) comparing the 2.5 and 4
cm devices began in early 1987. Conducted by the US
National Institute of Child Health and Human Develop
ment (US NICHD), the World Health Organization (WHQ),
and the Indian Council of Medical Research (ICMR), the
trials will enroll between 250 and 300 women foTone year
(97).
Few side effects have been reported in the small, prelimi
nary trials of Capronor. None of eight women in a US study
reported bleeding between menstrual periods. The aver
age length of the menstrual cycle was about four days
Preliminary trials using two, three, and four pellets have
been conducted in over 100 women in four countries.
With all three regimens the release of hormone was fairly
constant (198, 226). The daily close of Nl 1 and c onlrac cap
tive effectiveness increased with the number of pellets:
Hormone Release Rates and Numbers of Pregnancies
with Two, Three, and Four NET Pellets
No. of
Pellets
Mean Daily
Release (jig)
No. of
Women
No. of
Pregnancies
2
111 ± 20
150 ± 7
213 ± 9
50
51
30
3 al 6 months
2 at 12 months
0 at 12 months
4
Source: PARER (197. 198), Singh el .cl. C226I
The 4-pellet regimen appears to provide a high level of
protection against pregnancy for at least 12 months. Thus
further research will focus on this regimen.
More than half of the women using three or four NET
pellets experienced irregular menstrual patterns. Intermenstrual bleeding or spotting was the most common
problem. In time bleeding returned to preinsertion pat
terns, however. For example, among women using the 4pellet regimen, the percentage experiencing more than
five days of bleeding or sp. ning per menstrual cycle was
40 percent before insertion, 70 percent in the first month
after insertion, and 43 percent in the sixth month after
insertion (197, 198). Amenorrhea occurred in 14 percent of
women by six months. The pellets relieved moderate and
severe menstrual pain in most women who had experi
enced it previously (197, 226).
Table 3. Characteristics and Status of Biodegradable Implants as of March 1987
Delivery
System
Development
& Testing
Capronor (poly
(e-caprolactone) capsule)
Pellets
Research
Triangle
institute
Population
Council;
Endocon,
Inc.
POPULATION REPORTS
Hormone
Duration
of Action
Status of
Animal
Trials
Phase 1
Levonorgestrel
At least
18 months
Completed
Completed
Norethindrone
I year
Completed
Completed
using 2
pellets
Estimated
__________ Status of Human Trials__________
Availability
Phase III
Phase II
To begin in 1987 in 6
countries with
250-300 women
Completed in i
countries with 81
women using 1 or 4
pellets
Mid-1990s
Mid-1990s
K-65
be dispersed in the polymeric p.nlicle (micriy.plieie) or
contained in lire tore of rhe parliile (inir ror .ipsule).(2 >.
I47). Wnh bolli systems hoi nrone is released lirst by leach
ing or by diffusion through the carrier and later hy erosion
ol the rariiei -
Capronor (long capsule at left) and contraceptive pellets are both
long-acting implants that dissolve in body tissue and do not need
to be removed. The special inserter can be used with either.
Few women reported side effects other than irregular
bleeding. Breast pain or discharge occurred in three
women (4 percent). The very small amount of cholesterol
in each pellet—less than 2 percent of the cholesterol _in a
single chicken eeg—did not affect serum cholesterol levels in any of the women (198).
The pellets are inserted in the inner side of the upper arm.
The insertion procedure is like il... used with (_»pionor
and can use the same inserter. After the area is numbed
with local anesthetic, a_3 mm incision is made. The pellets
are inserted about 3 cm under the skin. Sutures are not
needed, and the wound is covered with a bandage. If the
pellets are to be removed before they biodegrade/a 5 mm
incision is needed. In preliminary trials 'pellets'brokelri5t5ouf5 percent of both insertions and removals. The broI ~ ken pieces were not ditlu ... ib remove, however.- When I
I researchers removed pellets, they noted lhal__fibrous '
• tlssue”fiad developed
id the pellets in most women.
This had not caused any inflammation or discomfort, how
ever, and had not interfered with release of NET (197,198).
Plans are being made to conduct larger clinical trials with
the 4-pellet regimen. A manufacturing process is being
developed so that It.. pellets can be produced easily and
inexpensively on a large scale (79, 224).
INJECTABLE MICROSPHERES AND
MICROCAPSULES
The size of microspheres or capsules and the amount ol
hormone they contain, as well as their quantity, largely
determine the daily dose of hormone. Smaller partici.
release hormone faster and so have a shorter duration of
action. Among particles of the same size, those with more
hormone and less carrier release hormone faster (25,92). A
3-month dose of injectable norethindrone microspheres
usually contains particles consisting of 50 percent hor
mone and ranging in size from .06 to 0.1 mm in diameter
(24). Sterilization of microspheres or capsules by gamma
radiation slightly increases hormone release (92).
For an injection, microspheres are loaded into a syringe
Then a sterile suspension fluid is drawn into the syringe. A
3-month formulation of norethindrone microspheres, for
example, contains about 2’Zi cc of fluid and is injected into
the buttocks with a 21 gauge needle (22) (see photo, p
K-68). The syringe must be shaken just before an injection
This prevents the larger, heavier spheres fromp^kig at
the bottom of the syringe (205). Larher formulation com/ posed of 80 percent polymer and 20 percent hormone
I were very dense, and researchers were not always able to
I inject all the microspheres (24). Microspheres of half polyI mer and half hormone
*
have eliminated this problem, de
I creased the amount of material injected, and reduced
(discomfort from the injection (22).
. ....................... ——■
In addition to contraception, microspheres are being used
to deliver drugs to treat medical conditions. In the US, for
example, a small trial is underway studying testosterone
microspheres in men with abnormally low production of
testosterone (146). In Europe several pharmaceutical com
panic’s arc
*
testing microspheres containing luteinizing
hormone releasing hormone (LHRH) antagonists to treat
endometriosis and prostate cancer (22). Microspheres witl
natural estrogen are now being tested in animals. Thesi
microspheres could provide estrogen replacement ther
apy for postmenopausal women (22).
lor contraception in women, injectable microspaces arc
being tested with various hormones (see Table^^Mosl
promising are microspheres with either norethindrone oi
a new progestin, norgestimate. Microspheres also art
being considered for male contraception. Possible for
mutations are testosterone alone or testosterone com
bined with LHRH analogues (146, 280).
»
Norethindrone Microspheres
Injectable microspheres and microcapsules consist of a
biodegiacluble copolymer and one or more hormones.
The many microspheres or capsules release hormones at
varying rates to achieve a fairly constant daily dose, like
that of implants. Depending on the formulation, a single
injection of microspheres, suspended in a sterile solution,
can provide contraception for one, three, or six months.
Like other injectables (see pp. K-69-76), microspheres and
capsules are easy to administer but, once administered,
cannot be removed.
The microspheres and capsules being studied use the
carrier poly(dl-lactide-co-glycolide). The polymers in this
carrier have been used safely (or years in biodegradable
surgical sutures (25). Progestins and other hormones can
K-66
Injectable microspheres containing norethindrone (NEThave been tested in almost 200 women. Results are prom
ising. In short-term clinical trials different formulations c
3-month injections have prevented pregnancy and causei
very lew side effects other than menstrual irregularities
Norethindrone microspheres were developed by Lee Bee
and Danny Lewis of the Stolle Research and Developmer
Corporation with support from the Program for Applie
Research in Fertility Regulation (PARFR). Family Health lr
ternational is conducting larger clinical trials in four cour
tries to test two formulations of a 3-month injection—wit
65 and 100 mg NET. Trials of the 65 mg injection in aboi
1,200 women have been approved by the US Food an
Drug Administration and will begin in 1987 K_2, 44).
POPULATION REPOR
Nil itn< tos| >h<‘i i*s prevent pregnant y with doses tom
parable to those In combined oral contraceptives. A I-
tabolism (.’ I, I II llir- < oiili.u eplive filer I ol the miri.o
spheres wears oil rapidly. Most women ovulate within two
month injer lion lonlaininp, a total ol 75 nip, Nt I ideases
on average tl.-llt mg Nt I pet day. A l inonlh infer lion
containing 100 mg NET releases 0.66 mg per day (26). By
comparison the daily dost
*
ol Nl I used tn some tom
bined oral contraceptives ranges (rom 0.5 to I mg in vari
ous formulations (102). In initial trials none of the 10
women receiving the 75 or 100 mg 3-month injections
ovulated during treatment (26). In the second phase of
trials, after more than 300 woman-months of observation,
one pregnancy has occurred among 60 women receiving
65 mg injections. None has occurred among 65 women
receiving 100 mg injections (44).
Either formulalions of Nl I mil rospheres ate being stud
ied. A one-monlh injet lion with IS or 10 mg Nl I has been
tested in about 30 women in Mexico. Also, animal studies
have been completed with various tormulations ot orieancTthree-month injections of NETand'the synthetic es-j
triSgFii ethmyT'estradiol. In animals' these formulations]
caused very little irregular bleeding and very slight endo-|
A 6-month injection with 200 mg NET looks less promising.
When it was tested in 10 women, there were no pregnan
cies during the 24-week period, but 2 of 10 women ap
peared to ovulate before six months, and one woman
conceived 26 weeks after the injection (205).
Irregular menstrual bleeding is the only common side
effect of NET microspheres. Amenorrhea or long cycles
with persistent spotting are the most common patterns
(205). Among 10 women each receiving a 3-month injec
tion, the total number of days per cycle with bleeding or
spotting ranger! from 5 to 9 with the 75 mg injection and
from 8 to 11 with the 100 mg injection (24, 26).
Other side effects are rare. Among 115 women, only a few
complained of mild headaches or nausea, and it is not
clear that these were caused by the injection (44 , 206).
There have been no infections at the injection site. No
changes have been observed in blood pressure, hemo
globin, serum lipoproteins, triglycerides, or glucose me
In clinical trials norethindrone microspheres prevent preg
nancy for three months. Microspheres are .06 to 0.1 mm in
diameter. The smaller microspheres release hormone faster..
(Stolle Research Corporation)
Table 4. Characteristics and Status of Injectable Microsphere and Microcapsule Contraceptives as of March 1987
Hormone
Norethindrone
(microspheres)
Development
& Testing
Stolle Research &
Development Cor
poration, Family
Health International
Duration
of Action
Status of
Animal
Trials
_________ Status of Human Trials__________
Phase 1
Phase II
Phase III
3 months Completed Completed
6 months Completed Completed in
Mexico & US
with 200 mg for
mulation
1 month Completed Completed in
Mexico with 15
mg & 30 mg for
mulations in 30
women
Ortho Pharmacvc..
Norgestimate
3 months Completed Underway in US
with 50 mg for
(microcapsules) cal, Contraceptive
mulation
Research & Develop
ment (CONRAD)
Progesterone
Stolle Research &
3 months Completed Underway in
(microcapsules) Development Cor
Chile & US
poration
Levonorgestrel Stolle Research &
3 months Completed Approved to be
(microspheres) Development Cor
gin in US
poration
Norethindrone Stolle Research &
3 months Completed Approved to be
(NET) & ethinyl Development Cor
gin in US with
estradiol (EE)
poration
30 mg NET & 5
(microspheres)
mg EE
POPULATION REPORTS
Underway at 8
sites in US,
Mexico, Chile
& Italy with 65
& 100 mg for
mulations in
160 women
Estimated
Availability
Early 1990s
Planned for
1987 with 65 mg
formulation in
1,200 women
No sooner than
Idle 1990s
Mid-1990s
Mid-1990s
No sooner than
late 1990s
No sooner than
late 1990s
No sooner than
late 1990s
K-67
melrial changes. This suggests that the conii,...
iiijei
lion may < ause less megulat bleeding in women thai.
mjei lions alone. Initial trials in wiimi-n ot a t-month injec -
Ill
( hinj rose.in hi-is have been testing monthly injet lions
<•1 mu IOI apsules iiiiitaining various doses ol lite piogeslin megeslrol acetate and the estrogen estradiol valer
*
lion have been 'n|imvi'(l and ale planned lot 1911/. tins
ale. the lowest sole etlec I*. <i< < lined with a uiontlily dose
injection will contain about 30 mg NET and al mt 1.3 mg
ethinyl jt-slradiol (22).
of 15 mg megeslrol acetate and 5 mg estradiol valerate.
With this regimen the pregnancy rale was I I per l(U)
woman-years tn a study involving -I t-l women. Sjrotling
occurred in only 3 percent of menstrual cycles, and only 9
percent of cycles were- either longer than 36 days or
Microcapsules with Various Other Hormones
Research is underway on microcapsules containing other
hormones. Animal studies with Ortho Pharmaceutical's
new progestin, norgestimate, suggest that it will cause less
spotting than other progestins. In six baboons microcap
sules containing 50 mg norgestimate suppressed ovulation
for 90 to 120 days (92 , 93). Endometrial biopsies on these
animals showed hormonal effects like those occurring nat
urally in the postovulatory phase of the menstrual cycle
(257). Spotting did not occur in any of the animals (92, 93).
Thus norgestimate may cause less irregular bleeding in
women than other progestins that have a more marked
effect on the endometrium. Norgestimate is a more po
tent progestin than NET and has no androgenic side ef
fects such as hair growth and acne (93). Therefore it is
likely to be highly effective and also popular with women.
Initial trials of a 3-month injection with 50 mg norgestimate
are underway in the' US (91).
Preliminary Inals of microcapsules containing the natural
hormone progesterone were carried out in 1986 in Chile
i and the US (146). Progesterone microcapsules arc inI tended specifically as a contraceptive for lactating women
to eliminate any possible efiects of synthetic progestins on
I breast milk production or composition or on the nursing
infant. The trials involved about 10 women receiving a 3month injection with 275 mg progesterone (146). This dose
appears high compared with other microsphere and mi
crocapsule formulations because progesterone is less po
tent than synthetic hormones. Preliminary results showed
that the microcapsules release a smaller than expected
amount ot progesterone per day. Plans are underway to
increase the progesterone in the microcapsules so that the
daily release rate will be about 20 percent high i. Initial
trials of the modified microcapsules are planned for 1987.
Another way to deliver progesterone that is being consid
ered is an injection of a micronized preparation of pure
progesterone—that is, a crystalline form ground to a finepowder. One injection would be effective for a month.
shorter than 20 days (100).
VAGINAL RINGS
Vaginal rings are different from the other new long-acting
hormonal methods. Although, like the others, they slowly
release hormone, vaginal rings are not injected or placed
under the skin. Instead, a woman simply places the ring in
her vagina and leaves it there. She- can remove it at any
time.
Levonorgestrel Rings
Research is most advanced on a ring developed by^h.World Health Organization (WHO) that releases ahouWo
pg levonorgestrel pc-i day. Ibis ring is designed to stay in
the vagina for three months. It consist. .>t an inner core
containing 6 mg levonorgestrel mixed with Silastic and an
outer shell of Silastic alone. The ring's overall diameter is
55.6 mm; its cross-sectional diameter, 9.5 mm. The ring
prevents ovulation in at least half of cycles (292, 302) and
also thickens cervical mucus, preventing sperm from en
tering the uterus (272).
The levonorgestrel ring is less effective than implants or
injectables. In a multicenter one-year trial involving about
1,000 women, there- were 25 pregnancies, for a rale of 3.5
per 100 woman-years (260). Like other progestin-only
methods, vaginal rings cause irregular bleeding, and this
accounted for most discontinuations. About 8 percent of
the women stopped using the ring because of vaginal
discharge, irritation, or infection, and about 4 percent,
because of expulsion. Expulsion is' most likely when
women squat Io defecate (97).
WHO has applied lor approval of the levonorgestre^^g
. in the UK. Approval is being postponed until machinery
. lor manufacturing the rings is completed and the manI ufactured rings are shown to release levonorgestrel at the
same rate as the handmade rings. The- manufacturing prot, cess should be final by late 1987. Approval is expected in
' 1988 (97).
Progesterone Ring
Another ring contains the natural hormone progesterone.
It is designed especially for breast-feeding women so that
they will not be exposed to synthetic hormones that might
ailed the- composition or quantity of breast milk. Like the
Norelhindrone microspheres offer the convenience of an in
jection without the large initial burst of hormone that occurs
with currently available injectables. For clinical trials micro
spheres are supplied in a sterile syringe. Fluid is drawn from the
vial, and the syringe is shaken just before the injection is given.
levonorgestrel ring, the- progesterone ring can remain in
the- vagina for three months. Currently, WHO and the
Population Council an- testing rings releasing 5 or 10 mg
progesterone- per day (260). According to a small study in
Chile, growth of infants and duration of breast-feeding
were very similar when infants of women using the rings
or TCu-200 IUDs were compared. Bleeding and/or spotting
(
POPULATION REPORTS
Table 5. Characteristic s and Status <>t Vaginal Rings as nt March l!)H7
Development
& Testing
Duration
of Action
Status ol
Animal
Trials
Phase 1
Levonorgestrel
WHO HRP
3 months
('ompleled
(ompleled
Completed
Progesterone
WHO HRP,
Population
Council
3 months
Completed
i ompleled
Ongoing
Hormone
Status of Human Trials
Phase II
Phase HI
I ompleled
Estimated
Availability
Approval m UK pend
ing, expected in 1988
tarly 1990
*.
WHO HRP - World Health Organization Human Reproduction Program
for more than six days per 30-day interval occurred more
often among the IUD users (55).
Combined Progeslin-Eslrogen Rings
The Population Council is working on several rings that
deliver both progestins and estrogens. These rings are
intended to be kept in the vagina for three weeks at a time
and removed for one week to allow monthly bleeding.
Preliminary studies in about 10 women showed that a ring
releasing 400 pg norethindrone acetate and 40 pg ethinyl
estradiol daily stopped ovulation in all women and caused
very little irregular bleeding. This ring is now being
changed to reduce the daily release ol ethinyl estradiol.
Human trials of the new version are planned for 1987. The
Population Council also plans to test vaginal rings with two
other progestins, ST-1435 and levonorgestrel acetate,
alone and combined with ethinyl estradiol (168).
Advantages and Disadvantages
Io date, lew women have tried vaginal rings. thus, as with
many of the other new methods, it is not clear how popu
lar they will be. In a uritish trial 26 of 27 women using the
levonorgestrel ring said that they preferred it to oral con
traceptives, condoms, and the diaphragm, primarily be
cause it was so easy to use (293). Earlier trials in eight
countries found that discontinuation rates were similar for
oral contraceptives and a ring of levonorgestrel and eth
inyl estradiol. Significantly more discontinuations among
ring users were for method-related problems, however,
especially difficulties or "unpleasantness" with inserting
or removing the ring (297).
Compared with the other new long-acting methods, the
big advantage of the vaginal ring is that a woman can put it
in and take it out herself. This means that she can start and
stop the method easily, without help from a health worker.
It also means that rings can be distributed through com
mercial channels and community-based distribution pro
grams mote . ily than some ol the other new methods.
Unlike barriei methods, vaginal rings do not i...ve to be
inserted just before intercourse. In fact, they will not work
if used only during intercourse. A woman can remove the
ring before intercourse, however. In early trials one-fourth
of users removed the rings al least some ot the time, often
because their partners could feel them (286, 297). Remov
ing the ring tor a short period—as long as 2 hours lor the
progesterone ring and possibly as long as 24 hours for the
levonorgestrel ring—will not decrease effectiveness (168).
Leaving them out longer may increase the risk of preg
nancy (55, 97).
The vaginal rings appear to have several possible disadvan
tages. Women who dislike touching their genitals may not
like inserting and removing (he rings, as earlier studies
indicated. Also, the preliminary data on the current ver
sion of the levonorgestrel ring suggest that it is less effec
tive than other hormonal methods, voluntary sterilization,
or the more effective IUDs.
LONG-ACTING INJECTABLES
Two long-acting injectables are widely available—depot
medroxyprogesterone acetate (DMPA; trade name DepoProvera; the Upjohn Company) and norethindrone enan
thate (NET EN; trade name Noristerat; Schering AC). Both
are highly effective, reversible methods. DMPA is ap
proved for use as a contraceptive in more than 90 coun
tries; NET EN, in more than 40. Although injectables have
proved very popular, controversies—particularly about
DMPA—have limited their availability in some areas.
Questions have been raised about long-term health risks,
especially cancer, but new studies are for the most part
reassuring. Some questions concerning cancer remain,
however. Research continues on both injectables.
Two vaginal rings (shown actual size) release hormone for 3 months.
The upper ring contains norgestrel; the lower, progesterone.
POPULATION REPORTS
The synthetic hormones used in both injectables were
developed in the 1950s. The progestin medroxyprogesterK-69
New Leaders in Contraceptive Research and Development '
I he leading roles in contraceptive research and devel
opment are changing. Tor a combination of reasons,
some pharmaceutical companies are increasingly reluc
tant to initiate contraceptive research and develop
ment. More and more, nonprofit organizations and
government agencies are taking the lead, and pharma
ceutical companies are collaborating with them. Re' gardless of who takes the lead, however, developing a
new drug remains a long, complex, and costly process.
Drug Regulation
Over the last several decades the process of contracep
tive testing has become increasingly standardized to
meet the requirements of government drug regu
lations. Many countries require specific senes of animal
and human tests to establish safety and efficacy before
a drug can be made available (118). Often these require
ments are modeled on those of the US Food and Drug
Administration (US FDA). The US FDA requires that
steroid contraceptives be tested in three animal spe
cies—rats for 2 years, beagle dogs for 7 years, and
monkeys (or 10 years. Human trials are usually carried
out in three phases with increasing numbers of volun
teers (see note, Table 1, p. K-59). Human trials can start
and progress from one phase to the next only after
animal trials have successfully reached certain stages.
While adequate testing is essential, the cost and time
spent on the tests now required has helped discourage
pharmaceutical manufacturers from developing new
contraceptives. A 7-year dog study or a 10-year monkey
study can cost between $500,000 and $2 million (US)
(60). The annual cost of early. Phase I human trials in the
US is aboul $TO,00(1 per person (.11). Furthermore, the
lengthy research and development process limits prof
its. In the US, for instance, patents now protect new
compounds for 22 years. If most of those years are
taken up in testing, little1 time is left for exclusive mar
keting. In hopes of shortening testing, many devel
opers are focusing on new delivery systems for com
pounds already approved—for example, the com
pounds now used in oral contraceptives._AJso, most
new contraceptives are intended for international dis(rTbuFion. Ihus researchers must meet the differing
regulations governing clinical (rials in many different
countries (95, 118,160). This, too, adds to costs.
Other Impediments
Concerns over legal liability and insurance costs, es
pecially in the US, also have discouraged some pharmaceutical manufacturers. For example, in 1986 the G.D.
Searle Company withdrew the Cu-7 IUD from the mar
ket because responding to a mounting number of law
suits, even though the company usually won, was very
costly. Today, only one IUD, the Progestasert, Is still
marketed in the US even though IUDs are a safe and
effective contraceptive method. Also in 1986, the US
Supreme Court affirmed an award of $4.7 million (US)
for a birth defect allegedly caused by spermicidal
jelly—even though the weight of scientific evidence
showed that the spermicide was not to blame. Manu
facturers cannot afford to risk the high cost of law
suits — win or lose—over a produc t that generates little
K-70
piolil. Contiai eplives may gcueiale Illite piolil it the
amount of sales is small, as with spermii ides, or if the
method is low-cost and long-acting, as with IUDs
■Also in the US, contraceptive developers are having
Ldiffic ulty finding | • ■ Im I liability insurant e. As a result,
■clinical testing In the US sometimes must be delayed
■for several years, as in the case of the biodegradable
Implant Capronor, or held to the minimum required by
lhe US FDA, as in the case of Np.rpl.4nt (8, 15).
Even when the required testing is finished, political
controversy can delay regulatory approval. Some oppo
nents of DMPA have made a political issue of fears that
women would be
* given injet tallies without their knowl
edge or lull undei standing. Controversy over this issue1
lengthened US IDA deliberations over Depo-Provera
and delayed approval in the UK until 1984 (196).
The Role of Nonprofit Organizations
While interest declines among pharmaceutical manu
facturers, a handful ol nonprofit organizations are em
phasizing contraceptive 1 research and development. In
1985 eight suc h organizations spent more1 (han $10 mil
lion (US) working on 2.1 new products (15).
.Nonprofit organizations currently involved in conlrajceolive researc h inc luck1 the- Human Reprocluctiipn Pro
fgram ol the World Health Organization (WHO); gov
ernment agencies, such as the Center lor Population
Research of the US National Institute of Child Health
and Human Development (US NICHD) and the Indian
Council of Medical Research (ICMR); and private re
search organizations usually receiving both public and
private funds, suc h as the Contraceptive1 Research and
Development Project (CONRAD), the Population Coun
cil, and Family Health International (FHI). Many of these
organizations receive support from the US Agency for
International Development. These organizations often
collaborate with each other, with the pharmaceutical
industry, and with other independent research institu
tions such as university centers (16).
Nonprofit research organizations (ace the same prob
lems as pharmaceutic al manul.iclurers in meeting na
tional regulations and obtaining US liability insurance.
In addition, because they often have sman_budgets and
I no distribution systems, nonprofit organizations must
I develop and maintain dose1 working relationships wnh
I governments and manufac turers.
'Calls are increasing for a simplified, more flexible approacli to drug regulation (5.1, 142, 252). In early 1987
WHO convened a meeting to discuss new guidelines
for toxicological studies of steroidal contraceptives.
The draft guidelines stress a flexible approach, in which
the characteristics ot the1 drug govern the design of
animal studies and clinical trials. They also stress the
need for systematic, long-term postmarketing sur
veillance. WHO has been invited to present the pro
posed guidelines to US FDA. Meanwhile, reform of
liability insurance in the US is being proposed (8, 244).
I Until such changes are made, however, new methods
I of contraception will still take many years to reach the
public.
POPULATION REPORTS
f
one .u elate (MI’A), the hormone in DMPA, is derived Iron)
the natural hormone progesterone. DMI’A is pre] .ned in a
nrii ror rystallino suspension. Thus tire hormone is not ahsoiberl immediately alter an mjectiim. the usual close ol
DMPA is 150 mg every three months. Six-month regimens
of 250 to ■150 mg DMPA are less widely used. The progestin
Ni l LN is derived from testosterone. Nil IN is prepared
in an oily solution. A 200 mg injection is effective for up to
12 weeks.
Effectiveness
Both DMPA and NET EN are highly effective contracep
tives. With the standard regimens, pregnancy rates are
usually lower than one per 100 woman-years for DMPA
and two per 100 woman-years for NET-EN (see Population
Reports, Long-Acting Progestins—Promise and Prospects,
K-2, May 1983). Unplanned pregnancies are rare because
both injectables suppress ovulation in the great majority of
cycles and because a woman needs only to obtain the next
injection at the right time in order to assure continued
effectiveness.
Several different regimens of DMPA have been used. In a
recent randomized trial of two DMPA doses, none of the
women receiving the standard 150 mg dose conceived,
but the pregnancy rate among women receiving 100 mg
every three months was 0.44 per 100 woman-years (268).
With higher doses and a longer injection interval—250 to
450 mg every six months—pregnancy rates have ranged
from 0 to 3.6 pei I00 woman-years (150, 162, 200, 214).
NET EN is given in both 2-month and 12-week regimens.
With the 12-week regimen, the first three 200 mg injec
tions are given at 8-week intervals, and subsequent injec
tions are given at 12-week intervals. The 2-month regimen
is markedly more effective. Two-year cumulative life-table
pregnancy rates with the 2-month regimen range from 0.4
to 1.8 per 100 women (112, 266, 271). In contrast, with the
12-week regimen 2-year rates as high as 6.6 per 100 women
have been reported (112,271). The World Health Organiza
tion (WHO) now recommends that NET EN be given at
intervals no shorter than 46 days and no longer than 74
days (about 7 to 10 weeks) (67). Schering AC, manufacturer
of NET EN, notes that contraceptive protection is not ade
quate if more than 12 weeks passes between injections
A pamphlet from the Philippines shows interested women learn
ing about Depo-Provera (DMPA). Depo-Provera is the most popu
lar long-acting progestin contraceptive, used by nearly 4 million.
The pamphlet was prepared by Kabalikat ng Pamilyang Filipino.
and recommends the 2-month regimen if the 1? week
regimen is not possible (61).
Administering injectables in the first week of the men
strual cycle provides the greatest protection against preg
nancy. It also ensures that the woman is not already preg
nant at the time of the injection. Injections after the first
week may not prevent ovulation in that cycle, increasing
the risk of pregnancy (227). In a Thai study involving almost
8,000 women, the pregnancy rate after one injection
among those who received DMPA in the first eight days of
their cycles was 1.6 per 100 women compared with 6.2 for
those who received the injection between the ninth and
twenty-eighth days of their cycles (84).
There are few known contraindications to progestin-only
injectables. WHO recommends that women should not
use injectables if they are pregnant, have cancer of the
breast or genital tract, or have abnormal uterine bleeding
(259). WHO also recommends that, before giving injecta
bles, health workers carefully consider the standard con
traindications to combined estrogen-progestin oral con
traceptives, even though it is not certain how applicable
Table 6. Characteristics and Status of Long-Acting Injectables as of March 1987
Hormone
Development
& Testing
Duration
of Action
Status of
Animal
Trials
DMPA
Upjohn
3 fhonths
Completed
Company
(150 mg depot
medroxyprogesterone
acetate)
Completed
Schering
2 months
NET EN
(200 mg norethinAC
or 12 weeks
drone enanthate)
Underway
HRP002
WHO HRP
3 months
(6.25, 12.5, and 25 mg
levonorgestrel
butanoate)
Completed
HRP011
WHO HRP
2 months
(20, 40, and 60 mg
levonorgestrel
3-oxime cyclopenlyl
carboxylate
WHO HRP = World Health Organization Human Reproduction Program
POPULATION REPORTS
_____Status of Humin Trials
Phase III
Phase I
Phase II
Availability
Completed
Completed
Completed
Approved in over
90 countries
Completed
Completed
Completed
Approved in over
40 countries
Completed in
3 sites in 50
women
Will begin
in mid-1987
Underway in
3 sites in 30
women
Will begin
in early
1988
Expected to be
available for pre
registration studies
in 1992
Mid-1990s
K-71
the
< hat
re. In addition, WHO advises that women with
<>i a lu-.loiy <>t diabetes during pregnancy should
be lullpwed caiekilly, Mine some l.iboi.ilmy lesls have
mei DMPA users betaine ptegnanl within 12 months, and
o' er 90 percent, within 24 months. Ihese tales are similar
hi those among funnel users ol oial < onlr.H cptives or
shown that DMPA alters carbohydrate metabolism (2.59).
IUDs (IZt>). I low long .1 woman lias used I IMI'A ami
Menstrual Changes
whether she has already had a child do not affect the,
speed with which letltltly returns (159, 176, 215).
Changes in menstrual patterns are the most common and
troublesome side effect of DMPA and NIT TN. Over twothirds of women using DMPA and over one-half of women
using NLT LN have no regular cycles in the first year of use
CIO, 37, 43, 240, 267). Women may stop menstruating al
together (amenorrhea), have very irregular bleeding or
spotting, or experience, changes in the duration or amount
of blood flow. Of these, amenorrhea is the most common
and occurs more often with DMPA. During the first year of
use about 55 percent of DMPA users do not menstruate for
90 days or more, compared with about 30 percent of NET
EN users (41, 130, 271). As women continue using injectables, fewer experience intermenstrual bleeding and spot
ting. and more experience amenorrhea (271).
Very heavy or prolonged bleeding, a potential health
threat, is uncommon (76, 130, 150, 272). In a WHO multi
center trial, for example, only 6 of 1,200 women (0.5 perreni) needed treatment for heavy bleeding in almost
14,000 women-months of use (272). Similarly, in a 12month field trial in Pakistan, only one of 2,147 women
required curettage for prolonged bleeding (130).
Generally, amenorrhea and light bleeding or spotting do
not require any medical treatment. Most family planning
providers find that they can allay women's concerns by
counseling them before an injection and reassuring them
if menstrual changes occur. Oral contraceptives or supple
mental estrogens to regularize menstrual bleeding are not
prescribed routinely (76, 259). Very heavy or prolonged
bleeding, however, does require medical attention. WHO
recommends either (1) one >mbined oral contraceptive
daily for 14 days or (2) an intramuscular .ejection of a
synthetic estrogen—5 mg estradiol cypionate or estradiol
valerate (261).
More women stop using injectables because of menstrual
disturbances than for any other reason. In recent trials 6 to
30 percent of women discontinued the method in the first
year because of changes in bleeding patterns (112, 130,
199, 251, 266, 270). Discontinuation rates vary widely, per
haps because of different cultural and religious attitudes
toward menstrual disturbances or because of the varying
availability of counseling and follow-up.
Reproductive Effects
Neither DMPA nor NET EN appears to have any permanent
effect on fertility. With both injectables, however, women
may not ovulate or conceive for several months after dis
continuation. This delay has caused concerns about rever
sibility, particularly with DMPA. Because of fears that
DMPA might cause permanent infertility, some national
family planning programs do not allow women Io use
DMPA unless they have had al least one child (133).
The contraceptive effect of DMPA often lasts well beyond
thre months. In the largest study to date the median time
to conceive after a DMPA injection was 9 months, or 5!6
months after the end of the presumed duration of effec
tiveness. Despite this initial delay, over 60 percent of for-
K-72
With NET EN, return of terlilily also can be delayed. In a
recent study of 69 women who stopped using NET EN to
become pregnant and who were followed for a year, aver
age time to conception was longer than among 92 former
TCu-200 IUD users. After one' year, however, 73 percent of
former NLI LN users and 114 perc ent ol former IUD users
had conceived. The difference is not statistically signifi
cant (289). In an earlier studv of 40 women, 78 percent
conceived within 12 months alter the last injection (74).
Most women ovulate within four months after discon
tinuation (72, 77, 253, 255). As with DMPA, duration of use
does not affect how quickly fertility returns (74).
Questions have been raised about possible harmful ef
fects on children exposed to injected progestin contracep
tives either in utero or during breast-feeding. Several stud,
ies in the 19. <>. reported no increase in birth defects or y/''.
prematurity when pregnant women were inadvertent^^ / j
161, 247). In a rec
What Providers Should Know
About Long-Acting Injectables
The standard regimens are 150 mg DMPA every
three months and 200 mg NET EN every two
months or 12 weeks.
2.
Injectables are very effective. Failure rates are
usually less than one or two percent.
3.
The weight of available evidence suggests no
increased risk of cancer with DMPA. Whether
NET EN affects risks of cancer in women has not
been studied.
4.
Injectables change menstrual bleeding patterns.
From 30 to 60 percent of users develop amenor
rhea.
5.
Medical treatment for menstrual irregularities^^
not necessary unless a woman is bleeding ve^^
heavily. This complication is quite rare.
■ 6. Women may be infertile for four to nine months
or more after an injection. Fertility returns even
tually, however.
7.
Injectables do not seem to interfere with breast
feeding. The small amounts of hormone in
breast milk do not appear to harm the infant.
8.
Before receiving an injection, women must be
aware that any side effects may persist for the 2or i-month period ol effectiveness and that re
turn of fertility may be delayed.
9.
If possible, injectables should be given during
the1 first week of the menstrual cycle to insure
that the woman is not already pregnant.
10.
Injectables have beneficial health effects. They
often increase blood iron levels, and they ap
pear to help protect against pelvic inflammatory
disease and ovarian and endometrial cancer. ‘
1.
POPULATION REPORTS
. users ol DMPA were (wo times more likely to have peIlphei.ll limb defer ts anil .iliolil live lunes in..... likely Io
have chromosomal abnormalities than children ol women
who used no conlrar option. Interpreting Ihese results is
/ difficult, in part beta.a e the number ol cases is small and
in some cases exposure long preceded pregnancy (177).
• Preliminary analysis from a study in Israel, involving nearly
200 adolescents who were exposed in ulero to medroxyI progesterone acetate and over 950 controls, found no
evidence of retarded or precocious development or any
I,disturbance in sexual development, sexual behavior, or
■growth among those exposed (101). These studies in
Thailand and Is.rael, supported by WHO and Family Health
International (FHI), are continuing to look at children ex
posed in utero to DMPA, medroxyprogesterone acetate
(MPA), or oral contraceptives (261).
The very small amount of hormone transmitted in breast
milk appears to have no effects on children even when
followed up to 10 years (127, 129, 247). A Chilean study
found that a higher percentage of DMPA users' four-yearold children weighed below average than did nonusers'
children. The researchers attributed this difference to fac
tors other than DMPA use, since the mothers using DMPA
were older, had more children, and had breast-fed their
children longer (127).
Cardiovascular Effects
Unlike oral contraceptives that contain estrogen, DMPA
and NET EN appear to have little effect on the cardiovascu
lar system. There have been very few reports of blood
clots or other cardiovascular complications in women
using injectables, but adequate epidemiologic studies
have not yet been conducted. In the laboratory most stud
ies find no change in blood pressure or in the coagulation
and fibrinolytic systems that affect blood clotting (111,150,
258).
Effects on lipid metabolism are less clear since long-term
studies are not finished. Most reports find either no
change in total cholesterol and triglycerides or a decrease,
a possibly beneficial effect (11, 12, 63, 88, 150, 167, 242,
262). In contrast, a few studies report an increase in cho
lesterol with longer use of DMPA (149) or a decrease in
high-density lipoproteins (HDL), both possibly adverse ef
fects (128, 138). The only study involving NET EN also
found a decrease in HDL (73). Because NET EN is chem
ically similar to testosterone, it is likely that it would re
duce HDL levels slightly. Whether the small decreases in
j HDL sometimes seen in women using injectables have any
I clinical importance is not certain. WHO trials are underIway in five countries to measure lipid metabolism in
women using DMPA and NET EN for short and long peri
ods (260).
Cancer
Questions about whether long-acting injectables cause
cancer have aroused controversy. This is the main reason
that DMPA has not been approved for contraceptive use in
the US. These questions have arisen because (1) two spe
cies of laboratory animals—beagle dogs and rhesus mon
keys—given large doses of DMPA or NET EN, usually for
long periods, have developed benign and malignant tu
mors of the breast or endometrium (lining of the uterus)
(61, 75, 247, 264) and (2)-until recently human studies have
POPULATION REPORTS
A pamphlet from the Sierra Leone Home Economics Associa
tion reminds women that DMPA works for three months.
been limited. Questions about the relevance of animal
studies to humans are still unresolved (2, 62, 70, 104, 264,
272).
. Two recent studies of women, however, provide some
iS reassurance that DMPA does not increase the risk of sev
eral types of cancer. WHO conducted a case-control study
•'involving over 1,500 cases and over 5,800 controls in
Kenya, Mexico, and Thailand. The US Centers for Disease
Control and other organizations conducted a smaller
study in Costa Rica involving over 700 women with breast
lam er, invasive cervical cancer, or cervical carcinoma in
situ and over 760 controls. Like otiier epidemiological and
clinical research in the US, Canada, and Thailand (66, 86,
148, 163), the WHO case-control study found no link be
tween DMPA use and cancer of the breast, endometrium,
ovary, or liver (263). In fact, like oral contraceptives, DMPA
may help protect against cancers of the ovary and endo
metrium (see Table 7).
The Costa Rican study found a two-fold greater risk of
breast cancer among former DMPA users than among
Table 7. Risks of Various Cancers and DMPA Use, World
Health Organization 3-Country Case-Control Study, 1986
Site of
Cancer
No. of Cases
Who Used DMPA/
All Cases (%)
No. of
Controls Who
Used DMPA/AII
Controls (%)
Relative Risk
for Women
Who Have Ever
Used DMPA
*
1.0
Breast
39/427 (9)
557/5,951 (9)
545/5,833 (9)
1.2
Cervix
126/920 (14)
Ovary
74/637 (12)
0.7
7/105 (7)
Endometrium
30/316 (9)
1/52 (2)
0.3
Liver
34/290
(12)
1.0
7/57 (12)
•Adjusted for center and for factors known to affect cancer risk. None of
these relative risks is significantly different from 1.0.
Source: World Health Organization (23b)
K-73
■ i<tin.1
ally ‘.ij’iiilu anl (!ilf<T<
*n<
<•. The re*bCdicheij icgaid these lesiilts as mi »»n< hr.ive, Iiiiwi*v<* i
while using DMPA or olhei steroid hormones (Jll,#2,i>0).
lhe number of cases is small—only 19 women with breast
ranter had ever used DMPA Iurlhennorc, (here is no
indication that risk increased with duration ol use, as
might be expected if DMPA caused breast cancer (143).
tract inter lions. A< routing ...... shirty <>l more
*
lli.m 1(H)
women with PID and more than 600 matched controjs,
DMPA useis wen
*
hall as likely as nonusers to develop
pelvic inflammatory disease, a major cause ol infertility
(83). Preliminary reports also suggest th.., DMPA protects
against vulvovaginal c andidiasis, a fungal infection (54). As
noted, DMPA also may lower the risk ol ovarian and endo
metrial cancer.
In the WHO study die risk of invasive cervical cancer
appeared to be slightly higher for former DMPA users than
for controls, but the difference was not statistic ally signifi
cant. The study found that women younger than 36 who
had used DMPA for more than four years were two times
more likely to develop cervical cancer than controls
younger than 36. Interpreting this finding is difficult be
cause the number of cases is small (263). Furthermore, the
Costa Rican study found no increased risk of either invas
ive cervical cancer or cervical carcinoma in situ among
former DMi.. ..sers of any age or with any duration of use
*
(171, 172). While both studies were able to control for
some variables known to influence risk of cervical can
cer -the woman's age at first intercourse and the number
of sexual partners—neither took account of other impor
tant influences—the sexual behavior of the women's part
ners or, in the WHO study, smoking (171, 172, 263).
Beneficial Effects
Like oral contraceptives, injectables have several bene
ficial effects in addition to preventing unplanned preg
nancy. Ilenipglobin levels often increase
*
in women using
DMPA or NET EN (42, 107, 262). This may help to prevent
anemia, a common problem among women in developing
countries. In addition, some women with sickle-cell dis
ease have less pain and fewer abnormal red blood cells
HMI’A .it
*.<>
*.ii'.
.i|>|>i
1.1 pioii-c I against some reproductive
Continuing Controversy Over DMPA
DMPA has been the subjec I of debate
*
for many years. On
one hand, critics argue that DMPA is unsafe because it
causes cancer in some laboratory animals and because not
enough is known to rule out long-term risks to women.
They also are concerned that injectables—because they
are so easy to administer—may be given to women with
out proper precautions and full informed consent (106,
145). On the other hand, supporters of DMPA point out
that epidemiological and clinical studies provide no clear
proof of increased risk ol canc er or other harmful effects
among DMPA users and that the
* relevance of animal tests
to humans is uncertain. In addition, they argue^fce
known benefits of DMPA outweigh any plausible risks' as
yet undetected (27, 259).
The ongoing debate has prevented the marketing of
DMPA as a contraceptive in the US. In 1967 the Upjohn
Company lirsi applied to lhe US Food and Drug Adminis
tration (US FDA) lor approval to market DMPA as a contra
ceptive. Elec • > years later, in 1978, the US FDA formally
denied approval even though its own Obstetrics and
Tests Underway on New Long-Acting Ester Injectables
A .12-year collaboration between the World Health Or
ganization (WHO), lhe US National Institute of Child
Health and Human Development (US NICHD), and sci
entists throughout the world has led to several new
injectable compounds that may prevent pregnancy for
two or three months.
In 1975 WHO convened a group of chemists and biolo
gists to begin the development of new contraceptive
steroids. Research focused on two progestins—norethindrone (NET) and levonorgestrel—that had already
been shown to be safe and effective in humans. The
scientists synthesized over 230 esters derived from NET
or levonorgestrel. (Ah ester is a combination of a
steroid and an acid.) US NICI ID then tested these com
pounds in animals. Four compounds, all derived from
levonorgestrel, were selected for further k .ung be
cause they consistently inhibited ovulation in animals
and also appeared to be long-acting (99).
The WHO Human Reproduction Program is conducting
studies of two of the four new compounds in women to
find the lowest effective dose (31) (see Table 6). Trials
with one compound—designated HRP002—suggest
that a 20 mg dose will prevent ovulation (or three
months (260). Preliminary effectiveness trials are
planned to begin in 1987 (97).
The appropriate dose for the second compound,
HRP011, has not yet been established. This compound
K-74
is chemically similar lo another progestin, norgestimale, that does not cause marked endometrial or men
strual changes in animals (see p. K-68). WHO plans to
begin small effectiveness trials of HRP011 in women,
which will determine whether it will have less effect on
. bleeding patterns than DMPA and NET EN (97). Initial
studies of HRP01I in a small number of women in the
| US are being planned for late 1987 (31).
The Contraceptive Development Branch of US NICHD
has completed 2-year toxicology studies of HRP011.
Studies in rats and monkeys with low, intermediate,
and high dose's—up to 50 times the human dose—
show no harmful effects (31).
These new compounds have several important advan
tages over existing injectables. Because of the chemical
properties of esters, the new injectables are released
from lhe ifijec lion site al a fairly constant rate, without
the initial high release that occurs with DMPA and NE T
EN. In addition, unlike the injectable microspheres,
which also have fairly, constant release rates, the new
injectables can be administered in a simple aqueous
microcrystalline suspension like that used for DMPA.
Thus they ran be manufactured easily and inexpen
sively. Like DMPA and NL1 LN, they will be admin
istered with a simple injection. Thus many different
’types of health workers could administer these new
contraceptives without special training.
POPULATION REPOS
CHILD SPACING METHODS IN MALAWI
\.lll< \ /(Uli \N1»1Z \ RULER \ M'\l \l. \\\ I
CK - <
Injectable contraception is one of several child-spacing meth
ods in Malawi. Because many health workers know how to
give injections, this method can be easily and widely offered.
I■
'
I
I
Gynecology Advisory Committee had twice recommended I
approval for certain groups of US women. In 1983 a Public '
Board of Inquiry, especially convened at the request oLthc.
Upjohn Company, conducted hearings to reconsider the
US FDA's decision and make a recommendation to the
Commissioner of the agency. The Board consisted of three
scientists jointly selected by Upjohn and the US FDA. In
late 198-1 lhe Board released its conclusions. Two of the
three members concluded that there was insufficient evi
dence to prove that DMPA was safe for general marketing
in the US (254). The third member recommended that
DMPA be approved for use by women who could not use
other methods (209). To date, the Commissioner of the US
FDA has not acted on these recommendations, and the
future of DMPA in the US remains uncertain. In 1986 the
Upjohn Company r« opened the issue by submitting new
data on the safety of DMPA, including the WHO study
results on cancer. Upjohn plans to submit a new applica
tion for approval of DMPA (59).
Since 1980 regulatory agencies tn Sweden, lhe UK, I rance,
and West Germany have approved DMPA for contracep
tion (246). Also since 1980, several national and interna
tional scientific groups have endorsed DMPA, including
the Toxicology Review Panel of the WHO Special Pro
gramme of Research, Development and Research Training
in Human Reproduction (the Human Reproduction Pro
gram) (259) and the International Medical Advisory Panel
of the International Planned Parenthood Federation (120).
Currently, the US Agency for International Development
does not distribute DMPA because jt is not approved for
contraceptive use by the US FDA. International donors are
providing DMPA and NET EN to family planning programs
in countries where these injectables have been approved
(see p. K-78).
MONTHLY INJECTABLES
Monthly injectables are widely used in Latin America and
China. They consist of an estrogen and a progestin com
bined. They are highly efl. . live, but questions about the
safety of the products sold in Latin America have not been
resolved, and the formulation used in China has not been
thoroughly studied. The World Health Organization
POPULATION REPORTS
(WHO) is tunenlly supposing reseau h on two new
monthly injei tables they .ippi-.u to bo <■((<•< live and safe
atitl may !»«-< <»in<- uv.iil.ihh- .i.
I'lHH
Istiogen progestin combinations injected monthly have
certain advantages over 2- ot (-month progestin-only in
jectables (96). They produce regular bleeding episodes
each month and cause- less spotting and other bleeding
irregularities. Also, they are less likely to cause amenor
rhea, which women may fear is a sign of pregnancy. Many
women in a Mexican study said that they preferred
monthly injectables because lhe monthly bleeding re
minded them to return for another injection. They
thought that remembering the dale of their last injection
over a 2- or 3-month period would be too difficult (64).
Also, if women experience side effects and want to dis
continue use, the side effects of monthly preparations/
generally subside more quickly than those of longer-acting
injectables (222, 243). hi~lalin America pharmacists may
promote monthly injectables because they can give the
injections every month. Also, women may be able to pay
for a monthly injection more easily than saving for a more
expensive longer-acting injection.
Monthly injectables have certain disadvantages as well.
These include the inconvenience of more frequent injec
tions, the higher total cost of 12 rather than 4 or 6 injec
tions pel year, and possible side ellecls ol lhe estrogen
component in some preparations (222, 296).
Two Preparations Now Available
Two estrogen-progestin formulations are currently in use:
(I) a combination of 75-150 mg dihydroxyprogesterone
acetophenide and 5-10 mg estradiol enanthate,
used primarily in Latin America, and
(2) a combination of 250 mg 17-hydroxyprogesterone
caproate and 5 mg estradiol valerate, used only in
China.
lhe lirst preparation is now used by an estimated 300,000
women in Mexico and perhaps as many more in other
Latin American countries. The preparation was originally
developed by Squibb Pharmaceutical Corporation, which
called it Deladroxate. Squibb no longer manufactures Deladroxate. The similar preparations currently marketed are
manufactured by several small companies in Latin America
and sold under various brand names including Perlutal
and Agurin (80, 98, 204) (see photo, p. K-76). In the US,
Squibb Pharmaceutical Company withdrew Deladroxate
from clinical testing in the late 1960s because of concerns
over (1) breast tumors in beagle dogs, (2) pituitary hyper
plasia in rats, and (3) p»■ ible accumulation of estradiol
enanthate in the body with continued use (89, 98, 243).
Subsequently, however, questions have been raised about
whether such animal findings are applicable to humans.
Research suggests that the adverse effects of Deladroxate
on animals may occur only with doses higher than the
equivalent of a contraceptive dose (2, 62, 82, 121, 272).
In clinical tests of 150 mg dihydroxyprogesterone
acetophenide and 10 mg estradiol enanthate involving
nearly 23,000 cycles in 2,400 women, no pregnancies were
reported. Between 8 and 26 percent of women stopped
using this injectable because of bleeding problems (29,
80). Return of ovulation may be delayed slightly (131). Little
K-75
Table 8. Characteristics and Status of Moodily Injectahles as of March 1987
Hormone
Development
& Testing
Duration
ol Action
Animal
Tria:
Phase I
WHO IIRI’,
I month ( omplcl' <1 ( oinplrlrd
Cycloprovera
(25 mg DMPA & 5 family Health
mg estradiol
International
cypionate)
HRP 102
WHO HRP,
l ompl«
*le<l
( omplrled
(50 mg NET EN &
family Health
5 mg estradiol val International
erate)
WHO HRP - World Health Organization Human Reproduction Program
other research is available on any aspect of the monthly
preparations currently marketed in Latin America.
Some are concerned that the synthetic estrogen in the
Latin American products may build up in the body over
time. This could contribute to the delay in return of fertil
ity after discontinuation or cause unforeseen toxic effects
(223, 243). Although no such effects have been reported,
very little research on estrogen accumulation in women
has been done. One study in four subjects found an
apparent accumulation of estrogen (89). Anothe. iound no
significant accumulation in six subjects (201). To avoid es
trogen accumulation, half doses on< <
• nth have been
tried, and some companies in Latin America sell them
(204). The lower doses prevent pregnancy effectively but
sv.. rely disrupt menstrr il patterns (201).
In China a formulation called Injectable
*
Number I ac
counts for less than one percent of all contraceptive use. A
woman who uses this method receives two injections the
first month and one injection every month thereafter (109,
178). The major obvious disadvantage of Injectable Num
ber 1 is that it causes very short cycles and prolonged
menstrual bleeding (243). Few toxicology and use-effec-
Human trials
Phase II
Phase 111
Availability
Inst ,ippio\«ils ex
peded in early 1990s
women
tinder way .it 1/
sites in 1,200
women
sites in 200
women
Undciw.iy al I ■'
cites in 1,200
women
Ins! approvals ex
petted in early 1990s
tiveness data on Injectable Number I are available, how
ever. It is not used oulside China.
Two New Preparations Studied
Two other estrogen-progestin injectahles provide virtually
complete contraceptive protection and excellent men
strual cycle control. Both are being tested and may be
marketed soon. They are:
(1) Cycloprovera, a combination ol 25 m^jfepot
medroxyprogesterone acetate (DMPA) and ^^g es
tradiol cypionate, and
(2) HRP102, a combination of 50 mg norethindrone en
anthate (NET EN) and 5 mg estradiol valerate (80, 98,
243).
Currently, the World Health Organization (WHO) and
family Health International (I HI) are about to complete
trials of Cycloprovera and HRP102 involving about 2,400
women in three countries. Preliminary results show that
both formulations are highly effective. Among women re
ceiving Cycloprovera, only one pregnancy occurred in the
first 655 woman-years of use. With HRP102, in 648 womanyears ol use four women have become pregnant, but two
may have been pregnant when they received their first
injections (288).
In early trials both preparations have produced bleeding
patterns like normal menstrual cycles (.1, 71, 113, 116).
Only the Philippine center has reported detailed results:
most women receiving HRP 102 for one year experienced
unchanged bleeding patterns, while those r^kivmg
Cycloprovera tended to have somewhat shorter, leWneavy
bleeding each month (96). In the first nine months of the
WHO/FHI multicenter trials, less than 5 percent of partici
pants have slopped use due to bleeding irregularities, anc
less than 2 percent, for amenorrhea (96, 97, 288).
Side etlects other than bleeding problems have beei
minor with both Cycloprovera and HRP 102. Slight weigh,
gain is common with both (28, 46, 80). Since both can bi
detected in the blood lor as long as three months after ai
injection, there may be some delay in the return of iertilit
after discontinuation (28, 71, 98, 134). The only available
study to date involved 18 Thai women who discontinue'
Cycloprovera to become" pregnant. Seven became preg
nanl by 3 months, and 7 more by 18 months (80, 135).
Various monthly injectahles consisting ol a progestin and an
estrogen are sold in Latin America. Little research has been
done on these formulations. Two new monthly injectahles.
developed by WHO, may be introduced by some family plan
ning programs through preregislration field trials in early 1988.
K-76
Cycloprovera and HRPI02 are not currently marketed. Sev
eral national family planning programs are planning pre
registration field trials beginning in early 1988 (97). Alon}
with the microspheres, microcapsules, and new long-act
ing esters, these new monthly injectahles will comprise j
new generation ol injectable contraceptives.
POPUl ATION REPORT
Provera have increased steadily in recent years, from about
USE OF INJECTABLES
million doses in I'ltl.’ enough Io piolerl I II million
women lor a year to .ihoul In 6 million doses in I986
enough Io pioiei 1 mole (haii -I million women (see table
hipn tables ait
* Lunenlly the only widely used long-acting
10). Limited quantities ol DMPA are produced by a number
of manufacturers apait liom Upjohn.
hormonal contraceptive. An estimated 6.S million women
are using them. About live million ol these women use the
longer-acting injectables, DMPA or NET EN, and the re
maining 1.5 million—mostly in Latin America and China—
use various monthly injectables (97, 109, 212). According
to surveys (see Table 9) and production and .ales data,
injectables are most widely used in Jamaica, Thailand,
Indonesia, Mexico, New Zealand, and China.
NET EN, marketed by Schering AG as Noristerat, also is
widely used. It is approved in more than 40 countries.
Schering AG reports that sales have been increasing
rapidly. The company sold about one million doses in 1981
but in 1986 sold almost five million—enough to protect
800,000 women for a year (69) (see Table 10).
DMPA, marketed as Depo-Provera by the Upjohn Com
pany, is the most widely used injectable. It is approved as a
contraceptive in more than 90 countries and has been
used in some for as long as 20 years (246). Sales of Depo-
The overall estimate of 6.5 million users is based on family
planning survey data, program statistics, donor agency
shipments, and manufacturers' sales. A precise estimate is
impossible because: (I) representative sample surveys do
Table 9. Percentage of Married Women of Reproductive Age Using Injectable Contraceptives,
as Reported in Representative Sample Surveys, 1974-1984
Region &
Country
AFRICA
Botswana
Burkina Faso
Kenya
Lesotho
Nigeria
Sudan (north)
Zaire (urban)
Kananga
Kinshasa
Kisangani
Lubumbashi
Zimbabwe
ASIA & PACIFIC
Bangladesh
Fiji
Hong Kong
Indonesia (lava
& Bali)
Indonesia (urban)
Jakarta
Medan
Semarang
Surabaya
Ujung
Korea, Rep. of
Malaysia (peninsular)
Nepal
Philippines
Sri Lanka
Year
1984
1986
1977-78
1984
1977
1981-82
1978-79
1982-84
% Using
% of ConlraAny
Inject ceplors Using
Method ables
Injectables
29
13
7
17
5
5
<0.5
1
l
■ <) s
4
9
9
»
.i
<0.5
<0.3
2
3
1984
1979-80
1974
1982
1976
9
42
72
28
<0.5
<0.5
3
0.5
44
36
54
46
33
37
54
35
7
5
13
1
I
Costa Rica
4
1
1983
1974
1979
1974
39
34
57
36
52
59
65
5
<0.5
<0.5
'<0.5
<0.5
<0.5
<0.5
2
2
5
7
8
25
26
26
20
<0.5
<0.5
<0.5
<0.5
1981
1978
1975
1982
Thailand
1975
1978
1981
1984
MIDDLE EAST & NORTH AFRICA
1980
Egypt
Jordan
1976
1983
Morocco
1979-80
Yemen Arab Rep.
17
13
24
8
<0.5
1
1
<0.5
Dominican Republic
Ecuador
El Salvador
Guatemala
Guyana
Haiti
Honduras
Jamaica
Mexico
3
6
9
12
12
<0.5
9
<0.5
<0.5
Year
1978
1978
1983
1979
LAIIN AMERICA & CARIBBEAN
Barbados
1980-81
Bolivia
1983
9
4
<0.5
1
Syria
Tunisia
Amazonas (urban)
Northeast region
Sao Paulo
Southern region
Colombia
<0.5
36
19
36
40
Region &
Country
Panama
Paraguay
Peru
Trinidad & Tobago
Venezuela
% Using
% ol ContraAny
Inject ceptors Using
Method ables
Injectables
>
20
I
J2
’.0.5
1
42
<0.5
1
4
<015
47
26
1982
1980
1978
1981
r. t
17
66
66
1978
1980
198b
1976
1978
1981
1975
1981
1979
1978
1978
1983
1975
1983
1981
1975-76
1983
1976-77
1978
1979
1982
1976
1979-80
1977
1979
1977-78
1981
1977
1977
48
51
63
67
65
(>(>
3.3
47
14
18
25
35
7
'»7
40
40
48
62
j1
39
<0.5
5
-
• 0.5
<0.5
<0.5
<0.5
05
<0.5
<0.5
1
1
>
‘.0.5
• 0.5
<0.5
1
< 0.5
<0.5
• 0.5
<0.5
7
8
>
3
3
5
1
1
z
I
43
I
49
<0.5
• 0.5
i
4
J
>
<015
- 0.5
.1
1
6
1
1
•)
i
17
15
6
7
7
11
1
•>
•>
4
2
<0.5
Source: London el al. (153), except Burkina Faso 1986: Burkina Faso (282); Kenya 198-1: Kenya Central Bureau ot Stalistiis <2911; Colombia 198(> and Mexico
1982: Ochoa (294); and Thailand 1984: Chamratrithirong et al. (39)
POPULATION REPORTS
K-77
lablc Id. Worldwide Sales ol Drpo 1’iovcia ISO (DMI’A)
and Noristeral (NET EN), 1975-86
Year
Ihousands ol Doses Sold___
Depo-Provera
Noristeral
4J8b
1975
1976
4,079
28
1977
4,7bb
78
|5
1978
7,041
1979
(>.880
7,028
1980
557
1981
6,788
1,035
1982
7,362
1,418
1983
10,066
1,441
1984
15,628
2,485
1985
14,527
4,100
1986
16,500’
4,800’
'Estimated
Source: Schering AG (69, 213); Upjohn International (33, 58)
not cover all countries, and most surveys are now at least
several years old; (2) program statistics on new clients are
a poor indicator of prevalence, since discontinuation rates
are not reported; (3) donor agency shipments and sales by
manufacturers do not reliably indicate current use be
cause largi hipments are typically delivered in one year
and used over the course of two or three years.
Among countries with surveys of contraceptive use (see
Population Reports, Fertility and Family Planning Surveys:
An Update, M-8, September-October 1985), Jamaica has
the highest percentage of women using injectables. In
1983, 8 percent of married women of reproductive age, or
15 percent of all conlr.u eptors, used DMI’A. One-third of
married women of reproductive age had used injectables
at some time (212). There is some evidence that usage may
have been higher previously. Family planning clinic rec
ords indicate that the percentage of new clients choosing
injectables fell from 34 percent in 1976 (17) to 27 percent in
1983 (212). Also, a 1984 Pan American Health Organization
study found overstocks of injectables in many clinics (248).
In Thailand DMI’A has been available foi more than 20
years. I he government family planning program has of
fered DMPA since 1979 and NET EN since 1984 (212). Ac
cording to the 1984 Contraceptive Prevalence Survey, in
jectables were the third most widely u d method, after
oral contraceptives and voluntary female sterilization. Be
tween 1981 and 1984 the percentage of married women of
reproductive age using injectables changed little, rising
from 7.1 to 7.6 percent. In both years about 12 percent of
contraceptors used injectables. (39). In 1984 well over
400,000 women were estimated to be continuing users,
and in 1985,26 percent of new
*clients
in the national family
planning programs chose injectables, mostly DMPA (133,
212).
Injectables are widely used in Indonesia, even though the
government has promoted IUDs and oral contraceptives
rather than injectables (117). In 1983 in one Indonesian
city, Semarang, 13 percent of married women of reproduc
tive age—almost one-fourth of all contraceptors—used
injectables. ■ .uonally, as many as 10 percent of conIraceptors used them. DMPA was introduced in 1967, but
the government family planning program did not distrib
ute it until 1978. NET EN also is available, but its use has
been restricted to specific areas Io prevent confusion with
DMPA, since NET EN does not last as long as DMPA (212).
Noipl.uil implanl'. h.ive lii'ei) .n.ul.ibli' ihiniii'k the n.i
Iional family pl,inning piogiain suite I9II(>, and u.w is'
growing rapidly (sec p K 1,-1).
In Mexico about 5 peri ent of married women of reproduc
tive age, oi It pen ent ol < initial eptois, use injet tables,
according to a 1982 national survey. Various monthly uijectables account for about 80 percent of injectables sold.
Both DMPA and Nt I I N aie available, with NI I EN more
popular. Controversy; ovei DMPA has suppressed sales.
Most women obtain injections at pharmacies (204). The
demand for injectables is higher in rural than in urban
areas (204, 212, 294).
In New Zealand an estimated 4 percent of married women
of reproductive age use DMPA. This may be the highest
level of use in any developed country. Depo-Provera has
been used in New Zealand for almost 20 years. Sales in
creased steadily from the late 1960s to 1982, when about
86,000 doses were sold. Perhaps partly due to a highly
publicized controversy over whether the injectable causes
serious side effects, sales fell to about 80,000 doses in
1983. In 1986, however, sales had again neared 86,000
doses (110, 207).
In China production figures suggest that just under one
percent of married women of reproductive age, or slightly
more than one percent of contraceptors, use the monthly
Injectable Number I, which is manufactured by the gov
ernment. A variety ol other monthly preparations are in
clinical trials (109, 273). The one million Chinese women
estimated to be using monthly injectables account for
about one-sixth ol .ill women using injec tables worldwide.
There have been reports that use of Injectable Number 1
has been declining recently (97).
Donor Agency Supplies of injectables
The United Nations Fund for Population Activities (UNFPA)
and the International Planned Parenthood Federation
(IPPF) are the major international donors of injectable con
traceptives. Between 1981 and 1986 they supplied about
5.1 million doses ol DMI’A—enough Io protect 320,000
women each year—and 1.5 million doses of NET EN
enough to protect 60,000 women each year.
DMPA accounted for about 90 percent of the injectf^s
provided by IPPF and 70 percent of those provided by
UNFPA, and NET EN accounted for the remainder. Of
DMPA, over half of IPPF supplies and almost 40 percent of
UNFPA supplies went to countries in sub-Saharan Africa.
Three countries—Nigeria, Zaire, and Kenya—received al
most one-fourth of the DMI’A shipped by the two agen
cies. About 40 percent of all IPPF supplies and half of
UNFPA supplies went to Asian and Pacific countries,
mainly to Bangladesh and Nepal. Only about 9 percent of
IPPF supplies and 10 percent of UNFPA supplies went to
Latin American or Caribbean countries, mainly to Jamaica
(123, 245).
Donor shipments of NET EN are smaller. UNFPA shipped
over one million doses, but only to eight countries. Over
95 percent went to Pakistan and Bangladesh (245). IPPF
supplied 32 countries but shipped less than a quarter of a
million doses, three-quarters of it to sub-Saharan Africa
and over half to Nigeria, Rwanda, and Zaire. The i< went
mostly to El Salvador and Mexico (123).
POPULATION REPORTS
INTRODUCING A NEW
CONTRACEPTIVE METHOD
Liboratoiy and clinical research to lest the ellecliveness
and safety of several new implants and injectables will be
completed by the late 1980s and 1990s. But introducing a
new method to the public raises other issues. Without
careful preparation, the new contraceptives may be ig
nored by health professionals and women; unwanted
pregnancies may occur; and complication and discon
tinuation rates may be high. To launch any new method
successfully, developers, manufacturers, and program
managers must carefully consider:
• manufacture and marketing,
• costs and pricing strategies,
• delivery systems,
• training of health personnel,
• communication to providers and potential users, and
• ,-ostmarketing surveillance.
Careful introduction of a new method on a worldwide
basis can require the skills of various organizations as well
as those of individual scientists and service providers in
many countries. For example, to assist with the develop
ment and introduction of Norplant, the Population Coun
cil has worked closely with the International Committee
for Contraception Research, a group of scientists organ
ized by the Population Council; Family Health Interna
tional (FHI); the Program for Appropriate Technology in
Heallh/Progruin for the Introduction and Adaptation of
Contraceptive Technology (PATH/PIACT); the Association
for Voluntary Surgical Contraception; the World Health
Organization (WHO); and the International Planned Par
enthood Federation (IPPF).
Manufacture and Marketing
Because of the shift in contraceptive research and devel
opment away from private commercial firms to govern
ment agencies and nonprofit organizations (see bi • p.
K-70), the process of manufacturing and marketing contra
ceptives is changing. At present, governments, interna
tional agencies, and private nonprofit organizations, such
as the US National Institute of Child Health and Human
Chinese workers package ampoules of Injectable Number I in a
new factory in Shanghai. The factory currently produces injecta
ble contraception for an estimated one million women a year.
(Courtesy of PATH/PIACT)
POPULATION REPORTS
Names for Norplant
How do you translate "Norplant"' Il is nol easy. The
Population ( ouiuil coined the name by combining
paits ol the woids "noigesticl" (the lormei name lor
levonorgestrel) and "implant." But women around
the world have chosen their own names for the
method.
Some names reflect the implants' appearance or
placement. In Ecuador Norplant is called el abanico
("the fan") because the implants are inserted in a
(an-like pattern in the arm. Other names are la mariposa ("butterfly"), los tubitos ("little tubes"), and
sometime- la capsula ("the capsule"). In Sri Lanka
women call Norplant tampatah ("down under"), be
cause the implants are inserted under the skin, or
"sticks" (195).
In Indonesia Norplant gels the name susuk from the
gold or other metal traditionally implanted under
the skin to bestow supernatural power on the user
(5,195). Since Norplant is so widely known as susuk,
this name is now used in pamphlets, posters, and
other educational materials (see photo, p. K-59).
Development (US NICHD), W) IO, the Population Countil,
and fill have taken the lead in developing new long-acting
methods. Such organizations do not manufac tore and dis
tribute contraceptives themselves, however. Thus arrange
ments must be made with commercial firms for large-scale
manufacture and marketing. For example, to produce
both the 6-capsule and 2-rod Norplant systems, the Popu
lation Council has granted an exclusive license to Leiras
Medica/Huhtamaki Oy, an international pharmaceutical
firm based in Finland. The agreement requires that Leiras
charge a lower price to public-sector organizations and
government programs than to commercial distributors
(287).
II is not certain who will manufacture and market the other
new methods. Many of the new long-acting hormonal
methods are being developed initially by nonprofit organi
zations. Private pharmaceutical companies in the US and
Europejiave the first option to market some of the new
long^acting methods such as Capronor, some injectable
microspheres, and some long-acting injectables and own
all rights to other injectable microspheres and capsules.
’Given concerns about product liability, however, particu
larly in the US, drug companies may be unwilling to mar
ket any new contraceptives even though tests prove them
to be safe and effective.
Local production of contraceptives in developing coun
tries is an alternative to international distribution by phar
maceutical firms. In China a factory built with support
from the United Nations Fund for Population Activities
(UNFPA) and technical assistance from PATH/PIACT is de
signed to produce about 30 million doses of Injectable
Number 1 each year (109). DMPA and several monthly
injectables are manufactured or packaged in a number of
Asian and Latin American countries (150). Local production
may be possible for some of the other new long-acting
methods once the manufac luring processes are estab
lished.
K-79
trials in-country. As part of the agreement with the Populaliun ( num il, I eir.is Medic a Jakes responsibility for regis
tering Norplant. Io date seven countries I inland. Swe
den, Indonesia, Thailand, Ecuador, the Dominican
Republic, and Colombia—have registered the 6-capsule
Norplant system, and one country—Finland—has regis
tered the 2-rod Norplant-2 (85, 189). Applications for ap
proval of the 6-capsule
.tern have been filed in other
countries in Africa, Europe, Asia, and Lahn America (124).
An application for Norplant-2 will be filed in the US in 1987
(85).
Cost
What do the new methods cost? While prices vary de
pending on quantity, timing of purchase, delivery sched
ule, exchange i.tlc, and oilier t.ulois, the implants and
injec tables are generally more expensive than oral contra
ceptives. Shown below are sample or expected prices
charged by manufacturers to donor agencies that buy in
large quantities:
Sample or Expected Prices to Donors for
Various Contraceptive Methods
Method
Combined estrogen-progestin oral
contraceptives
Norplant (5-year, 6-capsule system)
Norplant-2 (3-year, 2-rod system)
DMPA (3-month injectable)
NET EN (2-month injectable)
Cycloprovera (monthly injectable)
HRP102 (monthly injectable)
Current or
Expected Price Io
Donors (in US$)
Per Dose
Per Year
$ 0.15
per cycle
*
14.00
9.00
1.00
1.00
.80
.80
$ 1.95
2.80
3.00
4.00
6.00
9.60
9.60
’Price paid by US Agency for International Development for oral
contraceptives shipped to national family planning programs, as ol April
1987
Sources: Blackburn (281), Castle (36), Chatwal (40), Hall (97)
Prices are not necessarily the same for all purchasers and
are often lower for public or nonprofit organizations than
for commercial distributors.
Delivery in family Planning Programs
All of the new implants and injet tables are likely to he1
distributed largely Ihtough I.iiiuly planning piogiams, .it
least initially. What is the best way to introduce a new
contraceptive into a family planning program? Experience
with IUDs, oral conlrat eptives, and now Norplant sug
gests that pilot studies, a specific marketing or distribution
plan, and thorough training of health workers can improve
the way a method is an epled and how effectively and
safely it is used.
Introducing a new method on a limited basis—first in one
center or one district —is a good way to assess potential
demand for the product and to determine how to train
health workers and counsel users (277). The Population
Council has suppotied such pre-inlrodut lion trials for
Norplant tn 2U countries tn I alm Anient a, Asia, and Afrit a
(183). WHO has sponsored similar trials to introduce NET
EN and DMPA into family planning programs in six coun
tries and is'planning similar trials for Cycloprovera and
HRP1Q2 (57, 130, 199, 251).
The more channels by which a contraceptive method ijj
distributed, the more people will have at cess to it. Should
the new implants and injectables be offered only in clinics
by dot tors and other spet ially trained health workers? Or
can they be distributed through channels that aie more
accessible to the community -community-based distribu
tion, social marketing, or commercial sales? To date, Nor
plant has been oflered only in clinics and hospitals, as
recommended by the Population Council, WHO, .m IIPPF
(119, 269) As more health workers are trained, and experi
ence with the method grows, il is possible that Norplant
and other implants can be provided in temporary centers.
This has been done with male and female sterilization—
procedures more complex than inserting or removing im
plants.
A variety of health workers can learn to insert implants,
just as they have learned to insert IUDs and perform minilaparotomies. In an Indonesian study the average inser
tion times and complication rates were the same whether
Norplant-2, the 2-rod system, is less expensive than the £t_
capsule system, pa.tly because the manufacturing process
is almost completely automated. The cost of Norplant-2
will almost certainly be even lower as more devices are .
made (124). The trocar used with both systems costs about
$6 (85).
The prices of other new methods are not yet established.
Biodegracjuble pellets probably will cost less than implants
or injectables because they are easier to make (79).
The cost of supplies is only part of the cost of delivering a
contraceptive. Numbers of staff, staff training, and staff
time per client are all important to total
On one
hand, short-acting methods such as monthly injectables
require more clinic visits than longer-acting methods. On
the other hand, training health workers to deliver the
longest-acting methods—inserting and removing Nor
plant implants or IUDs and performing sterilization—is
more costly than teaching someone to administer injec
tions. Also, these methods require relatively time-con
suming procedures. In addition, implants and sterilization
plant in a woman's arm in a rural clinic in Kenya. This pilot
program is assessing the training and equipment needed to
deliver Norplant in clinics without electricity or running water.
(Population Council)1
t
POPULATION REPORTS
(5, (>). In Chile, Brazil, and the US, nurse-midwives and
nurse practitioners have inserted implants (52, 67). Be-
Certain training requirements aie sjietilir to Norplant im-
< ausv spe< i.il u.mung and lu-qm-nl pia< ti< c aiv ms essaly
liowevei, ii is unlikely dial Norplant could be ottered by
many pharmacists or other commercial providers.
By < onipanson with inserting implants, giving injeilions is
easy. Many people can learn to administer them. Around
the world paramedical workers, pharmacists, and commu
nity-based workers give injections of many different medi
cations, including contraceptives. For years mobile teams
in rural Thailand have administered DMPA without diffi
culty (150). Community workers in rural village dispens
aries have administered injectables in Haiti and Jamaica
(241, 248). In Matlab and other areas of Bangladesh, injec
tables have been provided through community-based dis
tribution projects (9,108). In Mexico and Egypt social mar
keting programs sell monthly and 3-month injectables in
retail outlets (225). No doubt the new injectables and in
jected microspheres can be delivered through the same
channels.
To offer injectables or implants, programs need to meet
the following requirements:
• Thorough training for workers (see below);
• Sufficient staff, particularly in community-based pro
grams, to ensure that field workers r an visit women
on schedule;
• An accurate and simple record-keeping system to
keep track of schedules;
• Sullir lent supplies ol contraceptives ano other neces
sary equipment—including syringes, disinfectant,
and autoclaves—from one source. In a pilot program
in Haiti lack of DMPA accounted for 6 percent of
discontinuations (241). In a community-based pro
gram in Abhoynagar, Bangladesh field workers had to
collect equipment from several different sow and
so were often unable to give injections on schedule
(108).
• With a long-acting implant, such as Norplant, plan
ning to assure that women can have the implants
removed any time they want and a system to notify
women when the implants should be replaced.
Training
Training all health workers is essential to introducing a
new method. For any of the implants and injectables,
training must cover:
• The manual skills needed to deliver services, such as
administering injections or inserting and removing
implants;
• Sterile technique, which is essential for all implants
and injectables;
• All characteristics of the method—indications, con
traindications, side effects, effectiveness, and dura
tion of action—so that health workers can help clients
make informed choices;
• Risks and benefits of the method compared with
other family planning methods available;
• Counseling techniques;
• Management of complications, especially heavy
bleeding;
• Care of equipment and storage of supplies (in a clean,
dry place; refrigeration is not needed);
• Follow-up of clients;
• Record-keeping (14, 126).
POPULATION REPORTS
reinovals (166). Adequate jnai tn e in removals may be hard
to obtain When1 Norplant is just being inlioiliu eil, Itaiil
ees olten will nut he able tn piai lire removals immediately
(190). PATH/PIACT has developed an artificial arm for
What Women Want to
Know About Norplant
What are women's major concerns about Norplant
implants? The Program for Appropriate Technology
in Health/Program for the Introduction and Adapta
tion of Contraceptive technology (PAI H/PIACT)
asked new users in the Dominican Republic. Ec
uador, Indonesia, Kenya, the Philippines, Sri Lanka,
and Thailand. Not surprisingly, the women had many
questions, such as:
• Does insertion hurt? How long will it take?
• After the implants are inserted, will they move
around in the body?
• Will people be able1 Io see the imjilanls?
• Will they look ugly?
• Do the incisions for insertion and removal leave
• Will the implants be uncomlorlable?
• Will the implants lncak it they are touched or
bumped?
• Will the implants make it hard to move the arm?
• Can users still work? Will the implants cause
weakness? (184, 274)
During counseling health workers should address
these concerns as well as describe effectiveness and
possible side effects. Women need to know that
they will receive a local anesthetic for insertion and
removal and that neither procedure is painful. Inser
tion takes 5 to 10 minutes. Removal lakes a little
longer—usually no more than 20 or 25 minutes. The
implants are inserted just under the skin, not in a
vein, as some women mistakenly thought. The inci
sions for insertion and removal leave little if any scar.
If possible, during counseling a woman should have
a chance to hold implants in her own hand so she
can see that they are soft and flexible. Once in
serted, the implants will not move, do not cause any
pain, and will not break even if they are bumped or if
a woman carries her child in her arms. After inser
tion, a woman can do any kind of work that she did
before. Neither Norplant nor any other hormonal
contraceptive weakens a user or her husband.
The implants are sometimes visible under the skin.
Usually they look like a vein but without color (184).
Few users are troubled by this. In an early clinical
trial, when implants were routinely inserted in the
lower arm, about 40 percent of acceptors reported
that family members or friends had noticed the im
plants. Even so, only 7 percent of users considered
the appearance of the implants to be the feature that
they most disliked (237). Now implants are often
placed in the inner side of the upper arm and so are
less visible.
teatlung insertion, but a device lor leaching removals is
still being developed (2'ilh.
Practice with removals is important (see box, p. K-62). A
pi.ir tilioni-i who has not had hands on experienie may
have problems or may be reluctant to remove implants,
especially if the woman has not used them for a full three
or five years (186). Even if doctors perform removals during
training, when Norplant is being introduced they may not
perform another for several years. Thus periodic refresher
courses are needed.
There are several ways to ensure that health workers are
trained in removal so that women can have their implants
removed on request. One approach is to leach practi
tioners in two stages. In Sweden training started just after
Norplant was approved, in 1985, and covered only inser
tion technique. A second segment of training will teach
removal techniques when women want to stop using Nor
plant (190). Another approach is to train just a few practi
tioners in removal at first and refer all removals to them. In
Indonesia central removal centers have been set up (165).
Practitioners also can be trained at these centers.
The Population Council has established four international
training centers—in the Dominican Republic, Indonesia,
Chile, and Egypt. In 1985 and 1986, 28 doctors from eight
countries were trained al the Dominican Republic center;
at the Indonesian center 13 doctors from India, 4 from
China, and 10 from five other Asian countries were
trained; and *1 horn Africa wete trained in I inland (Illi,
187, 250). In Thailand, where Norplant was approved in
1986, the Ministry of Health has set up 17 training centers.
About 700 doctors were trained by early 1987 (183). The
model training curriculum, developed by the Association
for Voluntary Surgical Contraception, the Population
Council, PATH/PIACT, and Family Health International,
calls for a 5-day program (14). Plans are being made to test
the curriculum in several countries (125).
Sterile technique has always been important with IUDs,
injectables, and steriliz '-on. Now the risk of transmitting
the ...us that cue . AIDS—acquired immune deficiency
syndiome—makes it essential. Worldwide, more than
45,000 cases of AIDS have been reported as of March 1987
(299), and neither a vaccine nor a cure has been found. The
human immunodeficiency virus (HIV), which causes AIDS,
is transmitted sexually and also in blood. A number of
researchers have suggested that, if contaminated needles
are used in health clinics, they could transmit HIV (35,156,
157,175, 179, 298) (see Population Reports, AIDS—A Public Health Crisis, L-6, July-August 1986). There is no evi
dence yet that this has taken place. Many other serious
I illnesses, including hepatitis B, also are transmitted by
! contaminated needles. Maintaining sterile technique can
be diliivult when syringes, other instruments, and the
equipment to disinfect them are in short supply. Even
under these circumstances, however, health workers
should never risk infecting their clients by using un
sterilized instruments. (For instructions on disinfecting
instruments, see box, p. K-63.)
f
Information and Counseling
In addition to health workers, other key audiences need
education and information:
• Family planning program and donor agency admin
istrators, government officials, and policy-makers
K-82
In Sri Lanka a focus group discusses Norplant. Information from
sessions like this was used to develop booklets explaining
Norplant to users and potential users. (Courtesy of PATH/PIACT)
who allocate funds and establish programs.
• Potential users, who need to know the risks and bene
fits of various methods before they can make an in
formed choice. Also, counseling on possible side ef-l
feds can ease women's concerns, increase their
satisfaction with the method, and reduce discontinua
tion rates (234).
• Journalists, broadcasters, and other communication
media personnel, whose' words and opinions reach
many people.
Informing the public about new contraceptive methods
should begin as soon as the products are ready for widespread testing Communication programs should continue after products are approved to keep potential users
well informed, to combat any rumors that may arise, and
to ensure that current users will return when they should.
. i
For Norplant, the Population Council, PATH/PIACT, and
Leiras Medica have developed special information mate
rials. The material for administrators and health workers
includes comprehensive information packets reporting
scientific data; training guides on insertion and removal;
and a newsletter, Norplant Worldwide, that describes the
latest research and program experience (85, 144, 180,194).^^
In addition. Population Council experts and Norplant re-^F
searchers meet with family planning officials and make
presentations at scientific meetings.
For potential users PATH/PIACT and the Population Coun
cil have developed information pamphlets in local lan
guages and adapted to local audiences in Ecuador, Indo
nesia, the Philippines, and Sri Lanka (see photos, pp. K-59,
83). A Spanish-language version for Latin America has
been completed, and an African version in English and
Swahili is being prepared (185). The pamphlets are meant
to be used during counseling to reinforce the information
given to clients (185).
Thorough and sympathetic counseling is important for all
methods, old and new. During counseling sessions, health
workers and clients should consider several issues—the
woman’s age and health, whether she and her husband | a.
want more children, how easily she can come back to the //)
clinic for supplies, and the availability of supplies for tem
porary methods. For some couples, one of the new longacting methods may offer distinct advantages; for others,
established methods such as oral contraceptives or conPOPULATION REPORTS
■’ doms may be preferable. As a long-acting method, Nor
used for years in oral < onlr.K eplives. Ehcii safely and side
plant is cs|><-< ially appropii.ito toi women who do not want
any mole i hildien tint do not want to be similized 01
.-lie. Is .ue well vsl.llilislied NiHlellieless. in new dellymy
cannot obtain voluntary sterilization as well as for women
who want a long interval between births. Also, since Notplant contains no estrogen, it is less likely to cause some
of the side effects that occur with combined estrogen
progestin oral contraceptives. Thus Norplant may be pref
erable to oral contraceptives for women over age 35, for
whom estrogen contributes to an increased risk of cardio
vascular side effects. The injectables, injectable micro
spheres, and shorter-acting implants may be best suited
for women who are spacing their children and also have
convenient access to clinics or pharmacies. None of the
new methods has been thoroughly tested in lactating
women. Studies of DMPA, NET EN, and Norplant, how
ever, suggest that the progestin-only methods have no
harmful effects on breast milk composition or production
or on the breast-feeding infant (see pp. K-63, 73).
If a woman chooses Norplant, counselors must make sure
she knows that:
• She can return to the clinic or center to discuss any
problems and concerns;
• She can have the implants removed whenever she
wishes, for any reason whatsoever;
• Irregular bleeding is common with Norplant; how
ever, in many women irregular bleeding diminishes
with time;
• In the rare instance that pregnancy occurs, the im
plants should be removed immediately.
• In addition to suspected pregnancy, she should return
immediately if she has severe abdominal pain, heavy
vaginal bleeding, arm pain, pus or bleeding al the
insertion site, repeated severe headaches, or blurred
vision.
• The 6-capsule Norplant system is effective for five
years and then should be removed; preliminary trials
show that the 2-rod Norplant-2 system is effective for
at least three years.
systems they may behave dillerenlly. I bus surveillance of
these new methods will be needed. Other progestins,
sinh as norgeslnnate, 51- 1435, and the new levonorgestrel
esters, are being tested for the first time. Postmarketing
studies are particularly important for these progestins
Among the new contraceptives, only Norplant implants
are on the market in several countries. WHO, the Popula
tion Council, and FHI are collaborating in setting up a
large prospective study to look lor any medium- and long
term effects of Norplant use. I he study, which will be
coordinated by the WHO Special Programme of Research,
Development and Research Training in Human Reproduc
tion, will involve 5,000 Norplant users and 5,000 controls
from 10 to 12 sitesTtrflCTOIoping countries. The pilot phase
of this study, involving some 450 Norplant users and 450
controls, will begin this year al three sites. All women will
be followed for at least five years even if they stop using
Norplant, and any hospitalization and health problems
will be recorded. Any beneficial or adverse effects on
"Health that might be associated with Norplant will be ana
lyzed.
User Satisfaction
About half of Norplant users keep the capsules for five
years. What is the best way to remind them when the
capsules need to be replaced? Several approaches are
being discussed. One possibility is to contact users by
telephone, mail, or personal visit. This is not always feasi
ble, however, and in large programs it would be very
expensive and time-consuming. Another approach, some
times used with IUD users, is to give each woman a card|
printed with the date for removal. The cards could be I
color-coded by the year that the implants were inserted. 1
Three or five years later messages could be posted in I
clinics and broadcast over radio and television advising I
women who have cards of a specified color to come to thej
clinic to have the implants replaced (193).
Postmarketing Surveillance
Experience with oral contraceptives and IUDs has shown
that some side effects and some benefits of contraceptives
are not discovered immediately. The animal and clinical
trials required in most countries before contraceptives are
introduced ensure that contraceptives are safe and effec- '
ttvein the short~~ru~ri~T3hly contihued~pos'fmarketing sur- <
'WtttaTfdd’onarge numbers of women, however, can detect
side effects that are rare or appear only after a long period.
Some of the hormones used in the new contraceptive
methods—levonorgestrel and norethindrone—have been
POPULATION REPORTS
In this pamphlet from APROFE in Ecuador, a woman tells others
why she is happy with Norplant: the implants do not hurt, and
she does not have to bother with other contraceptives any more.
K-83
l.ible'. .mil illlpl.mis, women (.III lie .issmed ill .ilinosl
complete contraceptive prole, lion without having Io lake
Wheievei ui|c( tables have been availahle. they have been
popular. In many developing lounliies people would
rather take medicines by injection than orally, perl.-.ps
because they associate injections with the antibiotics that
have been so effective in controlling communicable dis
eases. Also, injectables afford privacy that... , eals to some
women. A woman can obtain injections outside the home
without her husband's or family's knowing. Some women
preler monthly injectables to the less frequent DMI’A and
Nt f IN, according Io a Mexican study, because' the
monthly bleeding is a good reminder to obtain the next
injection (64).
Implants have been readily accepted in many of the coun
tries where they have been tested. Some researchers wor
ried at first that women would fear the insertion proce
dure or dislike the fact that the implants sometimes are
visible under the- skin (286). Initial experience with the
< h.luges in bleeding pallems lem.lin the m.l|oi i ailse ol
dissatisfaction with long ai ling piogesbn .... Iliods.
Amenorrhea is perhaps the most disturbing change be
cause women cannot be sure that they are not pregnant
(98, 154) '-'.o, some women think that regular menstrua
tion is essential to good health. Prolonged bleeding or
spotting also can be disturbing, especially it social or re
ligious customs resliiil the activities ol menstruating
women.
I he new long-acting methods now becoming available will
oTtnrwomeh’ mare choices al every stage in their re
productive lives. Developing good methods is only the
tirsfol m.'-ny steps to making them available, however.
Effective distribution, marketing, and information and
service programs also are essential so that potential users
really have a choice of these new methods available to
them.
BIBLIOGRAPHY
Asterisk (') designates an article' that was ol parlicul.it value in the pieparalion ol Ibis issue ol Population Reports.
1 ABDUIIA. K.A.. ElWAN, S.J.. SA! EM. H.S.. and SHAABAN,
M.M LfleCt ol early postpartum use ot the contraceptive
or tin1 mothers and their breastfed infants. Contraception
2 AD HOC CONSULTATIVE PANEl ON DEPOT MEDROXYPROl TSTE RONE ACETAI L. Report to US AID of the Ad I lor
Consultative Panel ol Depot Medroxyprogesterone Acetate,
New York Ealy, December 7-8, 1978. July 1980. 59 p. (UnVai do.1 a -r .iandgrin. b.-m . johannisson , r., and
Dll ZIAIUSY, I I’harniac cikinc-lic and pbatmatodynaum in
vestigations with monthly injectable contraceptive prejtara-
•4. Al I ANDI. B . KARMADIBRAIA. S., PRI) IARTONO, J.. LUBIS,
AHANDI, B., PRIHARIONO. J.. LUBIS, F., and SUitDI,
. Clinical trials or Norplant in Indonesia. In- Shaaban.
ten'
mt Egypt As-io! University. 19M. p. 41-5'2.
I. Ac. . .in It . PRIHAKlc . .. i. J . 11 Jills. I., SUIII1I. II . .me
contraceptive implants. 119117b 14 p. (To be published tn
■7 AHANDI, B., SAN1OSO DIAJADHAGA, S.S.I.
HADISAPUTRA, W. MOTiOiK, I.A., and SAMII. RS fivi
8 ALAN GUTTMACHER INSTITUTE (ACI). Risky justnessan overview ot the crisis in liability insurance. December
PiBt. 17 p (Unpublished)
contraceptive programme. Presented al the 9th Annual Conleien- >f Bangladesh fertility Research Programme, Dhaka,
10. Al I, M.N and )AI II. M.A. Iurther study on (he ellect ol
body functions. Bangladesh Medical Research Council Uul-
IPPI Mc-du al Bulletin B(2». I 1 April I«l74
|.P R1VIRA. k '. CROXAHO. H.H . COUTINHO. I M . and
loins. Philadelphia. Harper & Row, 19&4. p 431-440.
14 ASSOCIATION I OR VOlUNl-'RY SURGICAI CON-
K-84
POPULATION REPORTS
HEALTH
tough
choices
M
Y FRIEND, A DOCTOR IN HER LATE TWENTIES,
had an abortion this fall. She was using a barrier
contraceptive and had been conscientious about
its use. She’d tried birth-control pills but felt
lousy on them, and believed—correctly—that
since she didn’t see her boyfriend often, a barri
er method was a good choice for her. My
friend, though she was well-informed and intelligent, found
herself caught up in the same unfortunate situation that about
1.5 million other American women find themselves in each
year: with an abortion as her perceived best option.
It’s become clear that, in 1989, there are no perfect contra
ceptive methods for women. To gain efficacy, a woman may
have to sacrifice some safety; to avoid health risks, she may
lose spontaneity.
The choices are difficult ones. Women who became sexu
ally active using the pill in the pre-AIDS era may find it hard
to reorient their thinking. In addition to the difficult contra
ceptive choices a woman must make now, she must also de
cide how to deal with the small but real risk of fatal illness
from intercourse. No longer must women protect just their re
productive health; today they must also protect their lives (by
picking partners carefully and insisting on condom use). Al
though partner choice is probably the most important health
decision, condoms are requisite today if one is uncertain
about a partner’s HIV status. The reason is simple; the pill
does not protect a woman against any sexually transmitted
diseases, including AIDS.
The pill: new pros and cons
The pill has come a long way. It has changed from the highdose estrogen and progestin pill of the last decade to a combi
nation pill that uses the lowest possible doses of estrogen and
progestin to maintain efficacy and prevent spotting.
When birth-control pills (such as Enovid 10) were first in
troduced in 1960, the progestin used was a 10 milligram dose
of norethynodrel and the estrogen was 150 micrograms of
mestranol. Today, however, birth-control pills contain less
than a quarter of the old dosages. Current birth-control pills
Decisions abom,
birth control ,
have grown mor
complicated.
Erica Frank, M I)
reports new
> nndiQ^s on
®e pill and othei
§ contraceptives
also use different hormones (progestins such as ethynorf
diacetate and norethindrone, and estrogens like ethinyl est
diol). These changes—different hormones at lower &
ages—-have produced birth-control pills that may bet
likely to cause cancer, have fewer adverse effects on cbi
terol levels, and produce fewer skin problems.
«•'
How safe is today’s pill? According to Contract^
Technology (Irvington Publishers, Inc. 1988), a medical it'
book, a nonsmoker’s chance of death from taking the pill f.
year is one in 63,000; one in 16,000 for a smoker. Conjl
these pill risks with the death risks per year of having a b
(one in 10,000), automobile driving (one in 6,000), and:
torcycle riding (one in 1,000).
”■
The real advantages of the pill are its low failure rate an
ability to prevent risks associated with pregnancy. Wh^
percent of women who use no method of birth control m3
pregnant within a year, only about 1 percent of heterosext
active women who use the pill properly will become pregS
Historically, women feared using the pill because of lb
creased risk of blood clots, heart attacks, and strokes; be
low-dose pills have done much to decrease such cardim?
lar risks. It’s now clear that these rare cardiovasculare'
occur primarily in older women (over thirty-five) who sr
and in those with other conditions, such as obesity;
*
blood pressure, diabetes, high cholesterol, or a history ci
diovascular disease. Also, warning signs such as heads’
visual changes, sudden shortness of breath, or severe c
abdominal, or leg pain while on the pill have helped tot
potential problems for pill users.
The current health concerns with the pill; breast canct
cholesterol. Recent studies—featured prominently?
press—suggest that pill users may be at higher risk ofi
cancer. Although these articles have suggested an assoc
between the pill and breast cancer, the studies theni
have several epidemiological limitations. Some of the
control pills studied were the original, high-dose pills.r
low-dose ones currently prescribed; experts suggest th
cer-causing potential of the high-dose pills may be gt
Additionally, the reasons for the increased breast-cane
spuled among experts. Some said duration of pill use
-irnount; others cited a family history of breast cancer,
-set of menstruation, or bearing fewer children. It is
■nt to note that most previous studies found no signifijtionship between breast cancer and the pill. Furtherl.is newly reported elevated risk was suggested in
omen, a group in which breast cancer (even among
;) is extremely rare and for whom even the slightest
j risk makes scientists take note.
<. Holmes, M.D., Ph. D., professor of medicine and
of the Center for AIDS and Sexually Transmitted
at the University of Washington in Seattle, says.
hope the new studies linking breast cancer to the pill
o be false. However, this represents a good opportuvomen to reexamine whether they really require the
nancy rates that the pill provides. Some women may
they’d rather use a method like foam and condoms,
er protij^k'in against sexually transmitted diseases,
un the pSible adverse health risks associated with
smoking
women
who have
no cardiovascular
risks “may
continue
taking
the currently
ceive later. According to Dr. Hatcher, non
available low-dose
estrogen
until
as late as
ho should
useand
the progestin
pill? The pill
ideal
candidate
is
age fifty." He also
points
out
that
a
combination
ofmonoga
estrogen
healthy,
young,
sexually
pregnant now but would likeactive,
to be able
to con
and progestin quite
similar
to that found
in birth-control
mous,
nonsmoking,
and does
not wish topills
get
(estrogen replacement therapy in the form of Premarin and
Provera) has been shown to help protect against osteoporosis
and cardiovascular disease after menopause.
Other medical problems, such as severe headaches or ill
nesses requiring certain medications, may interact with birthcontrol pills; a recent fracture requiring a cast may also make
pill use inadvisable. If a woman falls into any of these catego
ries, she may still be able to use oral contraception, but should
discuss it with her doctor.
W
' Nonetheless, examination of all the evidence (the
ponsible way for women and their physicians to
.isions) still indicates that the pill now being preill probably represent, formost women, nosubstaneased lifetime risk of breast cancer.
ibout other cancers? Although experts continue to
ite data, risk of cervical, skin, and liver cancers is
not markedly elevated in pill users, as was formerly
i On the plus side, according to Robert Hatcher,
aior author of Contraceptive Technology, ‘ ‘There is
a good deal of evidence to
I dO6S not
suggest that the pill protects
against both ovarian and endometiial cancers.”
I 3 WOman
According to Geoffrey P.
Redmond, M.D., a Cleve-
A substantial number of women (as many as a quarter of
those who try using the pill) cannot tolerate the pill’s side ef
fects. Women may not feel well on the pill and may experi
ence spotting, acne, breast tenderness, increased frequency
of yeast infections, depression, fatigue, headaches, water re
tention, rash, hypertension, nausea, decreased sex drive, or
weight gain. But these side effects do not affect all women
(and can disappear if a woman switches to another pill formu
lation), and they may be countered by other benefits—for ex
ample, an improvement in sex drive, sexual spontaneity,
menstrual regularity and predictability, as well as a decrease
in acne and menstrual discomfort. Some data suggest that the
pill can also help to protect against benign breast disease,
heavy bleeding, iron-deficiency anemia, pelvic inflamma
tory disease, and ectopic pregnancy.
tnv CPYliallv
iny bCAUdliy
Barrier methods
For a woman who does not want to take the pill, other options
are less than perfect. Although condoms are critical protec
tion against sexually transmitted infections, the use of con
doms only will produce a pregnancy in about 10 percent of
typical couples who use the method for a year. Condoms,
which are more effective as a method of contraception when
used with a spermicide, usually fail because they’re not used
regularly. They also fail because they’re not put on precoitally; they’re used with petroleum jelly (which causes rubber to
deteriorate); or they’re reused, which makes them prone to
breakage. In addition, condoms must have a one-inch sperm
reservoir at the tip and must be removed immediately after or
gasm. Similarly, although spermicidal foams, suppositories,
creams, and jellies help to prevent sexually transmitted dis
eases (by killing infectious organisms), they typically fail as
contraception; in couples using them for one year, about 15
percent of the time.
Methods such as the sponge, cervical cap, and diaphragm
may permit more spontaneity than does the condom. These
vaginal barrier methods, used with a spermicide, can be ex
cellent birth-control options for women who have infrequent
intercourse and are willing and able to use them. However,
many women find them messy, uncomfortable, and inconve
nient; failure rates are about 15 percent a year. It is t-222
*an<^ Clinic Foundation endocrinologist specializing in
hormonal diseases of women
ed diSCaSOS an<^ children, the pill may
also have variable effects on
unr
cholesterol levels. While difingAIDS
ferent brands of birth-control
pills contain estrogens that
ittle in their effect on the body’s cholesterol level,
contain very different types and levels of progest are responsible for lowering the “good” (HDL)
1 and raising the “bad” (LDL) cholesterol. This
l-raising effect of progestins is one reason (in addiiblems with decreased efficacy and spotting) to
rogestin-only “mini-pill.” Dr. Redmond believes
Future “birth-control pills will be selected accordr effects on cholesterol.” He recommends that
birth-control pills with low levels of “good” proch as those found in Demulen-1/35, Ovcon-35,
and Modicon). According to Michael Kafrissen,
ctor of clinical reproductive research for Johnson
•tical Research Institute (associated with Ortho
<tical), new progestins that have even better effects
rrently “dominate the market in Europe and may
ruse in the United States in the next two years.”
221
Vol. 34, No.
(2,-kc^.
1480
OBSERVATIONS ON THE ANTIGENICITY AND CLINICAL EFFECTS OF A CANDIDATE
ANTIPREGNANCY VACCINE: P-SUBUNIT OF HUMAN CHORIONIC GONADOTROPIN
LINKED TO TETANUS TOXOID’t
ELOF D B. JOHANSSON. M.D.
*
JAIME VASQUEZ. M.D.»»
ELSIMAR COUTINHO. M.D It
KALYAN SUNDARAM. PlI.D.I
HAROLD NASH. Ph D.ll
G. P TALWAR. PH D 1
SHELDON SEGAL. Ph D I
TAPANI LUUKKAINEN. M D #
The Population Council. Rockefeller University. New York. New York 10021,
The A ll India Ineitute ofMedical Science,. New Delhi. India.
The Rockefeller Foundation. New York.New York 10036.
Department ofMedical Chemistry,University ofHelsinki.Helsinki. Finland,
Department ofObstetric, and Gynecology, University of Uppsala. Uppsala. Sweden,
Observations on the antibody response and clinical effects of injection of purified
ft-subunit of human chorionic gonadotropin covalently linked to tetanous toxoid were
made in 15 healthy young women who had previously undergone tubal ligation.
Antibodies detectable by radioimmunoassay were found in 14 of the women. Clinical
surveillance and immunologic, hematologic, and biochemical tests indicated excellent
local and systemic tolerance to the antigen No significant adverse effects on menstrual
function, endocrine status, or health were found. Fertil Steril 34:328, 1980
ANTIGENICITY AND CLINICAL EFFECTS OF ANTIPREGNANCY VACCINE
hormones. This possibility derives from the fact
that the p-subunit of hCG is unique, whereas the
a-subunit is common to luteinizing hormone (LH),
follicle-stimulating hormone (FSH), and thyrotro
pin. Another principle was that of linking the psubunit to a foreign protein, tetanus toxoid (TT), in
the expectation that the human immunologic sys
tem would respond to the new entity as "foreign’’
and form antibodies to both its parts.
The initial investigations gave promise that ap
plication of these principles achieved the desired
ends.2 17 They showed that antibodies produced in
monkeys and in humans in response to the vaccine
were capable of neutralizing the biologic activity
of hCG,
*
2 and that their cross-reaction with hLH
or hFSH” appeared minimal. Studies conducted
in monkeys’0 13 gave no evidence of toxic man
ifestations. Similarly, no evidence of toxicity or
interference with normal menses was seen in four
women to whom the vaccine was administered.8
In view of these encouraging results, clinical
pharmacologip studies were undertaken in four
clinics under the auspices of the International
Committee for Contraception Research of The
Population Council. The objectives of the trials
were as follows: (1) to evaluate the magnitude,
constancy, and duration of antibody response; (2)
to determine whether immunization gave any evi
dence of toxicity or unwanted side reactions; (3) to
determine whether the antibodies neutralized the
biologic activity of hCG in in vitro and in vivo test
systems: and (4) to examine the cross-reactions
between the antibodies and other glycoprotein
hormones.
MATERIALS AND METHODS
The concept of a vaccine against pregnancy is an
attractive approach to fertility control and one
which has received increasing attention in the last
decade. The effectiveness of antibodies against
hormones in interfering with their action has long
been recognized.’ Interference with the action of
human chorionic gonadotropin (hCG) should pre
vent it from stimulating the corpus luteum to con
tinue the synthesis of the amount of progesterone
required for maintenance of the endometrium in a
state to receive and nurture the trophoblast. Re
cently, Talwar and colleagues at the All India In
stitute of Medical Sciences have reported on
laboratory, animal, and human studies with a vac
cine prepared from the p-subunit of hCG.2’7 The
design of the vaccine rested on several principles.
One was the use of only the p-subunit of hCG with
the objective of reducing the chances that the anti
bodies would cross-r^ with other glycoprotein
Received January 30. 1980; revised April 14.1980. and June
6. 1980; accepted June 13. 1980.
tre of Canada. The Ford Foundation. The Rockefeller Founda
tion Council. Inc., New York.
tReprint requeata: Harold Nash. Ph.D., The Population
Council, Rockefeller University, 1188 York Avenue, New
York. New York 10021
5The Population Council. Rockefeller University. New York.
TThe All India Inatitute of Medical Sciences. New Delhi.
India.
iTThe Rockefeller Foundation, New York.
# Department of Medical Chemistry, University of Helsinki,
Helsinki. Finland.
••Department of Obstetrics and Gynecology, University of
Uppsala. Uppsala. Sweden.
ttConaultorio de Planiflcacion Familiar, Santiago. Chile.
HMatemidade Ciimerio de Oliveira, Universidade Federal
de Bahia. Salvador, Bahia, Brasil.
328
Subjects and Dosing Regimens. One clinic in
O each
of four countries (Sweden, Finland, Chile,
and Brazil) participated in the studies after having
approval from institutional human experimenta
tion committees and government regulatory agen
cies. Subjects were informed of the purpose of the
trials, of the procedures to be used, and of the
status of understanding of safety. To be eligible for
enrollment in the trials, subjects had to be less
than 35 years of age, have been sterilized by tubal
ligation, be available for regular follow-up, have
regular menses, not be currently breastfeeding,
evidence normality on pelvic examination, not be
sensitive to TT, have no underlying chronic or
acute diagnosable disease, show no significant
clinical morbidity, and not be on hormone or anti
biotic therapy. Tubal ligation was included as a
329
criterion because of lack of knowledge of con
traceptive effectiveness and the desire to observe
antibody response and health effects without the
complication of pregnancy. Subjects are identified
by code names and by clinic in Table 1.
Two different regimens of vaccination were
used. One regimen, designated regimen A, was
used in 12 of the 15 subjects. Preparation A in
volved use of vaccine precipitated with aluminum
hydroxide. p-hCG antigen (80 pig) was given in
each of four doses spaced 2 weeks apart. For injec
tion, aluminum hydroxide precipitate suspended
in 0.5 ml ofsaline was homogenized with 0.45 ml of
sesame oil and 0.05 ml of Polysorbate 80. Prepara
tion B involved adsorption of the antigen on cal
cium phosphate. Each injection provided 240 pg of
P-hCG antigen. Two injections were given, spaced
1 month apart. For injection, the calcium phos
phate precipitate was suspended in 0.5 ml ofsaline
solution.
Physical Examinations and Laboratory Tests.
Before vaccination, tests were conducted to assure
that the subjects were healthy and met criteria for
admission and to establish baseline levels from
which changes caused by the vaccine could be
judged. These tests included physical and pelvic
examinations, clinical chemistry, fasting plasma
cortisol, hematology, urinalysis, luteal phase plas
ma progesterone, plasma gonadotropins, DNA
antibodies, titere for anti-hCG and anti-TT anti
bodies, and skin test for TT hypersensitivity.
During the 1st year after vaccination, physical
examinations, clinical chemistry, hematology,
and urinalysis were performed at the end ofthe 1st
month and thereafter at 3-month intervals. After
the 1st year they were done at 6-month intervals.
Cortisol and DNA antibodies were determined at
6-month intervals. Blood samples for antibody
assay were obtained monthly during the 1st year
and thereafter at 6-month intervals.
Clinical chemistry tests run on serum samples
at regular intervals, as outlined above, included
glutamic pyruvic transaminase (SGPT), glutamie
TABLE 1. Subjects and Regimens in Clinical
Pharmacology Study
University of Uppsala Kallg. Ahlb. Lans
University of Helsinki Bjork. Hallo. Loob
University of Helsinki Aalt, Hein. BorgConsullorio de Planifi- Reye, Pen. Valle
cacion Familiar
Alne, ABdS. MASdS
University of Bahia
•For description of regimen see text
Is
w
Vol. 34, No.
330
October 1980
NASH ET AL
oxaloacetic transaminase (SGOT), total bilirubin,
alkaline phosphatase, urea nitrogen, inorganic
phosphorus, total protein, albumin, albumin
globulin ratio, glucose, cholesterol, calcium, and
thyroxine. With a few exceptions, clinical chemis
try measurements were made by Bio-Science
Laboratories, Van Nuys, California. Serum sam
ples were shipped frozen, packed in Dry Ice. In
exceptional cases, the clinical chemistry measures
were made in the investigator’s home clinic. Uri
nalysis and hematology were conducted in the lab
oratories of the individual investigators.
Approximately 2 years after immunization of
the subjects, a senior obstetrician-gynecologist (A.
B.), who had not been involved in the studies, vis
ited all clinics to interview vaccinated subjects
independently to determine whether there was
any symptomatology suggestive of an autoim
mune state. He also determined the efficacy with
which information had been transferred in in
formed-consent procedures. Women have returned
to the clinic for observation on a regular basis since
vaccination, and such follow-up is continuing (ex
cept for one subject who moved from the country).
The period since vaccination has been 3.5 to 4
Antibody Titration. Anti-hCG titers were mea
sured by the ability of the sera to bind I26I-hCG
iodinated by a modified chloramine T method.18
,2fiI-hCG (250 pg), specific activity 40 to 50 p.Ci/pg,
was incubated with 4 p.1 of serum in a total volume
of 1 ml for 2 hours at 37° C followed by 16 hours at
4° C. Separation of bound and free radioactivity
was achieved by the addition of 1 ml of 25%
polyethylene glycol as described by Creighton et
al.19 Results are expressed as nanograms of hCG
bound per milliliter of serum. At the end of the
experimental period, samples were retitrated us
ing a single lot of iodinated hCG; it is these titers
that are reported. Further cross-check was af
forded by titration of samples at both The Popula
tion Council and The All India Institute of Medical
Sciences. Agreement was generally satisfactory.
The results reported are those obtained at The
Population Council. Anti-TT titers were measured
by the passive hemagglutination procedure of
Boyden.20
Vaccine. The vaccine used was prepared at the
All India Institute of Medical Sciences by coupling
the 3-subunit of hCG with TT using 1-ethyl3-(3-d i methyl am i nopropyl )carbod i i mide rea gent
(ECDI) in aqueous solution. The ^-subunit of hCG
was of high purity (10,000 lU/mg ofprotein). It was
further immunochemically purified by absorption
on anti-ovine LH immunoadsorbent as described
elsewhere.4 TT was obtained from the Pasteur In
stitute (430 Lf/ml, 2,000 Lf7mg of protein N).
Ahlb
Possible urinary tract
1/10
Bjork
Fluid retention
Weight gain
Breast tenderness
Short cycles
Hypoglycemic attack
1/10
2/10
V10
1/10
Halls
Rash at injection site
2/8
Varicose vein operation
Edema
4/10
Weight gain
1/10
Vaginitis
Adnexa slightly enlarged 1/6
Slight neovaecular change 1/5
Influenza
1/6
Loob
Aalt
Hem
Borg
Reyi
Pere
Valle
Urinary infection
Adnexa slightly enlarged
Influenza
Uterus slightly enlarged.
tender
Uterine infection
Bronchitis
Rash at injection site
Excessive menstruation
Slight pain in colon
Migraine
Mild skin Infection
Colostrum
Dizzinessand vomiting 1st
1/12
1/12
1/7
1/7
3/14
1/14
Herpes on lip
1/14
Colostrum
Premenstrual abdominal
3/18
2/18
Adnexal pain
Dysmenorrhea
Nausea and vomiting
Tonsillitis
Trichomonas infection
Headache
Influenza
Dyspareunla
Adnexal enlargement and
1/18
1/18
1/18
1'18
1/18
1H
I'7
I'7
Alne
ABdS
MASdS
A
1/11
1/9
1/12
1/8
2/12
1/12
1/12
1/12
1/12
1/12
1/8
1/6
2/5
2/13
1.
}
1
V13
Oligomenorrhea
1
Soreness at site
Dental abscess
.
Pelvic inflammatory
1^
1/7
VI1
ANTIGENICITY AND CLINICAL EFFECTS OF ANTIPREGNANCY VACCINE
331
TABLE 3. Clinical Chemistry Measurements of Vaccinated Subject* before Vaccination, during Response,
and after Return of Antibody Titan to Baseline
1W."
Nwmalnu><.
*
Durin<
Total protein (gm/100 ml)
6.6-83
7.62 X 0.40
7.17 x 0.70
7.34 x 0.60
Albumin (gm/100 ml)
4.40 x 0.33
4.33 x 0.53
3.5-6.0
4 39 X 0.40
Albumin-globulin ratio
1.0-2.2
1.67 X 0.67
1 66 x 0.47
1.54 X 0.62
Cholesterol (mg/100 ml)
208 x 33
135-316
193 X 30
195 x 30
Glucose (mg/100 ml)
70-110
86.6 X 14.8
83.4 x 13.3
86.2 x 11.9
Inorganic phosphorus
25-4.8
3.69 X 0.67
3.69 x 0.92
3.38 x 0.46
(mg/100 ml)
Calcium (mg/liter)
4.6-56
4.95 x 1.46
6.74 x 199
5.31 x 1.47
Alkaline phosphatase (unite)
67.5 x 16.3
35-148
62.4 x 18.2
54.9 x 21.3
Uric acid (mg/100 ml)
4.23 x 1.15
2.8-76
3.78 x 1.08
4.14 x 1 15
14.2 x 4.55
Urea N (mg/100 ml)
14.6 x 4.01
8-26
14.5 x 4.70
Bilirubin (mg/100 ml)
<1.6
0.65 x 0.25
0 68 x 0.46
0.70 x 039
16.5 x 8.68
SGPT (unite)
18.19 X 7.04
6-40
20.2 x 6.47
SGOT (unite)
23.3 x 5.97
22.8 x 6.21
13-69
28.0 x 7.92
Thyroxine (pg/100 ml)
6.91 x 1.39
7.21 x 1.30
4.6-11.2
6.48 X 1.16
"Values are means x standard deviation. Sea ’Material! and Methods** for further definition of “during” and “port-."
To effect coupling, 8 mg of the processed 0the type of TT and the medium in which it was
subunit were mixed with 1000 Lf of TT and 40 mg
suspended.
of ECDI in 8.0 ml of 0.05 M sodium phosphate
Analysis of Results. For purposes of analysis,
buffer (pH 7.4) in 0.9% saline, and the mixture was
findings were grouped into three time intervals for
incubated for 6 hours at 4° C against 0.05 M
each subject. They were labeled "pre-," "during,"
sodium phosphate buffer (pH 7.4) in 0.9% saline. It
and "post-” treatment. The "during" treatment
was then filtered through a Millipore membrane
period encompassed the 200 days after the first
(0.45 p.m pore size) to sterilize, and 5.0 ml ofsterile
vaccination or the period of significant hCG anti
10% potassium aluminum sulfate dodecahydrate
body titers, whichever was the longer. The signifi
solution was added. After thorough mixing, 5.0 ml
cance of difference between values obtained dur
of 10% sodium carbonate solution was added to
ing these three periods was tested by using Stu
precipitate aluminum hydroxide. The suspension
dent's t distribution, comprehending all observa
was distributed into sterile glass vials. Prepara
tions and taking into account the covariance of the
tion of the calcium phoephate-adsorbed material
repeated observations on the same individuals. To
was similar in principle, the preparation of cal
calculate the mean value of a set of observations
cium phosphate being effected by adding sterile
during a specified time interval (e.g., "before"), the
NaaHPO< and CaCla.
mean value for each individual was calculated
Analysis of this batch of vaccine on sucrose den
first, and the resulting value was used in the deter
sity gradients (5%to 40%) was carried out by cen
mination of the mean for all individuals. Some
trifugation at 105,000 x g for 16 hours and subseobservations on individuals were missing.
quent estimation of 0-hCG in each fraction by
radioimmunoassay. These determinants indicated
RESULTS
that only 10% of the p-hCG was coupled to TT in
this particular batch. Subsequent experience has
Patient Observations and Complaints. Com
shown that the degree of conjugation varied with
plaints voiced by subjects during the interval from
TABLE 4. Hematologic Parameten before Vaccination. during Response. and after Return ofAntibody Concentrations to Baseline
Normal ru
*.
*
Na
*
Brfora
*
Dunas
Hemoglobin (gm/100 ml)
13.4 x 1.6
12.9 x 0.8
12.9 x 1.1
Hematocrit (%)
37-47
39 6 x 2.6
39.8 x 2.2
39.9 x 2.6
White blood cells (thou6.3 x 1.8
6-10
6.3 x 1.2
a&nda/aq mm)
Lymphocytes (%)
20—40
35.9 X 7.8
36.2 x 7.8
36.8 x 6.6
Neutrophils (%)
40-60
54 6 x 9.6
54.1 x 7.1
66.1 x 8.9
Monocytes (»)
4-8
5.67 x 2.3
4.81 x 1.9
4.33 x 1.1
Basophils U4)
0 36 x 0.4
O-l
0.20 x 0.4
0.65 x 0.9
Eosinophils (%)
4.11 X 3.5
1-3
4.16 x 2.5
3.60 x 2.2
Sedimentation rate
13-6 x 7.6
<20
11.9 ± 4.3
12.2 x 6.1
"Values are means ± standard deviation. See "Materials and Methods" for further definition of "during” and “port-."
Vol. 34, No. 4
ANTIGENICITY AND CLINICAL EFFECTS OF ANTIPREGNANCY VACCINE
October 1980
TABLE 5. Significant Chang" with Direction of Change
between Earlier and Later Value/ Indicated by Arrows
first vaccination to the present, and conditions de
tected by physical examination, are summarized
in Table 2, together with indication of whether the
event occurred "during” treatment or "post-” treat
ment. The number opportunities for registration
of the condition (clinic visits) is also indicated.
There were two instances of rash at the injection
site and another instance of some pain at the injec
tion site. Edema and weight gain, which were in
terpreted by the clinician (T. L.) as being premen
strual in origin, were recorded in two subjects fol
lowing vaccination. Slight adnexal enlargement
in two subjects, adnexal pain in another, and
adnexal enlargement and pain in a fourth were
encountered. Colostrum was recorded in two sub
jects and breast tenderness in another. One subject
had a transient episode of rheumatic joint pain.
Body weight increased an average of 0.5 kg be
tween pretreatment and "during" treatment
periods and an average of 0.5 kg between "during”
and "post-.” There were five losses and eight gains
in the first instance, and three losses and seven
gains in the second.
Clinical Chemistry and Hematology. Clinical
chemistry and hematology findings "before," "dur
ing," and "post-" treatment are summarized in
Tables 3 and 4. Parameters that changed suf
ficiently to meet tests of statistical significance are
identified in Table 5. The mean values of ail clin
ical chemistry measures fell well within the "nor
mal” range for each parameter with the exception
of serum calcium values (Table 3). The "before"
treatment mean for serum calcium exceeded the
"normal” limits because of exceptionally high
values for the clinic in Brazil. Among the hemato
logic measurements, the mean eosinophil values
exceeded normal limits at all times. The reason is
not known. It may represent parasitic stimulation.
Plasma cortisol values were obtained "during"
treatment on seven subjects. Values below the
"normal” range of 5 to 20 pg/100 ml were recorded
in two subjects. Subsequent values were in the
normal range for one of the subjects. Later analy
ses have not been obtained on the second subject.
DNA antibody readings slightly above (1.2 and
1.3) the normal of under 1.0 jig of DNA bound/ml,
but in a range considered nonspecific, were
obtained for four subjects "during" treatment.
Values have been consistently below 1.0 "post-"
treatment for all except one subject for whom
"post-” treatment analyses are not available.
Clinical chemistry and hematology findings
were also analyzed for evidence of trends in indi
vidual subjects and for evidence of notable changes
Days post voteino lion
Flo. 1. Antibody responses in women vaccinated with 0-hCG-
in the percentages of subjects with values falling
outside the "normal” limits (as defined by the test
ing laboratory). Among clear-cut trends in indi
vidual subjects were a decrease in alkaline phos
phatase in one subject (Halla) and an increase in
another (Hein); decreases in SGPT in three sub
jects (Aalt, Halla, and ABdS) and increases in
monocytes in one subject (Loob). Trends in the
number of subjects with individual values beyond
the "normal” limits were as follows: three subjects
with "high" inorganic phosphorus values "during”
treatment and none at other times; five subjects
with hemoglobin below 12 gm/100 ml "during”
treatment and only one before treatment; and four
subjects with "low" SGOT and three with "low”
SGPT "post-” treatment versus none before treat
ment.
333*
All urinalysis results were normal.
Although the number of pertinent data is small,
progesterone assays of plasma samples taken dur
ing the luteal phase (defined as 18 days since the
last menses and 4 to 11 days prior to the next
menses) gave no indication of correlation between
progesterone levels and anti-hCG titer. Among 19
samples with binding capacity for 12AI-hCG lees
than 2 ng/ml, the average progesterone level was
5.8 ng/ml, and six samples had values less than 4
ng/ml; among 13 samples with binding capacities
above 2 ng/ml, progesterone levels averaged 7.7
ng/ml, with three samples having levels below 4
ng/ml.
Menstrual Cycles. Menstrual cycles have been
analyzed in terms of days of bleeding and days
between bleeding episodes. Totaling the two give
*
the cycle length. Values for individual subjects are
summarized in Table 6. Treatment has not caused
significant effects on the number of days of bleed
ing and no impressive trend has been seen for any
individual subject. Neither are there significant .
trends in the average number of days between
bleeding for the group as a whole, or for individual
subjects. One subject (Aalt) did show a 120-day
period of amenorrhea following vaccination, from
which she recovered spontaneously. She had occa
sionally experienced periods of amenorrhea dur
ing the previous several years.
Antibody Responses. Antibody responses in
terms of anti-hCG titers are represented in Figure
1. Responses differed in both duration and intensi
ty, with the longest duration of detectable titers
being 400 days. Only one subject (Borg) failed to
show a response. Responses in two other subjects
(Halla, Valle) were extremely low.
All subjects showed a response in anti-TT titers.
An attempt to correlate anti-hCG and anti-TT re
sponses is represented in Figure 2. It shows the
areas under the anti-hCG and anti-TT curves dur
ing the first 400 days after vaccination in arbitrary
units. A trend toward a greater anti-hCG response
with a greater anti-TT response is evident The
greatest discrepancies from the trend lie in four
subjects who evidenced a high anti-TT response
and only a low anti-hCG response. There was no
clear-cut correlation between previous TT vac
cination and magnitude of anti-hCG response. In
most cases, the anti-TT titers and the anti-hCG
titers rose simultaneously. In two instances, very
high anti-TT titers were attained (1:10,400), while
anti-hCG titers were still at zero. hCG titers had
reached 6 and 1.8 ng of l26I-hCG bound/ml of'-’
serum 2 weeks later.
Vol. 34, No. 4
ANTIGENICITY AND CLINICAL EFFECTS OF ANHPREGNANCY VACCINE
Das C, Salahuddin M, Talwar GP: Investigation on the
ability of antisera produced by Pr-B-hCG-TT to neutralise
the biological activity of hCG. Contraception 13:171,1976
Nath I, Gupta PD, Bhuyan UN, Talwar GP: Autopsy report
on rhesus monkeys immunized with Pr-B-hCG-TT vaccine.
Contraception 13:213, 1976
14.
Nath I, Whittingham S, Lambert PH, Talwar GP: Screen
ing for autoantibodies in human subjects immunized with
Pr-5-hCG-TT. Contraception 13:225. 1976
15.
Nath I. Dubey SK, Talwar GP: Hypersensitivity reactions
in monkeys immunised with Pr-B-hCG-TT. Contraception
13:231, 1976
16.
Talwar GP, Sharma NC, Dubey SK, Salahuddin M, Dm C,
Ramakrishnan 8, Kumar S, Hingorani V: Isoimmuniza
tion against human chorionic gonadotropin with cocjugatee of processed B-subunit of the hormone and tetanus
toxoid. Proc Nati Acad Sci 73:218. 1976
17.
Das C. Talwar GP, Ramakrishnan 8, Salahuddin M.
Kumar 8. Hingorani V. Coutinho E, Croxatto H. Hemmingaon E, Johansson EDB. Luukkainen T, Shahani S,
Sundaram K. Nash HA. Segal SJ: Discriminatory effect of
anti-Pr-B-hCG-TT antibodies on the neutralization of the
biological activity of placental and pituitary gonadotro
pins. Contraception 18:35, 1978
18.
Catt KJ, Dufau ML, Tsuruhara T: Studies on radioligand
receptor assay system for luteinizing hormone and cho
rionic gonadotropin. J Clin Endocrinol Metab 32:860.1970
19.
Creighton WD, Lambert PH, Meiacher PA: Detection of
antibodies and soluble antigen-antibody complexes by pre
cipitation with polyethylene glycol. J Immunol 111:1219.
12.
NASH ET AL
Fin. 2. Comparison of ■rran under anli-hCG and anti-TT
reeponee curve
*
for subjects receiving p-hCG-TT. •. Responses
in subjects who had had previous vaccinations; -o-, subjects who
believed they had not recieved previousTT vaccination but who
had appreciable anti-TT titers before receiving p-hCO-TT vac
cine.
Antisera were capable of neutralizing the activ
ity of hCG in stimulating testosterone production
in Leydig cell cultures. They showed some cross
reaction with hLH as has been detailed in an ear
lier publication. 17
DISCUSSION
The findings of this study confirm the report by
Kumar et al.8 that antibodies capable of interact
ing with hCG can be elicited in humans by cou
pling the purified 0-subunit with a protein that is
antigenic to humans. The magnitude of the re
sponse is somewhat lower than that reported by
Kumar et al." This may be a result of the small
percentage of the p-hCG that was actually coupled
to TT in the present study. The potency of 0-hCG
polymer as an antigen for humans is not known
but it cannot be high, as indicated by the moderate
antibody response of most subjects in the present
study.
The level of antibody titer required to interfere
with pregnancy is unknown. Some estimate of the
amount of hCG that might be produced by the
developing trophoblast can be calculated from the
data of Braunstein et al.21 These investigators
estimate that at 10 days after ovulation the
•rophoblast consists of approximately 3000 cells,
October 1980
each producing 1.4 X 10‘2 IU of hCG/celVday. The
total production at this rate would be 4.2 jig/day.
At 16.5 days, the date of Braunstein et al.21 indi
cate 10
* cells and a production rate of 7.9 x 10’4
lU/cell. This represents a total production of 79
p.g/day. If one assumes that pregnancy termina
tion requires hCG production to be neutralized for
4 days following the first appearance of hCG in
maternal blood, the requirement based on this
date would be neutralization of approximately 40
pg of hCG. Assuming the correctness of these esti
mates and assuming that only the antibodies in
the serum are available for inactivation of hCG,
binding capacity for 20 ng of hCG/ml of serum
would be required for effectiveness.
The study has given no evidence of disturbing
physiologic effects as judged either by symptoms
and complaints or by clinical chemistry. The up
ward trend in average serum protein levels is
small and reaches significance only in comparison
of levels before treatment and levels after antibody
titers had returned to baseline. The upward trend
in uric acid serum levels is small, and no values
were above the "normal" range. Some were below
the normal range. The downward trends in serum
transaminase values are not believed to have clin
ical significance. The higher frequency of "high"
inorganic phosphorus values "during” treatment
is difficult to interpret and there is no significant
trend in mean values.
Although there were four instances of adnexal
enlargement or pain, this condition occurs with
appreciable frequency in untreated women, and
the absence of a control group examined at equal
frequency makes the finding difficult to interpret.
The one episode of rheumatic joint pain is not
thought to be related to the vaccine. Upon reques
tioning, the subject was found to have had such
episodes with fairly high frequency before admin
istration of the vaccine.
In conclusion, the trial of the vaccine has con
firmed that it elicits production in humans of anti
bodies capable of combining with hCG. This alone
gives no assurance of effectiveness in preventing
pregnancy, and the marked variation in response
among subjects indicates a need to modify the vac
cine before satisfactory effectiveness can be ex
pected. Modifications will require additional safe
ty tests. However, it is reassuring that no signifi
*
cant evidence of deleterious effects on the health or
well-being of the subject^emerged from the pre
sent studies.
1. Thompson KW: Antihormones. Physiol Rev 21:688, 1941
2. Talwar GP. Dubey SK, Salahuddin M. Shastri N: Kinetic
*
of antibody response in animate injected with processed
beta-hCO conjugated to tetanus toxoid (Pr-B-hCG-TT).
Contraception 13:153. 1976
Talwar GP. Dubey SK, Salahuddin M. Das C. Hingorani V,
Kumar S: Antibody responses to Pr-B-hCG-TT vaccine in
human subjects. Contraception 13:237, 1976
Talwar GP, Sharma NC. Dubey SK, Salahuddin M, Shastri
■ubuni t of human chorionic gonadotropin for minimization
13.
traceplion 13:131, 1976
Dubey SK, Sharma NC, Talwar GP: Survival of animals
injected with Pr-B-hCG-TT. Contraception 13.196, 1976
6. Prasad CR, Srimal RC, Dhawan BN: Acute toxicity and
pharmacology of p human chorionic gonadotropin conju
gated tetanus toxoid (pr-B-hCG-TT). Contraception
13:189, 1976
7.
Gupta L. Dubey SK.Talwar OP: Investigations on pharms.
copoeial safety, microbial sterility and pyrogens of Pr-phCG-TT. Contraception 13:183, 1976
8.
Kumar S, Sharma NC, Bgjgj JS. Talwar GP. Hingorani V:
Clinical profile and toxicology studies on four women im
munized with Pr-B-hCG-TT. Contraception 13:253, 1976
9.
Ramakrishnan S, Dubey SK, Das C, Salahuddin M, Talwar
GP, Kumar 8, Hingorani V: Influence of hCG and tetanus
toxoid injections on th
* antibody titers in a subject immu
nized with Pr-B-hCG-TT Contraception 13:245, 1976
10.
Shanna NC. Goal BK.
JS, Talwar GP: Metabolic,
20.
Boyden SV: The absorption of proteins on erythrocytes
endocrine and organic functions in monkeys immunized
treated with tannic acid and subsequent hemagglutination
with Pr-p-hCG-TT. Contraception 13:201, 1976
by anti-protein sera. J Exp Med 93:107, 1951
11.
Salahuddin M, Ramakrishnan S, Dubey SK, Talwar OP:
21.
Braunstein GS.GrodinJM.VaitukaitisG, Rose GT: Secre
Immunological reactivity of antibodies produced by Pj-£tory rates of human chorionic gonadotropin by the normal
hCG-TT with different hormones. Contraception 13:163,
trophoblast Am J Obetet Gynecol 115:447, 1973
6.
CONTRACEPTION
PHASE I CLINICAL TRIALS WITH THREE FORMULATIONS OF
ANTI-HUMAN CHORIONIC GONADOTROPIN VACCINE
PRINCIPAL INVESTIGATOR:
INVESTIGATORS:
ABSTRACT
GP Talwar
V Hingorani/ S Kumar2, S Roy/
A Banerjee3, SM Shahani4, U Krishna5,
K Dhall/ H Sawhney6, NC Sharma,
Om Singh, A Gaur, LV Rao, K Arunan
S Mokkapati, S Datey, S Gupta,
COORDINATING UNIT7:
M Roy, BK Singh, LN Gaur
BN Saxena7
PROJECT COORDINATOR:
National Institute of Immunology, Nev Delhi
2.
3.
4.
5.
6.
All India Institute of Medical Sciences, New Delhi
National Institute of Health & Family Welfare, New Delhi
TN Medical College S BYL Nair Ch Hospital, Bombay
Seth GS Medical College & KEM Hospital, Bombay
Postgraduate Institute of Medical Education and Research,
7.
Chandigarh
Indian Council of Medical Research, New Delhi
Comparative phase I clinical trials were carried out in 5
centres with three formulations of beta-hCG-based vaccines
inducing antibodies against human chorionic gonadotropin. The
objectives of these trials were to determine their relative
immunogenicity, duration, reversibility and safety.
A total
of 116 tubal ligated women volunteers were enrolled in the
study and 101 subjects were followed-up for one year or more
until the antibody titres declined to near zero levels. Every
woman receiving the vaccine produced anti-hCG and anti
tetanus antibodies. Clinical examination carried out at
intervals of 4-6 weeks revealed no abnormality. No serious
side effects or adverse reactions were reported with any of
the formulations during primary immunization with three
monthly injections' of the vaccine. Eleven women, however,
demonstrated hypersensitivity to test dose at the time of the
booster injection. The reaction was to tetanus toxoid;
gonadotropin subunits conjugated to another carrier did not
evoke any such reaction. Progesterone in bleeds taken at midluteal phase, as well as complete progesterone and estradiol
done in two
immunized women, indicated normal ovulatory
cycles.
Immunization with these
formulations
had
no
significant effect on haematological, clinical chemistry and
other metabolic parameters. In summary, the results indicate
that none of the three beta-hCG-based contraceptive vaccines
had any adverse effects clinically, on endocrine status and
metabolic
parameters.
Formulations
A
and
B
induced
comparatively higher anti-hCG titres than M. Thus, further
work can be undertaken to study the efficacy of these
vaccines in humans for preventing pregnancy.
INTRODUCTION
Reprint
requests:
Dr GP Talwar, National Institute of
Immunology, New Delhi 110 067.
A number of contraceptive vaccines which induce the
formation of antibodies against human chorionic gonadotropin
(hCG) are under development.
A prototype vaccine consisting
of the beta-subunit of hCG linked to tetanus toxoid (TT) was
found effective in generating antibodies in women against
hCG, together with creation of immunoprophylaxis against
tetanus (1).
The antibodies were competent to bind with hCG
administered exogenously
and neutralize the bioactivity of
the hormone in vitro and in vivo (1,2). The antibody response
was reversible
and phase I studies conducted in six centres
in five countries showed that the vaccine was safe and devoid
of side effects (3-6). However, it was noticed that there was
a wide variability of antibody titres amongst the recipients
and those with inadequate titres were not protected from
pregnancy.
Submitted for publication September 29, 1989
Accepted for publication November 14, 1989
MARCH 1990 VOL. 41 NO. 3
301
302
MARCH 1990 VOL. 41 NO. 3
C
"T
CONTRACTION
CONTRACEPTION
Further research was directed towards the development of
formulations with improved immunogenicity.
Addition of an
adjuvant, sodium phthalyl lipopolysaccharide (SPLPS) in the
first injection increased antibody titres. Antibodies with
better bioneutralizing capacity were produced in experimental
animals by using a heterospecies dimer, where beta-hCG was
associated with alpha-ovine LH (7). Similarly, a mixture of
beta-hCG and beta-oLH, each linked to carrier, gave a better
immune response in monkeys than the subunits alone (8) . It
was further found that repeated injections with a given
carrier such as TT did not produce high response in all
animals. However, monkeys hyporesponsive to the TT-linked
vaccine produced higher titres when the hormonal subunit was
presented on an alternate carrier, such as cholera toxin
chain B (CHB).
These investigations led to the development
of two new formulations for the beta-hCG vaccine besides the
earlier version beta-hCG-TT (formulation B). These were:
alpha-oLH-beta-hCG-TT/CHB (formulation A) and mixture of
beta-hCG-TT/CHB and beta-oLH-TT/CHB (formulation M) .
The
present study was undertaken with the objectives of
determining the relative immunogenicity, reversibility and
safety of these formulations in women.
This communication is
a report on the multi-centric clinical trials carried out on
these
vaccine
formulations.
The
approval
of
the
Institutional Ethics Committee was obtained, besides the
permission of the Drug Controller of India.
MATERIALS
AND
METHODS
Beta-hCG purified from hCG (10000 to 13000 lU/mg) was made
available by the Population Council. Ovine LH subunits were
purified from crude lyophilized sheep pituitary powder
(Phoenix Chemical Ltd., Christchurch, New Zealand) by
following the procedure of Liu and Ward (9). The homogeneity
of the subunits was checked on sodium dodecyl sulphate
polyacrylamide
gel
electrophoresis
(SDS-PAGE),
where
individual subunits migrated as single diffuse bands in a 10%
gel. Heterospecies dimer of beta-hCG and alpha-oLH was
generated as described elsewhere (7).
Tetanus toxoid (Wyeth Laboratories, Marietta PA, Batch
No. 4381, 350 Lf/ml) was purified on a Sepharose-6B column.
The high molecular weight (150 kD) component was used for
conjugation. The homogeneity of cholera toxin chain B (Batch
CHB 10000, Institut Merieux, Lyon, France) was checked on
SDS-PAGE: toxin B chain migrated as a single protein band of
about 12 kD molecular weight.
Conjugates of gonadotropin with carrier were prepared by
coupling beta-hCG, beta-ovine LH or heterospecies dimer with
TT using a hetero-bifunctional agent, succinimidyl-4-(Nmaleimidomethyl) cyclohexane-1-carboxylate, and with CHB' by
the periodate oxidation method as described (10).
The three vaccine formulations investigated were B, A and
M. These were adsorbed on aluminium hydroxide (Alhydrogel,
Batch No. 1635 Superfos, Vedbaek, Denmark) under aseptic
conditions. Each ampule marked for the first injection
contained one mg of detoxified lipopolysaccharide (SPLPS).
Each preparation was tested for sterility and pyrogenicity
before release to the clinics.
The subjects enrolled were tubectomized women of 25 to 35
years of age,
of proven fertility,
reporting regular
menstrual periods, non-lactating with no known history of
allergy, and willing to come for regular follow-up. The
volunteers were enrolled after obtaining their written
consent. The protocol envisaged the study on a total of 105
subjects, distributed over five collaborating centres located
in 3 different parts of the country. Each formulation of the
vaccine was investigated at two dose levels, i.e. 100 pg and
500 pg gonadotropin content. Thirty subjects were to be
immunised with each vaccine formulation, 15 at 100 pg dose
level and 15 at 500 pg dose level (3 per dose per vaccine per
centre). Fifteen subjects were to receive vehicle only and
serve as controls (3 per centre).
The subjects after enrollment were followed-up for 2
cycles to record the menstrual cycles and basal clinical
chemistry and haematology values. Progesterone levels in
blood samples taken between day 21 and 25 of cycle were also
determined.
Before each injection, subjects were tested for possible
sensitivity to the vaccine by injecting a test dose (0.05ml)
intradermally. The vaccine in a volume of 0.8 - 1.0 ml was
given intramuscularly into the gluteal muscle. Primary
immunization consisted of 3 injections at an interval of 4-6
weeks; a booster injection was given at 24-32 weeks.
The
subjects were clinically examined at 4-6 weeks intervals or
earlier if considered necessary by the subject or the
investigator during the study period of one year. All the
subjects were asked to maintain their menstrual diary card.
Antibody titres against hCG and other characteristics of
the antibodies were determined in blood samples taken at 4to 6-week intervals (10). Cross-reactivity with hLH was
determined by a competitive inhibition assay. Anti-carrier
antibody levels were determined by enzyme-linked immuno
sorbent assay. Various dilutions of each antiserum (1:200 to
1:8000) were incubated at 37°C for 1 hr with the respective
antigen coated onto 96-well plate. After washing, incubation
was carried out with protein A-horseradish peroxidase conju
gate, colour developed with orthophenylene diamine and
hydrogen peroxide, and absorbance read at 490 nm. Anti-TT and
anti-CHB titres were computed from readings in linear range
and expressed as units/ml serum. Haematological parameters
(eg. hemoglobin, total and differential leucocyte counts,
platelet count and packed cell volume) and clinical chemistry
304
RflAnru inon vni
wn -
MARCH 1990 VOL. 41 NO. 3
CONTRACTION
CONTRACEPTION
TABLE II: Details of dropout cases
parameters (eg. glucose, cholesterol, creatinine, bilirubin,
urea, alkaline phosphatase, SGOT, SGPT) were repeated at 24
weeks and 52 weeks following immunization.
Injection
lation
RESULTS
A total of 116 subjects were enrolled, out of which 15
dropped out from the trial (Table I) . Amongst these, two
subjects were excluded from the trial due to non-adherence to
the study protocol, one subject had completed initial
immunization schedule but was lost to follow-up at 32 weeks.
2nd
1st
Code
Dose(pg)
Enrollment
Dropouts
Alpha-oLH-beta-hCG
-TT/CHB
A
100
500
17
16
*•
Beta-hCG-TT
B
100
500
18
16
4
1
Beta-oLH-TT/CHB +
beta-hCG-TT/CHB
M
100
500
16
17
i
2
Control (Vehicle only)
c
-
Total
Dizziness,
palpitation
and fever
No complaint
No complaint
Erythema 6x5cm,
inj. not given
B-100
No complaint
No complaint
M-500
Redness,
edema, urti
caria, fever
2nd injection
not given
M-500
Redness,
itching, inj.
not given
1
16
3
116
15
Medical reasons
The remaining 12 subjects did not complete immunization
schedule and discontinued the treatment due to different
reasons; 4 subjects due to reactions following injections, 5
due to other medical reasons and 3 owing to personal reasons.
The details of subjects discontinuing
due to side effects
and other medical reasons are given in Table II. In the
remaining 101 subjects who completed 52 weeks or more of
observation, no serious side effects were reported with any
formulation.
Reactions to Primary Immunization
A-500
Dizziness
No complaint
No complaint
B-100
Fever, pain
at site
No complaint
Did not come
for inj. due
to PID
B-500
No complaint
No complaint
Edema feet,
face and
joint pain
M-100
Erythema
Joint pain,
swelling
swelling of
(6x5x3 cm)
interphalangeal joints
of fingers
and right toe
Control
No complaint
Out of 88 subjects who were immunized with different
formulations of the hCG vaccine, 63 subjects did not have any
complaints following first injection
(Table III).
The
remaining 25 subjects (28%) had minor complaints such as
erythema,
pain at site of injection,
fever,
oedema,
306
MARCH 1990 VOL. 41 NO. 3
Erythema 6.booster
not given
A-100
TABLE I: Subject enrollment and dropouts
Vaccine
Booster
3rd
Reactions
305
No complaint
Diagnosed t<
have TB,
booster
not given
Symptoms
persisted,
booster
not given
Inj. not
given due to
joint pain
No complaint
Chronic
bronchitis
booster
not given
MARCH 1990 VOL. 41 NO. 3
CONTRACEPTION
TABLE III : Reactions/complaints* following 1st injection
Formulation
(Subjects)
A-100
(14)
A-500
(15)
B-100
(14)
B-500
(15)
M-100
(15)
M-500 Control
(15)
(13)
13
10
11
No complaint
8
11
10
Erythema/
swelling
at site
2
1
2
1
-
2
-
Pain at site
2
3
-
-
3
2
2
Fever
2
A-100
(14)
1
2
-
3
1
2
Leg pain
-
-
1
-
-
-
1
1
-
-
-
-
-
1
-
-
-
1
-
-
-
-
-
-
.
-
following 2nd/3rd injection
A-500
(15)
B-100
(14)
B-500
(15)
M-100
(15)
M-500 Control
(15)
(13)
2nd injection
13
13
14
12
13
11
Erythema/
swelling
at site
-
-
1
2
1
-
Pain at site
1
-
1
2
-
1
-
1
-
-
2
1
1
-
12
.
Fever
1
Weekness/
dizziness
Formulation
(Subjects)
No complaint
Generalised
rash/itching
Nausea/
vomiting
10
CONTRACEPTION
TABLE IV: Reactions/complaints
*
Joint pain
1
-
-
-
Muscle/
leg pain
1
1
-
-
-
-
-
Nausea/
vomiting
1
-
-
-
-
-
13
14
13
14
14
14
13
1
1
-
1
1
-
1
1
1
3rd injection
Some subjects reported more than one complaint.
No complaint
Pain at site
generalised rash, transient joint pain, nausea, muscle pain
and giddiness. Out of 13 controls, 3 subjects (23%) also
reported pain at the site of injection, fever and weakness.
The number of subjects with such complaints were less
following the second and third injections (Table IV).
The data was also analysed for the number of subjects who
developed side effects after one, two, three or all four
injections. Amongst the 49 subjects who reported side effects
following injections, a majority of them (31 cases) reported
complaints only once. Only one subject had complaints
following all four injections.
Hypersensitivity Reaction to Booster
Out of 89 subjects who received booster dose of the
vaccine, 11 subjects manifested senstivity to test dose
(Table V). Hypersensitivity reaction to the test dose in ten
subjects was obviated by giving the booster injections either
without carrier or with alternate carrier such as CHB.
This
indicated that the sensitivity was to the carrier TT and not
to the hormonal subunits attached to it.
MARCH 1990 VOL. 41 NO. 3
307
Fever
1
-
1
_________
* Some subjects reported more than one complaint.
Hormonal Profile
The protocol envisaged progesterone estimation in only one
blood sample taken during the luteal phase. In spite of our
best efforts, the blood samples could not be collected every
time during the mid-luteal phase. However, the data was
analysed retrospectively in relation to the day of onset of
menstruation. Table VI represents the data in women whose
blood was drawn between 3
and 7 days before the onset of
menstruation. The values are indicative of ovulatory cycles.
It is further apparent that the progesterone values are not
influenced by the prevailing anti-hCG antibodies, nor with
the degree of cross-reaction with hLH. In two women, it was
MARCH 1990 VOL. 41 NO. 3
CONTRACEPTION
TABLE V: Hypersensitivity
time of booster injection
Formulation
Complaint
A-100
Reaction
reactions
with
test dose
at
the
CONTRACI
Table VI: Progesterone values in 20 serum samples drawn
between 3 and 7 days prior to onset of menstruation in women
after immunization with the vaccines along with prevailing
anti-hCG titres
Reaction due to
Sample
No.
Progesterone
(ng/ml)
Anti-hCG titre
(ng/ml)
% hLH cross
reactivity
TT
A-100
Reaction after
12 hours
Carrier
i
2
A-500
Reaction
TT
4
5
6
•7
8
g
10
11
12
13
14
15
16
17
18
19
20
A-500
Reaction
Carrier
A-500
Generalized itching
after 12 hours
Carrier
A-500
Pain at site
Carrier
B-500
Fever for 3 days
after 24 hours
Carrier
B-500
Odema and redness at
site after 12 hours,
disappeared in 2 days
Carrier
M-100
Reaction
Carrier
M-100
Reaction
Carrier
M—500
Large wheal formation,
itching and redness
Carrier
9.0
8.2
3.6
8.3
9.5
17.2
7.4
10.4
• 12.1
10.0
23.5
11.4
27.5
7.7
11.5
3.7
7.4
8.8
8.1
9.4
640
600
585
85
145
118
270
420
47
95
275
202
55
90
190
88
90
195
195
45
52
62
70
32
66
64
38
43
54
52
64
83
60
25
51
45
40
61
45
36
Antibody Response
possible to draw blood on a voluntary basis on alternate days
during the luteal phase. The profiles of estradiol and
progesterone are shown in Fig. 1. These levels again indicate
that the cycles were ovulatory.
Haematological and Clinical Chemistry Parameters
Haematological parameters (hemoglobin, differential and
total leucocyte counts, platelet count and packed cell
volume), metabolic parameters (glucose and cholesterol),
hepatic function tests (bilirubin, SGOT, SGPT, alkaline
phosphatase) and kidney function tests (urea and creatinine)
were done before and after immunization at 24 weeks and 52
weeks. The data indicate that the pre- and post-immunization
values for the above parameters were comparable and were
within the normal range (Tables VII, VIII).
MARCH 1990 VOL. 41 NO. 3
309
Every woman immunized with the vaccine generated anti
bodies reactive with hCG. Table
IX
gives the mean peak
titres
obtained
with
the
three
formulations.
The
characteristics of the antibodies are reported elsewhere
(10) . The antibodies had high affinity for hCG and were
effective in neutralization
of hCG bioactivity in vivo and
in vitro. At 52 weeks, anti-hCG levels were less than 20
ng/ml in 62 out of 88 subjects and in the remaining 26
subjects, titres declined to less than 20 ng in the next 2 to
12
months' time,
indicating the reversibility of the
immunization. Antibody titres required to prevent pregnancy
have been computed to be 20 ng/ml (5,11). In every woman
immunized with any of the vaccines, the titres were well
above this threshold. For formulation B and A, the mean
duration of antibody levels above 20 ng was 34 to 37 weeks.
The duration with M was comparatively shorter (17-20 weeks).
310
MARCH 1990 VOL. 41 NO. 3
CONTRACEPTION
Serum estradiol and progesterone profiles
during luteal phase in subjects 06-STY
immunized with B-500 and 06-NAC immunized
with A-SOO. Anti-hCG titres during the
period are also given.
N orm al
Figure 1::
la b o r a to r y v a lu e s a r e g iv e n in p a r e n t h e s is .
Contraception
MARCH 1990 VOL. 41 NO. 3
MARCH 1990 VOL. 41 NO. 3
311
CONTRACTION
CONTRACEPTION
KA
u n it s (c e n tr e 5 ) , u /L ( c e n t r e 6 ) . N orm al la b o r a to r y v a lu e s a r e g iv e n in p a r e n t h e s is .
TABLE IX : Anti-hCG
vaccine formulations
Formulation
n
in women
immunized with
threb
Peak anti-hCG titres (ng/ml)
Mean + SEM
A
29
322 + 75
B
29
392 + 115
M
30
136 + 65
Coincident with anti-hCG response, the vaccine also
produced an elevation of anti-TT in previously immunized
subjects or induced response as a result of primary
immunization with TT-conjugated
vaccine (Table X) . The
antibody titres were high in most of the women and persisted
above protective level over 52 weeks of observation. Women
receiving CHB-conjugates also had anti-CHB antibodies.
TABLE X: Anti-TT and anti-CHB response in immunized subjects
Peak titres (units/ml)
(range)
Formulation
Anti-tetanus
Anti-cholera
A
150 - 7800
45 - 1500
B
95 - 5300
H
380 - 3300
40 - 1850
DISCUSSION
In a comparative phase I clinical trial with 3 different
formulations of beta-hCG vaccines. A, B and M, none of the 88
subjects reported
any serious adverse side effects during
one year of observation. About 28% of the subjects immunized
with the vaccines complained of minor reactions such as
erythema, pain at site, fever and joint pain after the first
injection. However, reactions such as pain at site and fever
314
MARCH 1990 VOL. 41 NO. 3
titres
MARCH 1990 VOL. 41 NO. 3
CONTRACEPTION
CONTRACEPTION
2.
Ramakrishnan S, Dubey SK, Das C, et al. Influence of hCG
and tetanus toxoid injections on the antibody titers in a
subject immunized with Pr-p-hCG-TT. Contraception 1976;
13:245-51.
3.
Kumar S, Sharma NC, Bajaj JS, Talwar GP,
Hingorani V.
Clinical profile and toxicology studies on four women
immunized with Pr-p-hCG-TT. Contraception 1976;13:253-68.
4.
Hingorani V, Kumar S.
Anti-hCG immunization - phase I
clinical trials.
In: Talwar GP ed. Recent Advances in
Reproduction and Regulation of Fertility. Amsterdam:
Elsevier/North Holland, 1979:467-71.
5.
Nash HA, Talwar GP, Segal S, et al. Observations on the
antigenicity and clinical effects of a candidate anti
pregnancy
vaccine:
p-subunit
of
human
chorionic
gonadotropin linked to tetanus toxoid. Fertil Steril
1980;34:328-35.
6.
Shahani SM, Kulkarni PP, Patel KL,
Salahuddin M, Das C,
Talwar GP. Clinical and immunological responses with Prp-hCG-TT vaccine. Contraception 1982;25:421-34.
7.
Talwar GP, Om Singh,
Rao LV.
An improved immunogen for
anti-human chorionic gonadotropin vaccine eliciting
antibodies reactive with a conformation native to the
hormone without cross-reaction with human follicle
stimulating hormone and thyroid stimulating hormone. J
Reprod Immunol 1988;14:203-12.
8.
Talwar GP, Om Singh, Singh V, et al. Enhancement of anti
gonadotropin response to the
p-subunit
of
ovine
luteinizing
hormone
by
carrier
conjugation
and
combination with the p-subunit of human chorionic
gonadotropin. Fertil Steril 1986;46:120-6.
9.
Liu WK, Ward DN. The purification and chemistry of
pituitary glycoprotein hormones. Gen Syst Pharmacol
1975;1:545-70.
10.
Om Singh, Rao LV, Gaur A, Sharma NC, Alam A, Talwar GP.
Antibody response and
characteristics of antibodies in
women immunized with three contraceptive vaccines
inducing antibodies against human chorionic gonadotropin.
Fertil Steril 1989;52:739-44.
11.
Jones WR, Bradley J, Judd SJ, et al. Phase I clinical
trials of a World Health Organization birth control
vaccine. Lancet 1988;1:1295-8.
12.
Kharat I, Nair NS, Dhall K et al. Analysis of menstrual
records
of women immunized with anti-hCG vaccines
inducing antibodies partially cross-reactive with hLH.
Contraception 1990;41:293-99.
were also reported by some subjects (23%) enrolled in the
control group. The complaints were not repetitive in nature
and not in the same subject.
Immunization with
the three vaccine formulations did not
significantly alter the menstrual regularity (12). This is in
conformity with the previous findings that women immunized
with beta-hCG-TT and having antibodies partially crossreactive with hLH, continued to ovulate normally and
menstrual regularity was maintained (1,3,6). The mid-luteal
progesterone values and the hormonal profiles
as indicated
by progesterone and estradiol levels also indicate normalcy
of ovulatory cycles and confirms the previous observations
(1,3,6). Neither the haematological parameters nor any of the
metabolic parameters including liver and kidney function
tests revealed any change following immunization.
Taken together, the results of the present study demon
strate that immunization with three different types of betahCG-based vaccines did not produce any adverse effects.
In
every case, immunization produced antibodies reactive with
hCG along with antibodies against TT and CHB. The antibody
response was reversible; the mean duration of antibody levels
above 20 ng per ml was 34 to 37 weeks for the B and A
formulations
and
the
antibodies
were
effective
in
neutralizing hCG bioactivity in vivo (10). Formulation A and
B were comparatively more immunogenic than formulation M.
ACKNOWLEDGEMENTS
This study was supported by grants from the S & T Mission
Project of the Department of Biotechnology, Government of
India, the International Development Research Centre (IDRC)
of Canada and the Rockefeller Foundation, and benefited from
cooperative interaction with the International Committee for
Contraception Research of the Population Council, New York.
We thank Dr YY Tsong, Population Council, for making
available
beta-hCG in a collaborative IDRC project grant,
and Institut Merieux, Lyon, for the kind gift of cholera
toxin chain B. The reagents for hLH, progesterone and
estradiol RIA were generously supplied by the WHO Special
Programme of Research, Development and Research Training in
Human Reproduction under the provision of matched assay
reagents. Ms Sweety Chawla rendered valuable technical help.
REFERENCES
1.
Talwar GP, Sharma NC, Dubey SK, et al. Isoimmunization
against human chorionic gonadotropin with conjugates of
processed p-subunit of the hormone and tetanus toxoid.’
Proc Natl Acad Sci USA 1976;73:218-22.
MARCH 1990 VOL. 41 NO. 3-"
MARCH 1990 VOL. 41 NO. 3
315
<’l inical trials are in pi"xjrnss on two vaccines.
Both
of
initially designed to control fertility.
It
has
in
the
them
were
been ' found
however
these
that
are
also
useful
TWO VACCINES UNDER CLINICAL TRIALS FOR CONTROL OF FERTILITY
treatment
of reproductive tract hormone
cancers.
dependent
AND REPRODUCTIVE HORMONE DEPENDENT CANCERS
Human chorionic gonadotropin (hCG), a product of trophoblasts
and
Talvar, Om Singh, S. Snd, J. Srinivasan, Rahul Pal and
Hema Gupta
marker
of
Witiji clinical collaboration of:
of
human
Vaccination against this hormone can thus
in the ailtocrine function of the hormone and
the growth of the cancer cells.
curb
Similarly a large percentage
S.M.
of the prostate are dependent
of . carcinomas
Shahani,4 U. Krishna5
an
oncofetal
Evidences are available for this hormone or one
intercede
Banerjee,3
hCG is
protein.
lung cancer ceils.
New Delhi-110067, India
A.K.
and
synthesized
also
by
its subunit to be a growth factor for proliferation of
national Institute of Immunology,
K. Dhall,1 K. Buckshee,2 L. Saraya,2
is
early pregnancy,
a number of tumor cells.
secreted
on
androgens.
and B.N. Saxena6 for anti-hCG vaccine;
Testicular androgens are, in turn, regulated by gonadotropins
S.K. Sharma,1 S.N. Wadhwa2 and J. Frick7 for anti-GnRI! vaccine.
1. Post Graduate Institute of Medical Education and Research,
Chandigarh
under
the control of gonadotropin releasing hormone
Any
immunization
hormones,
would
of
growth
strategy
can
which
also have influence
as
benign
well as
(GnRH).
these
inactivate
on
hormone
cancerous
cells.
dependent
this
In
2. All India Institute of Medical Sciences, New Delhi
presentation,
it is intended to describe the clinical
trials
3. National Institute of Health and Family Welfare, New Delhi
on two vaccines, one against hCG and the other against
GnRH.
4. T.N. Medical College, Bombay
One
The
same
5. K.E.M. Hospital, Bombay
vaccines
stage
for
6. Indian Council of Medical Research, New Delhi
immuno-therapeutic intervention in hormone dependent cancers.
7. Landeskrankenanstalten, Salzburg
set
of trials are to achieve contraception.
advanced
have
to the clinical
trials
COUNTER hCG VACCINE
In
early
development
considerations
of
hCG
the
choice
of
birth
control
vaccines
70's,
that
this
hormone is
an
a
target
for
was
based
on
early
signal
of
as
OJ
and
i< .ersible
pre i mp I -antat i on
embryo
it
and
has
a
establishment and maintenance of pregnancy.
available
composition
form.
purified
in
and
The hornone
was
its
Moreover,
the primary sequence of
response against this hormone.
its
molecular
of
the
our
own
CTPs, even though devoid of cross-reaction
with
peptide
another group
(CTP)
of
BhCG.2
in
had poor immunogenicity.3,4 They demanded the
strong adjuvants and the antibodies generated had
use
of
relatively
lower capacity to neutralize the bioactivity of the
hormone.
in
the
peptide.3 Another difference in the the initial stage of
the
This
two
was ascribable to a limited number of epitopes
approaches
protein5
was that we advocated the use of
a
carrier
whereas Stevens2 proposed chemical modification
to
overcome tolerance to a "self" peptide.
The first prototype vaccine proposed by us consisted of
subunit
of
hCG linked chemically to tetanus
observed.
B
(TT).5
toxoid
side effects of
no
any
significance
These findings were confirmed by probing trials on
the same vaccine conducted by the International Committee for
Contraception Research of the Population Council at Helsinki,
Uppsala, Santiago and Bahia.12
antibody
advocated
carboxy-terminal
experience,
was
subunits
While we proposed the use
entire B subunit of hCG,1
hLH,
in
Two different approaches emerged to induce
known.
the
rede
critical
The limitation of this vaccine was the high variability of
titres
antibody
insufficient
individuals
amongst
against
An adjuvant, sodium phthalyl derivative
the vaccine.
(SPLPS),
lipopolysaccharide
injection. 3
was incorporated in
the
the
fact that hCG assumes a bioactive conformation only when
the
change
made
was
to
two subunits, alpha and B are associated. Individual subunits
the native conformation to a large extent .and are
loose
recognized
by
Association
with
immunological
stimulating
the
receptors
human
on
the
alpha
subunit
cross-reactivity
with
hormone
(FSH) and thyroid
target
had
hormone
alpha
subunit
associating
vaccine
conjugate
competent to induce anti-hCG response in women.
These
trials demonstrated the ability of this "structured"
to
induce
antibody
response.5*10'11
The
were
indeed
was
early
vaccine
response
was
was taken of the fact that
with
BhCG
without
the
capability
manifesting
immunological cross-reactivity with the human
the
alpha subunit.
The complex alpha-oLH-BhCG, a heterospecies dimer (HSD),
even
Leydig
a higher steroidogenic potency than the native
cell
system.14*15
of
stimulating
of
determine whether the
risk
the
follicle
heterospecies, such as ovine, retained
Advantage
not
tissues.
human
from
probing clinical trials with this
first
enhance
Another
immunogenicity of BhCG, taking
for human use at that time. After due experimental and safety
to
of
the
cognizance of
intrinsic
(TSH).
undertaken
with
pregnancy.
Further research was undertaken to improve the immunogenicity
of
This vaccine was adsorbed on alum, the only adjuvant approved
studies,6-9
those
and
were not protected
titres
Antibodies induced
by
hCG
HSD
had
in
were
induced by i'.I.v.:
neui ra I i z 11
for
•uipm ioi
those
bionctivity
of the hormone.1 J Thus one of
by ’ these researches was USD
indicated
immunogenici ty
Compa ra t i ve
the
and
safety
and
BhCG
TT
BhCG
and
Bol.ll
linked
experiment
had
linked
which
separately to carriers)
89^
were
trials
(formulation B) besides another formulaition (mixture of
fk
formulation
on
maintained;
was
carriers
to
linked
to
undertaken
regularity
Menstrual
ovulation.
of
formulations
in
animal
shown promise16 but was not found to
an
be
thyroglobulin and anti-C reactive protein reactivities.
equally
immunogen in humans.
high
year or more of follow up (88
one
completed
vaccine
<and 13 vehicle only)17,10 and 41 (36
vaccine
<and
only) have
vehicle
5
to
led
phase
of
I
7. Antibodies
women
who
receiving
the
receiving
the
101
respectively on
conducted
trials
cli nical
Two series
hCG bioactivity
inactivated
both,
vitro
in
(binding
of iodinated hCG to receptors) and in vivo
induced
testosterone
production
mice
in
and
(hCG
hypermic
response of ovaries in immature rats).17'20
following
the
8.
hCG
challenge was given in immunized women starting
from
conclusions :
day 9 post LII surge.
ml
2.
receiving
woman
Every
anti bod ies.
the
vaccine
produces
anti -hCG
with
500,
per
hCG.
In control women, hCG was detectable in the
The peak ti tres vary from 222 to 6085 ng
each
antibody
case, the antibody response was
declined to near zero
titres
The
urine
samples everyday following hormone
its
concentration
within
a
immunoreactivity
levels
immunized
affinity constants of the antibodies for hCG
was
of
high order (Ka 109 to 1011 M”1) .
Wh i 1 e
the
ant ibodies
had
cross-reactiviity
with human LI!, no cross-reactivity with
hTSli
was
investigated.
The
in
any
of
the
ol:
varying
hFSH
serum
hLH cross-reactivity did
not
and
samples
impair
women
progesterone
increased
with
antibody
values did not
ID
of
morning
administration;
time.
was measurable in the urine
bearing
days
titres.
hCG
No
samples
The
increase in immunized
of
serum
women
the
manner that they did in the control
women.
The
extent
to which hCG challenge was overcome,
varied
with
Women with titres
above
in
degree
observed
10,000 & 15000
and
period of 2 years.
3.
1000, 1500, 3000, 6000,
reversible
for formulation A at 300 ug dose level.
In
Injections were given on seven
the
prevailing antibody titres.
300 ng had no
prolongation
of the luteal phase.
conventional
contraceptives till the schedule of
injections is completed.
;
the
phenomenon.
An alternate carrier strategy was adopted
which
was
the
human
first
observation
evoked anti-hCG response in the expected manner.22
immunogenic vaccine is USD linked to carrier(s).
iers in alternate sequence proved to be
indicated
the
use
of 300
as
ug
most
The use
better
of
than
Analysis of dose
repeat immunizations with a single carrier.
response
the
trials
11
started
have
in
3
centres in India with the approval of the Drug Controller and
respective Institutional Ethics Committees.
involve
study,
with
patency
progesterone
phase
their husbands.
of
levels
ovulation
be
at an interval of 6 days.
Immunization
schedule
Anti-hCG Immunization in Lung Cancers
A
number
large
will
75
The vaccine employed will be USD linked to
TT
The
prevented
by
stage
of human lung
cancer
patients
produce
In many cases, there is discordinate synthesis
an
anti-sense RNA for
do
not
women
will
use
subunits
of
A human lung tumor cell line ChaGO
from progression to anchorage
transfected,
alpha-hCG.26
grow as tumor
mass
(unpublished
data).
thus
Cells
mice.26
nude
in
Preliminary
is
growth
independent
and
experiments
. demonstrate that serum of a human subject immunized with
USD
linked to TT/DT (formulation A) inhibited about 65% of
tumor
cell growth at a dilution of 1:1000.
Booster
per
(DT).
received
the first injection of the vaccine.
by
luteal
the
antiserum decline to levels below 150 ng (group A) or
toxoid
At
after
confirmed
injection will be given as and when hCG binding capacity
diphtheria
women
15
its
ml
and/or
manuscript,
Similar results are obtained with antibodies against hCG
consist of 3 primary injections given 6 weeks apart.
ng (group B).
1500
the
in two bleeds taken during
be
will
and
active
Before enrollment
would
cycle
A total of
in
180 women of proven fertility, sexually
cohabiting
would
The study
where
followed
draw conclusions on efficacy.
writing of this
of
alpha and ft subunits.
with this vaccine
cases
completing the two cycles of basal observations had
hCG.23-25
Phase II Clinical Trials
Phase
will be studied t*
'
time
the
for
dose
the
immunization.
In
month.
delayed, pregnancy test will be performed.
cycles
light of these studies and clinical tri< i Is,
every
clinically
women
The
be
maintain menstrual diary card and will
would
of
This
75 ng, contraceptives will be withdrawn.
or
ng
immunosuppros
mice.
primary
J
In women attaining titres above 150
potent
A
titres
recombinant
vaccine to
induce
has been developed by us recently.
high
The
of
BhCG gene has been verified earlier.
an
immunoreactive and bioactive peptide.27-28
anti-hCG
authenticity
It is expressed
The gene
as
for
specie!'.
construct
dependence
where
on
pregnancy,
immuno-interception
pregnancy.36
In
continues
in
termination
of
gonadotropin
to
leads
baboons too, anti GnRH antibodies
have
an
abortificient effect during very early phases of pregnancy.37
Male
No
immunized with GnRH vaccine
animals
adjuvants
manifested
reduction
of
with
permissible
* and
spermatogenesis
reproductive accessory gland function.38
chemothe
The possibility of developing a male vaccine based on anti
COUNTER
GnRH
GnRH.VACCINE
is
a
GnRH
decapeptide
made
It
hypothalamus.
the
by
the secretion of pituitary gonadotropins. These
immunizations
is demonstrated by the
above
mentioned
studies. The approach has however a serious handicap,
concomitant
reduction
of testosterone, which
will
namely
not
be
turn
act on gonads to generate gametes. They
also
regulate
acceptable for contraceptive purposes. Ladd et al.39,40
the
secretion
sex
steroids.
worked
out
which
restore
libido
and extratesticular needs of androgens while
keeping
of
ovarian
or
testicular
Immunization against GnRH can block all these steps.
regimes of androgen
supplements
have
the animals infertile.
Early experiments
did demonstrate the block of both
male
and female fertility by immunization against GnRH.29'30
They
Our laboratory has given attention to the possible use
of
however required the use of Freund's Complete Adjuvant
(FCA)
anti GnRH vaccine for treatment of prostatic hypertrophy
and
carcinoma of the prostate. A semi-synthetic vaccine was
made
which
not
is
permissible
studies
making
employing
response
possibility
The
against
GnRH,
of
employing
adjuvants, such as alum, was reported by
us
in
Amino
caproic
acid was attached to epsilon amino
D-lysine.
group
of
lysine and through this spacer, carrier linkage was effected.
on immunodominant epitopes of GnRH was
obtained
This
monoclonal
was
by
substituted
antibodies32
and
immunizations
by
carrier.33"35
It
was observed that passive or active immunization against this
can
which glycine at position 6 was substituted by
Further
DSA
various sites of linkage to the
decapeptide
in
TT.31
where
information
by
permissible for humans.
antibody
inducing
can suppress the progression of estrus in
inhibit
ovulation in rodents
and
in
dogs.
conjugate
gives consistently high
antibody
response.
Rats immunized with this conjugate show a drastic atrophy
the
prostate.41 Reduction of prostate size is also
in
monkeys
carried
(unpublished
of
observed
Toxicology
studies
were
out in two species of animals of both
sexes,
which
baboons.
10
data).
the
pnrmiS5ion
the
of
Drug
Regulatory
Institutional
Ethics Committees, Phase T/II clinical
have
with
started
India.
in
hospitals
immunization
this
two
major
results
show
the
belief it
of
studies
have
also
some patients. Similar
in
trials
in
vaccine
Early
the
and
Authorities
teaching
started
in Salzburg under Prof. Julian Frick
and
at
Santa
Domingo.
Early results in these clinics indicate
a
marked
fall
Prostate Specific Antigen and in
in
Immunization
Postpartum
Against GnRH
density
for
bone
of
Prolongation
of
Anovulatory Cycles
GnRH agonists have recently been employed in 9 post-partum
any
without
to observe continued inhibition of ovulation,
women
side effects.42 Immunization
significant
could
against
GnRH
achieve the same end objective. The advantage will
be
that only periodical injections will be required and the cost
of treatment will be far lower.
studies
Teratology
Mothers
immunized
were
conducted
in
bonnet
monkeys.
with GnRH vaccine, soon
after
delivery,
continue
to lactate and feed the infant. The growth
infants
remains
abnormalities
developmental
weaning
similar to those of the control
of any type were
of the infant, the immunized monkeys
as
criteria,
whereas the control monkeys regain
determined by hormonal
noted.
have
profiles
anovulatory
of
the
group.
No
After
remained
and
other
cyclicity
in
course of time. It is planned to start immunization trials in
women
the
uses
in the post-partum phase,
in several
of
this vaccine may be in endometriosis
menopausal
immunization
ascerta ined.
women.
in
However
these
the
two
benefit
conditions
under
countries
South to South collaborative programmes. Other
if
possible
and
in
post
any
of
such
remains
to
be
synth'.' .c
SUMMARY AND CONCLUSIONS
After
Two vaccines, one inducing antibodies against hCG and
other
against GnRII have been discussed.
the
Regulatory
studies
Laboratory
coupled with probing clinical trials have led to an optimized
Cor producing antibodies against hCG
formulation
minimal
expected
threshold to
protect
beyond
centres
in India have shown
an
pregnancy.
against
Phase I clinical trials conducted in two series on 142
vaccine
produces antibodies in each recipient, the antibody
response
several
that
the antibodies are effective in
inactivating
is
reversible,
the
bioactivity of the hormone and that the immunization
free
of
is
to
menstruate
regularly.
No changes in metabolic and endocrine
parameters
are
No immunopathological reactivity of any
type
is
induced by this vaccine. Formulation A (HSD-TT/DT) at 300
ug
any
seen.
has
dose
side effects. Women
continued
been selected for phase II efficacy
which
trials
have started in 3 centres in India.
A live recombinant vaccine has been made carrying the gene
of
BhCG joined to membrane anchored sequence.
has
produced
with
very high titres in monkeys.
This
vaccine
Clinical
trials
this vaccine are planned in 7 countries in
cancer patients. Lung cancer cells make hCG. An
study
human
lung
experimental
shows that the hormone or its subunits have
autocrine
function in the growth of the tumor cells.
Another
stage
makes
vaccine
which has reached
antibodies
against
GnRII.
the
The
clinical
vaccine
trials
is
a
analog of GnRII linked through a spacer
toxicological studies and approval
to
of
DT/TT.
Drug
the
and'Ethics Committees phase I/II clinical
trials
have started on the-vaccine in carcinoma of prostate patients
in 2 centres in India and one centre in Salzburg and
‘another
in Santa Domingo. Early results show efficacy of immunization
some
patients.
postpartum
women
in
women
the
in
due
interval.
The vaccine is planned
to
prolong
amenorrhea
to
and
be
used
in
inter-child
^'V.s'ye.cJ',
AJOivfc. Vl-Llbcuin?, v.c .
I,
/V-zAnsclio .
I
<-
6^-6 - Cfr ^Grji <2-c P+id7i.'i
b-tf-ftcj C<_l^ ClGJiaC-9.
tx.
^aocH
lek in
*--j1
«\c
t'C<l
(51- Qxi LnyiCTIIc-J .
LHs^-tU
1- z3a.<.x.Ja|e .
hfr-1
BIRTH
CONTROL
LJH
A 1 I 1 OOI
N I1
The Vaccgne Alternative
i August 1947. me United
ctivcty collaborating
tr
Wi:
stances it identifies as foreign.
But why should it deem foreign
LI IRH—which is. after all. pro
duced naturally in the body’
Reading it as * one of ours." tlsc
body has no reason to attack n.
common to LIIRH itself.
Tulwar’s lab synthesized a
number of such LHRII variants.
“Il was very elegant.** he say*.
referring to thfir btoclwimcal
I
kxa/e. WLCciuz.
I
(p
C4
Ubled cages—no more bananas
------ ...u mUUuBu, nuu »«icu up ironi run to nunikcys Madhwa Raj and Moudgnl reindependently dioyn Hut ncu- and Run passive lo active immu- suits, in I9MJ reported that in
I
I
Science
198^
reliable ovulation predictor—require only the conventional inccnto be harmed by such compulsory vaccination. Manufacture
eves of the marketplace. There is no dearth of market incentives for cn of jyese vaccines threatened to withdraw from the held because
antiviral drugs, and research in this field is burgeoning. If use- of ever-increasing liability suits, and the Waxman bill was designed
efficacy agamsr the AIDS virus can be demonstrated, the FDA is to Jtcm $uc|j a crisis in vaccine production Revenues come from a
likely to expedite marketing of such an agent. An mmlationmiposed on any childhood vaccine. Like any insurance
prediction test faces only straightforward FDA barriers, ryp^^-^yHcm, the beneficiaries are expected to pav the premium ibr risk
fewdrops of urine, Jklivi, or blood arc required)
The Waxman bril does nor address rtsell to die problems . .I
---- TKTwher four approaches, however, base certain handicaps, du vaccines, whose administration is noc obligaron, nor docs
elimination of which will require major legislative or social changes attention ro rhe even more senous problem associated wi
society tolerates very little risk, (iij Development times covering one AIDS epidemic, and the public’s interest in an AIDS vaccinc. for die
or two decades make any investment extremely risky', be it a California legislature to examine rcnfcdics to the product liability
company’s money or an investigator’s career. If initiative and barrier standing in the way of vaccine research^ The bill introduced
support were to depend on nonprofit or governmental agencies, by Assemblyman John Vasconcellos (52) is specifically limited to
long-term commitments would have to be made, (iii) Until now, AIDS and applies only to California. However, it represents a
only large, multinational pharmaceutical companies have had the promising model for federal legislation covering other vaccines and,
resources and expertise for drug developments of the magnitude of u j ^h to emphasize, also for contraceptives
these four contraceptive approaches. Given the long development The key provisions of die California bill arc that such a vaccine is
time, recovery of the investment and generation of profit require a recognized as “unavoidably unsafe” and thus exempt from strict
long proprietary position, which the present patent laws do not offer liability lawsuits. The bill’s key feature of restricting the manufactur
es). (iv) The legal exposure to liability suits could be extremely eft liability and of funding compensation for medical costs, loss of
risky. Impotence or prostatic cancer—two conditions commonly earnings, and pain and suffering out of an extra charge imposed on
associated with aging in males—arc likely to attract litigation by the price of the vaccine, would be essential in the contraceptive field.
men who may take their pill for 40 years and then blame it for their Improvements can be made in these legal models (5J), notably a
misfortune. Cases of permanent sterility would likely be attributed further restriction of ton law application, which is opposed by trial
to an antifertiliry vaccine if millions of nulliparous women opt for Lawyers’ lobbies, as arc most other provisions of these bills.
such a method of birch control, (v) Large pharmaceutical compa- Contraceptives and vaccines are obvious targets for superlitiganies. selling many products and having many stockholders, are likely bon, because they arc not curative drugs to be taken by people
to be more sensitive to threatened boycotts and political pressures already ill; they are administered to healthy people co prevent a
than smaller companies. A menses-inducer may well fall victim to a condition that the person may never get. Even though a no fault
fear of such pressures, even though it may be the most efficient way mjurance program, structured around self-funding, would be the
to reduce abortions
single most important incentive for the gradual reentry of the
How can the hurdles be cleared that now stand in the way of a pharmaceutical industry into the field of contraceptive innovation,
contraceptive revolution or even of modest progress’ History there are differences in perception between vaccines and contracepdemonstrates that no major advances will occur without the pamci- eves that operate against extending anv special incentives io die
paoon of the pharmaceutical industry—in production, distribution, fcnrr class.
development, and even research The tdea that such derisions should the societal and personal costs of an undcsircd pregnanes and of
be left to the marketplace is useless, for the market has already an unwanted chdd are simply not equated by the public to the
spoken: given rhe cost, time, and litigation risks, it is not worthwhile immediately evident health consequences of a disease, be it measles
ro invest in the development of new contraceptives. A survey of or AIDS. Among some groups in the United Stales, contraception
leading RSeD therapeutic categories for 1988 (fS) does not list „ mheremly suspect because of iu actual or perceived rifat on
contraceptives even among the first 35 rankings If society wants a „ul|
Finally, U.S.
j, Iikc|y lo |IX,k askance at
well-stocked contraceptive supermarket, society will have to provide incentives that, directly or indirectly, may benefit phannaecurteal
the impetus Of all incentives, addressing the litigation problem us companies, when such firms are generally among the most profitable;
the United States would be of overruling importance In fact, this is jeemn of U.S. industry. But when another decade or two of minor
precisely the area where some moves have finally been initiated by ^rovements of easting methods, or even of dunimshed conua
legislators prompted by the crisis in vaccine production and the even apOve choices, has passed, and the number of abortions, legal nr
bigger nerd for RSeD of new vaccines for infectious diseases, from dlcgal, has not dropped significandy. when this bitter pill is tasted
AIDS to malaria (SO). Strangely, rhe similarity in the problems faced by the nett generation, then the rime may be ripe for substantive
by the developers and producers of vaccines and most contraceptives changes.
Conclusion
Modification of Product Liability
In view of the present political and social climate in die United
The National Childhood Vaccine Injury Act of 1986 was intro- States, and the minimal participation of die pharmaceutical industry
duccd by Congressman Henry A. Waxman and constitutes a form of jn contraceptive development, all we can expect well into the
no-fault insurance against possible injuries from the seven pediamc beginning of the 21st century arc minoi modifications of existing
vaccines (51). The rationale for this limitation was that all children methods, different delivery systems for steroids, possible improve
must receive such vaccinations to attend school and that a lew are ments in sterilization techniques and barrier mcthods.’morc precise
SUI
OUI
Science
Dau28. Juli 1989 IP 4 9 16
Queue
progressively loweredsince the middle 1970s. The same resets anon
also applies to some of the beneficial, noncontraccptivc effects of die
The Bitter Pill
well as cndometnal, cancers (J). Will the protection persist lor
Carl Djerassi
Hie introduction of the pill into medicine came at the bes
ossiblc time, and also at the worst Ic was a time, before th.
thalidomide tragedy, when new drugs were rapidly being nitio
Fundamentally new approaches to birth control—for duccd; pharmaceutical companies, the media, and the public pro------ rV2 ...—r---------.
, c
, ciaimeu ano accepted tne benefits or the postwar chemotherapeutic
an anoferolny vaccroc—cannot be realized before the
Evcnr bkm 1k lt a mcdicji onc or a stxiaJ
MKh
century, and then only if the virtuaj withdrawal of „
„pteio„. „mcd
, -IKhni,k(gll41
the pharmaceutical industry from thn field can be re- ft,.-!, jK)proTOltobcthcworstoftMn«,b«iuscthess.ntdeodc
versed. Major changes m product lubdity would be the uw
mponJn[
c„n(cnlcj wilh KI1IIJ|
most significant incentive. contemporary society—women’s role in s-xricn-^environmental pro
depending on the unique character of the U.S?-litigation ;
The early influential books of the modem leinin'isr ni
X 19S1 WHEX OU
*
USEAXCH CTOCT IN Mtx.co Cm emphasized
hjsiKd the urgent nKd
,)n,rK ■ „
need for
for lm
improvedd 1Vnuk
female cconn
jeevmphshed 1)1= ta. synd»U ol ro oral coniracqMivc (I), Simone de Beauvoir's 77., S««/S« («) .uicd cxpliu.lv, rod Ita.
Mexico had 28 million inhabitants (2), u row lux 86 million Fnc<h„,,
Fm. ...
.
. . ►
I
i of this
century ns population will probably equafthar of)
contributed to that aim. But an informed and highly motivated
group of women—primarily American and, by world standards,
’exceedingly affluent—while emphasizing their abhorrence ar inale
TX.
o ’
‘‘xnuuaon.
nronglv enuorod die pel (8) rod fiequenth did ro
L9 biDum On my 65th btrdxby, n had ezccoped 5 bdhon and at djmn [o
fo’ womcn jj
dlc „orldM T|„v
±c present growth rate wdl ^d> 8 bdlron «/my 100th binhdav
wh^c fi„, idcm,ol d snldk, dotu,„e„Kl| iunie
PL Today the popuboros of Europe rod Al™ ant virtually
ksJ
*
w|n) cjf|K.r
Kfenucd. approximately 500 null™ each. In pro 35 vexr^-.n spite
u*d humln
of famine
and
disease
—
Africa
s
populanon
will
triple
unless
the
•„
..
.
6
.
,
...
,
pill had not been tested more thoroughh. b
xqured immunodeficiency syndrome (AIDS) epidemK interferes
mtocurrent of such feeling, prists. Even in rh. li.e,.
wuh conventional demograptuc ptedreoons Europe, popubnon
oro„,
d hv
.
L
r
.
. .
WJ
_____ _
.. ... a_ W—’s Hedd, Book CoDeeuve, one exn find ii rented due -dee
Food and Drug Administration [FDAj approved the pill for
that the United States is the only country other chan Iran in which marketing
in 1960 without adequate testing or study. . . . The pill
decade. The quality of birth control in the United States is not likely
®'^anUC cx^,yncny
'ears about 1.2 million
ro ebroge bj ehe vex, 2000, wld. die eoroequem fikehhood du.
SUCh
,
■ be •no significant
• ' -c
.
. number
. (1.5
i. r mihon), ofr marketing experiments
are. unavoidable,
however,
and occur
there
will
reduction
in the
.a
.
...
... with
. .
, now take phee
. annually
.. in the
. United
,, j'States. Indeed,
. j ’ evoy vaccine
person will be exposed
abortions
that
• andz,drug to ..which a \
...fur <>ni!b
, contraceptive choices
. . r tn the
, United
J States
c
. endj of<-_!_•
of time. Only1 medicines used to 1 rear acute conditions and
the
at the
this penods
r
’1
dosages of the progestational and estrogenic ingredients, it must bq
Introduction of Steroid Oral Contraceptives
remembered that abortion was completely illegal at that tiiiicj
Until the introduction of rhe birth control pill in the early 1960s, experimenting with lower dosages might well have led to higher
abortion (then illegal in all but a few countries) was virtually the failure rates for which no alternative could be offered to die women
only available method of birth control separated from.coitus. In my on whom the new dosages were tested.
opinion, it was this property of the pill and the privacy it offered a
woman, rather than rhe pill's efficacy, that made its initial acceptance
j
” Tro®’.?1
drade-,h'
fj''”0"5 01 Retrenchment of Pharmaceutical Industry
nearly 10 million American women had nude the pill the most
popular method of birth control.
When tn 1970 I wrote Birth Control Aja 1984,1 pointed out (11)|
Yet even now. almost three decades later, epidemiological reports that unless major and largely unpopular changes
progestational and the estrogenic components of the pill have been
Science
n
28 Juli 198914 9 1 6
Quelle
______________ Datum
_~
...
were instituted, birth control in 1984 would not differ much from were higher than for any other drug category. These legal costs arc
that which existed in 1970. I emphasized that our increasing in the end paid for by the millions of women who benefit from the
knowledge of human reproduction and of actual is well as porennal piU and who would probably object greasy if they were returned io
side effects, along with women’s concern atxmt safety and risk the narrow contraceptive opripnsbf pre-World War II days. The
aversion (shared by most of contemporary American society), made cost of a monthly regimen of the pill has increased nearly rcntold in
it necessary to plan on a 12- to 20-ycar dcvcloprrtmt prriod tor any the United States during the past dozen years, even though most
new chemical contraceptive agent. At that time, there were 13 major pills now on the U.S. market have been “off iMoent” for many years.
pharmaceutical companies (9 of them in the United Sates) that Fear of litigation and unavailability oPinsurancc has eliminated
conducted research and development (R.&D) in cOfTtnucptjoo; by market competition; until 1988, no generic versions of the pill were
1987, the number had dropped to four (only ctoe df them in the available, and even the ones that have appeared recently cover only a
United Sates). Today none of the active progtscmonM and estro- fraction of the market (22) and are, in arty event, manufactured by
genic ingredients of the pill is manufactured in the Utiictd States, the producers of the proprietary formulations.
The withdrawal of the large U.S. pharmaceutical cWTTpanics from
Pi“ Use in the United States
?
tn monkeys) demanded in 1969 by tne rDA (1J) in rtsponre to
concerns about the tong-term effects ofsteroid CWItfjfctptives These No new active ingredients have appeared in thej pills sold in the
requirements were not modified (M) until 20 ytart hrer as a result United States since the 1960s. By contrast, three new- ones (desogescf overwhelming evidence presented by foreign rtgohroxy agencies trei, norgestirrutc, and gcscodcnc) were introduced in Europe in the
and the World Health Organization (WHO) (IS) about the fiirility 1980s (23). The leading European manufacturer of the must
of such special “overkill” mandates. Second, dfe impact of the advanced pill has so far not introduced its product (dcsogestrcl) in
congressional “Nrbcm Hearings" (16) conducted ttfWcen January the United States—in part because of potential liability' exposures
and March of 1970 was exaccrbaod by the commeriGuy of self- (24). Yet this product has onc of the lowest dosages of all pills and. I
interest groups and further sensationalized by the press, thus giving moreover, has an improved metabolic profile compared to the other
the contncepoon field an extremely poor tfnagt, The fact that the progestational steroids currently available to women in the United
pharmaceutical industry chore not to testify befort Senator Gaytord States (25).
Ndson’s committee, and the subsequent disarttf of the Daikon The negative publicity of the Nelson hearings (16) resulted in
Sbidd rnrauterine device (IUD), only aggravated th: hostility (17). both justified and unjustified caution about the pill. Consumption
The third blow, and m the end the most devasoung, has been the dropped by over 20% to about 8 million women tn the United
changes in the litigious character of our society during the past two States in the 1970s (although it continued to increase in Hurd
decades, especially where drugs and medical practice arc concerned. World countries) but then started to rise again to the current all
Unquestionably, the fear of litigation had a salutary impaa on some time high of more than 13 million American consumers (26). The ;
practitioners and manufacturers in medicine in general and on birth consensus now is that for healthy young women, the pill is the must
control in particular. The Daikon Shield is a prime example ofa case effective contraceptive method and probably onc of the safest
in which litigation was essential. At the same time, contemporary Women in their middle thirties or older w ere thought to be ai
tort law, with respect to legal liability, has altered medical practice increased nsk in terms of cardiovascular complications, and the
for the worse. In the case of contraceptives, litigious practices have current pattern of use among such women in the United States
been extreme. In 1986, for instance, the Ortho Pharmaceutical reflects these beliefs, although the most recent epidemiology J ,
Company tost a 55,151,030 judgment in Georgia because itscvidcncc concerning low-dose pills suggests that such nsk applies I
spermicide Ortho-Gynol, used by a woman while she was unknow- only to heavy smokers (27). As a consequence of these concerns, and
epidemioiogical evidence (19). And although in most malpraaice(2«)j that this essentially irreversible method now surpasses pill use
.and produCT
*liability
cases (for example, that of asbestos) the among couples in the United States.
'plaintiff recovers no more than one-third of the financial judgment. The attitude offeminist activists toward the pill has also changed.
the remainder being consumed by the legal community (20), such Although one can still find occasional anachronisms like the “burn j
liagaDon has added an enormous financial burden to precisely thatasrain contraceptive fundamentalism” exoressid < in 10R4
-
LprotcCT, the consumer.
has no use for the pill and even denigrates the diaphragm in favor of
\The impact of litigation on the pill is especially instructive.coitus interruptus, the cervical cap, and omdoms), the current
Indisputably, some women have been physically harmed by the pill, po«ban of most informed feminist spokeswomen toward contra-
to demand tens of thousands of documents, that out-ol-court care of the pill, this includes dissemination of the potential negatr
settlement of such litigation is often cheaper than defending it in side elects as well as of the more recendv discovered noiKontracei
court. The Office of Technology Assessment (OTA) in its 1982 tive benefits (5).
report (21) stated chat liability costs in the oral contraception field Women are now reprerented in substantial numbers in dctisioi
I
making bodies dealing with contraception, such as the advisui
'IJ .
-
4
Anti-pregnancy Vaccine
9^^In Trouble, - By Satyendra Tripathi
The hum of research workers continues as usual at the bio-chemistry
department of the All India Institute of Medical Science here, where
several promising projects on fertility control are underway. However,
the crucial project which is in advanced etaoes - the development
of an anti-pregnancy vaccine - is in trouble.
Of the two matJor grants to this project from international agencies
one was somewhat abruptly terminated last December and the other
one became the target of a a scandalous article published almost
simultaneously in the donor country, featuring the views of two
scientists whose motives may not be altogether above the board.
I What is more the two developments are alleged to have some indirect
links between them.
’
'■
The withdrawn grant was 6com the WHO’s Expanded Programme for
*
Research in Human Reproduction (EPRHR) which had been supporting
the project since 1972. Initially the grant was of 20,000 dollars
a year but the project was accorded high priority in 1976 and its
share of the WHO grant to the research and training centre at the
AIIMS was increased.to 80,000 dollars a year.
What had dismayed Dr, C.P, Talwar, head of the biochemistry department is that two successive expert committees consituted by the
EPRHR’to review the progress of the project, gave no disapproving
•indication after their site visits and examination of experimental
data 1 in 1976 and 1978 respectively.
While none of the reports of the review-panels has been made avail
able to Dr. Talwar, the first committee expressed its satisfaction
jn.no uncertain terms to him and to Dr. V, Ramalingaswami, the then
director of AIIMS.
I
I
(
I
I
/II
What had dismayed Dr. C.P. Talwar, head of the biochemistry depart
ment is that two successive expert committees consituted by the
EPRHR to review the progress of the project, gave no disapproving
■indication after their site visits and examination of experimental
data in 1976 and 1978 respectively.
While none of the reports of the review-panels has been made avail
able to Dr. Talwar, the first committee expressed its satisfaction
in.no uncertain terms to him and to Dr. V. Ramalingaswami, the then
director of AIIMS.
.According to.Dr. Ramalingaswami, now director general of „th$ Indian
Council of Medical Research, it gave a "generally favourable review
with some suggestion's for further animal trials to test.the vaccine’s
toxicology aspect."-.
.
..
These suggestions he said, were subsequently carried out as far as
possible. The second review panel did not communicate its assess-.
ment even verbally.
According to Dr. M,A. Belsey, Generva-based senior scientist conn
ected with WHO’s research divsion on human reproduction who happened
to be in New Delhi, the EPRHR may have cancelled +he grant due to ,
misgivings on the clinical trials of the vaccine on human subjectsas the data.is not yet sufficient to show that the vaccine will
not disttarb the hortnal hormone balance in women in the long run.
He said WHO has adopted very rigorous guidelines for clinical trials
in projects aided by it to guard against rash experiments of. new
products on humans. However, he said as he was not directly con
nected with the EPRHR. he could not be certain as to the actual
reasons for the grant’s termination.
According to .Dr. Ramalingaswami, now director general of ,.th$ Indian
Council of Medical Research, it gave a "generally favourable review
with some suggestion's for further animal trials to test,the vaccine’s
toxicology aspect." -
Dr. Talwar brushed aside this argument on two counts. Firstly, he
said the WHO grant was specifically for animal studies and this
’money was never used for the clinical trials which have been funded
by the Family Planning Foundation ot India and the trials at six
—Centres abroad were supported by the Population Council of New York,
These suggestions he said, were subsequently aarried out as far as
possible. The second review panel did not communicate its assess-.
ment jeven verbally. ...
In any case if the EPRHR wanted further animal experiments, the
termination of its grant for that very purpose would not be the
to go about it, he said.
According to Dr. M.A, Belsey, Generva-based senior scientist connected with WHO’s research divsion on human reproduction who happened
to be in New Delhi, the EPRHR may have cancelled *he grant due to .
misgivings on the clinical trials of the vaccine on human subjectsas the data,is not yet sufficient to show that the vaccine w£n
not disttarb the normal hormone•balance in women in the long run•
As for the safety aspects of his vaccine, Dr. Talwar vigorously
^denied any adverse results in extensive animal trials during the
past five years and human trials in the past three years on 63 women
conducted in India, Finland, Sweden, Chile & Brazil.
... 5
if Indian Express 5th March 1979.
He said WHO has adopted very rigorous guidelines for clinical trials
in projects aided by it to guard against rash experiments- of new
products nn humans. However, he said as he was not directly connected with the EPRHR. he could not be certain as to the actual . '
reasons-for the grant’s termination. ...
-
;
inv xj^Mkawn grant was ricom the WHO’s Expanded Programme for
ResearW^in Human Reproduction (EPRHR) which had been supporting
the project sinoo 1972. Initially the grant was of 20,000 dollars
a year but the project was accorded high priority in 1976 and its
share of the WHO grant to the research and training centre at the
AIIMS was increased to 80,000 dollars a year.
• Dr. Talwar brushed aside this argument oh two counts. Firstly,1 he
.
said-the WHO grant was specifically for animal studies and this
j
11 money was never used for the clinical trials which have been funded
by the Family Planning Foundation ol India and the trials at six
centres abroad wero supported by tho population Council of New York,
. the
way
He also pointed out that in all these countries the ethics committees
and public'health authorities had given clearance for the experiments.
He. seems to think that the reasons for the termination of the grant
might well be other than scientific, like, the interests of a rival
American scientist, Dr. Verson Stevens. sa~id to he a protege of ’
DrT A. Kessler who lbeads~tTioEpRHR.
—------------------ :--------- :-----;—-
Mr^^itVorK^a^!:^cwhicS’cis^o^^^e^^^ 1
auje of family plangrams take years to become established.
and strenuous educational efforts are re come increasingly entangled in politics.
McPherson has been well regarded by
population experts, who believe he is
committed to the spread of family plan
ning and doing the best he can in the
But in most of the family planning
environment provided by the Adminis
community, natural family planning is
regarded as ineffective, unpopular, and percent of (hose benefiting from federal tration. which has made curbing abortion
expensive. Joseph Spcidel of the Popula family planning programs. 1 he per capita the cornerstone of its population policy.
tion Crisis Committee says the dropout com in these programs is $473 (largely However, family planning people have
____ r ' - become increasingly dismayed by his
rale from programs is about 50 percent.
I. compared willingness to accommodate to pressures
.med a foothold in a few other places
<ich as the Philippines. Peru. Sri Lanka.
and the Seychelles. Lanctot says there
arc reports from Zambia that among ru
ral women it "is improving and changing
developing world are auare of the fertility cycle. Natural methods are practiced
by only 2 to 4 percent of contraceptors in
Contraception Research Lagging
assessment of his work.
The article referred to earlier, published in a recent issu-e of a
popular Canadian magazine, "Macleans11, begins by claiming that
trust in his vaccine caused unwanted pregnancies for two women 8..
ab abortion
for a third subject.
It 2potes Dr. Bernhard Cinader, a member of WHO task force for
research on human reproduction, and Dr. Stevens to establish that
the human trials are not warranted by the available data and .
portrays Dr. Balwar as a rash scientist.
The article seems to be aimed at a rousing public opinion against
the continuation of the dollar 160,000 grant to Dr. Taiwar's project
from the International Development Research Centre of Canada. It
concludes that, "Canada, by contributing funds to Dr. Talwar's
work at the AIIMS, New Delhi, i seems to be an unwitting accomplish";
And that in this project "women will continue to be used as guinea
pigs and countries like Canada will face a continuing foreign
aid dilemma".
According to Dr, Talwar, the article amounts to a calculated mis-otepresentation of facts to tnwart the progress of the Indiarr~vaccine
zwhlch he claimed w-s alreaov patented in 1H countries to the ire
of his competitors.
Regarding the allegation about the inefficacy of the vaccine in
the three cases, he clarified that these pregnancies had occurred
due to carelessness on-the part of the subjects.
According to him, every subject is initially given 4 shots of the
vaccine at fortnightly intervals followed by an 8-week lag period
required for sufficient bu'ild-up of anti-bodiesywhich check implant—
:ation of fertilised ovum in the uterus. The women were asked to
use other contraceptive methods during this period and to come
for regular check-ups to determine the anti-body count. ,
. .
These particular women had' failed to use contraceptives in the
prescribed period with the unwanted result. He, however, denied
bis vaccine haying ever caused any abortion.
In a sharp rejoinder to the article, Dr. Talwar has challengedDr. Stevens and Dr. Cinader to confront him on an appropriate
Scientific Borum where he can drfend his work, rather than resorting
to malicious propaganda in non-scientific magazines. Though the
Canadian grant has been recently renewed such attacks during the
election year in Canada, Dr. Talwar fears, could cause further
setbacks to the programme,-;
bf" Abortion, Sans Tears
anwu"Sr
r'1' P'’nnin* “■
NIH S C"'" fOr
«1««. .h« develwoHdwuX been
!! ■ - —------ umuegrauapte contraThe U.S. investment has actually declined inieaftSfiars ceptivc implant, has been halted because researchers were '
unable to obtain product liability insurance. Because liabil- ‘
because of a sharp drop in research by pharmaceutical
markei. no company is coming out with a genTfcT^i
The Population Crisis Committee reports that global contraceptive
even though patents are expiring on almost
expenditures—over half of which are made by the U.S. all
of them.
government—totalled about $175 million in 1984. Most of I
There have been no dramatic breakthroughs tn family
this was on basic research in reproductive biology. The I
planning
practices since birth control pills and intrauterine
total devoted to applied research on contraception is I
devices
were
introduced
25 years ago. Sterilization remains,
estimated at about $40 million. According to the World I
primary mode of birth control in the developing worldK
Bank, the field could readily absorb a doubling of this | (he
followed by abortions, which are performed at the rate .if5
amount over the next few years.
ovcr 4Q million unnuallv.
<_ .
Prior to 1970. American pharmaceutical companies led
The hottest development for the near term is Norplant.
the field in nminrrnr,’.,
.,,k
rr*
an implant developed by the Population Council, which
Expenditures of between $15 million and 1
provides contraception for up to 5 years. Used in Finland
formerly also held two positions as director of research at (where it is manufactured) and Sweden, it has been studied
Pasl 3 years in clinical trials in this country, and
Svnter Cull/Rill ■.t„-.tlIIXHT->1-u -.fr-v.
t -r——.
Tpjohn and G D. Searle has
approval is gained as expected?says Wayne rardenTfthe
Population Council, this will be "the first totally new
. -.wuu.u .o Hicmnij,;, anu omy a tew firms remain in the method
since IUD’s were introduced."
field, according to Djerassi
*
——-----------------------A variety of long-term avenues of research, including
Companies have been backing out because of inhibitory 1 new male contraceptives, an antipregnancy vaccine, and
federal regulatory policies and the skyrocketing costs nil reversible sterilization are being pursued. Since it may take
liability insurance. Upjohn has been trying to get Food and I two decades between the development and widespread use
Drug Administration approval for Depo-Provera. its 3-1 of a new method, the likelihood o( a major breakthrough
month injectable contraceptive, for the past 18 years. I before the end of the century is virtually nonexistent. Some
Although Depo-Provera is used in 80 countries and has of ihe more promising technologies are postcoital drugs
been endorsed by the World Health Organization m FDA and menstrual inducers, lut no Agency for International
Development funds can go to research on any alleged or
compelling (Siifnci-. JJ November 1984. p. 9501. The FDA suspected
abortifacienl agents.
will be reconsidering ih>- mitt/r ....... k..> .k..,.
.V
a lavuruoic UCCISIon.
development. The N.tionjl In,mute of Child
Product liability fears are even more compelling. Court commcephvc
Health and Human Development, which home, the Center
awards for alleged damage from contraceptives are ex for Population Re,earch, ha, proposed 1 4-yegg ••'pecial
tremely high, in pan because they arc used by a "healthy"
d‘>e^°pmcnl ' wl"ch would
population, says Djerassi. and anv negative outcomes arc ’
blamed on the drug. The industry as a whole has been IwTTnd the World Bank, the World HeLthOrtln'iemto^
shaken bv the cxnenenee of a u u..h;n. u.k.-,k k...
and other international bodies are now treking to form a
global
consortium
to
advance
cooperation and stimulate
shield’and which recently filed lor bankruptcy. Gabriel funding in feniluy and contraception
research
CciaMc e
vet.
mim X^ol; : rA3e.a
Injectable Contraceptive Synthesis: An
Example of International Cooperation
'-Pierre Crabbe, Egon Diczfalusy, Carl Djerassi
Until now pharmaceutical companies
have played the dominant role in the
field of chemical contraception because
ones, most ot wh’icn'are io?
cated in developing countries, were con
tacted by WHO headquarters staff to "de
termine whether they would be receptive
to the idea of participating in the pro
gram. The arrangement proposed was
that WHOrfn addition to supplying liter
ature, material, and chemicals, would
fund each laboratory to the extent of
$10,000 to $15,000, the sole requirement
being that 5-gram quantities of pure ste
roid would have to be delivered to WHO
headquarters. Patent rights would re
main with WHO.
temational pharmaceutical companies,
the World Health Organization (WHO),
» part of its Special Programme of Re Chemical Objectives
search, Development and Research
lion, of the wide array of disciplines Training in Human Reproduction, estab
The objective of the chemical syn
lished a task force to determine whether thesis program was to modify chemically
eral public (/). During the past decade. such a development program could be an active contraceptive steroid drug into
however, the pharmaceutical industry
a "prodrug’* that would either be in
has reduced, on an absolute and relative dustry. At a meeting at the WHO head active or less active than the parent ste
quarters in Geneva in January1973 (J). it roid. A simple and efficient way to
traceplivc field (2). This is particularly was concluded that the development of a achieve this goal is to protect the free 17hydroxyl group of an active steroid by
inserting an appropriate acid chain, thus
Summary. Since many contraceptives appropriate for use in developing countries producing the corresponding 17-ester
are not of major interest to the pharmaceutical companies in developed countries, the (prodrug). When administered to hu
World Health Organization has sponsored a program whereby contraceptives are mans, such a prodrug is converted into
des eloped outside the traditional pharmaceutical industry channels. This program an active contraceptive agent by enzy
might serve as a model for the development of other drugs or even pesticides.
matic hydrolysis in vivo (5). The rate at
which the hydrolysis occurs determines
whether the prodrug might be suitable
new, long-acting contraceptive agent for use as a long-acting, injectable con
would be worth combining with an effort traceptive. The main goal of the program
at institution building in lesser developed initiated in 1976 was to design novel ste
roid esters that could serve to enlarge the
initiation and organization of this pro number of long-acting injectable con
gram. The results obtained to date sug traceptives available to women. The
gest that this program might serve as a strategy was typical of that used fre
model for other drug development pro quently in industrial organizations in that
grams outside the traditional pharmaceu it involved the initial preparation of a
tical industry mechanism. For example. number of esters of the known con
the development of drugs for such para traceptive agents I7a-hydroxyprogessitic diseases as leishmaniasis, schistoso- lerone, norethisterone (norethinyltestos
terone (NET)), and levo-norgestrel. The
list of steroid esters to be investigated
a similar approach could also be envis- has now been expanded to well over
250 compounds.
In July 1975, a group of internationally
The natural male sex hormone, testos
recognized steroid chemists (4) with past terone, was also included in the pro
Initiation of Program
or current experience in the pharmaceu gram. since esterification of its free hy
The development of new injectable tical industry attended a meeting held droxyl group might afford potential can
contraceptives requires that a concerted under WHO auspices at Stanford Uni didates for an injectable male contra
effort be made to synthesize novel ste- versity. These chemists compiled a list ceptive. NET was selected as a poten
ruid compounds and subject them to of approximately 150 hypothetical ste tial progestogen, since laboratory and
thorough biological evaluation. Since roid compounds that they considered clinical experience has shown that it
such an effort was not being made by inis one of the safest progestogen; avail
jectcd to biological screening in
able and is no longer protected by pat
ents. Levo-norgestrel, although still cov
ered by patents, was chosen because of
traceptives. They also proposed 15 labo its high progestational potency. It is thus
ratories as candidates for participating in a good candidate for conversion into
the program to synthesize new steroids. long-acting derivatives by esterification.
003t» 8075/SO/D829-O9SCWO.75X) Cupynjhl © I960 AAAS
SCIENCE. VOL. 209, 29 AUGUST 1980
Organizational Aspects
Eventually. 12 laboratories agreed to
participate in the program. The laborato
ries are located in Australia. Brazil. Bul
garia. German Democratic Republic,
Iran, Mexico, Nigeria. Poland, Singa
pore. Spain, and Sri Lanka (6). The par
ticipants each received a list of 16 to 20
mit a research proposal outlining how
they intended to synthesize the acid
chain to be introduced into the steroid
molecule. They were also asked to sub
mit a budget. Both items were reviewed
by the WHO Secretariat with the aid of
at least one outside referee and the coor
dinator of the program (7). Once the pro
posals were approved, a CTS agreement
(8) was drafted which permitted funding
to be instituted.
During the first 3 years of the program
the coordinator visited most laboratories
at least once. The purpose of the site vis
its was to brief the investigators about
the precise objectives of the program and
operating details. So offer appropriate
scientific information and advice, to be
come familiar with the local research fa
cilities, and to solve a number of admin
istrative problems. Each center had dif
ferent difficulties, for example, inexperi
enced personnel, lack of sophisticated
equipment and instruments, inclement
weather conditions, or frequent power
failures. Most centers faced one com
mon problem, namely, that of complying
with the cumbersome and time-consum
ing regulations that many of the coun
tries impose on importers of chemical re
agents and small equipment items. It
soon became evident that many of the
developing countries would do well to
overhaul their customs regulations if
they wish to upgrade and expedite scien
tific research. The only feasible solution
for the chemical synthesis program
proved to be for WHO to keep in Geneva
part of the money allocated to each cen
ter. The WHO Secretariat ordered di
rectly the chemicals for the principal in
vestigators in accordance with their
requests and budgets, and arrangements
were made to ship the chemicals through
the auspices of WHO international chan
nels. The organization of such a network
is difficult, but in the long range it proved
to be crucial because it saved a great deal
trations.
In addition to providing background
information and technical literature to all
principal investigators, the coordinator
was in charge of examining and labeling
the samples (a code number was used for
29 AUGUST I960
The bioassay chosen for the determi
nation of the duration of action of longacting progestogens was the suppression
of cstrus in female rats, with depotmedroxyprogesterone acetate and nor
ethisterone enanthate—the only two cur
rently available long-acting injectable
contraceptives—being used as com
parison standards. Tests for prolonged
androgenic activity were carried out in
castrated male rats, with the weight in
crease of the ventral prostate being used
their possible impact on the filing of pat as the measure of biological activity and
ents on behalf of WHO for the most testosterone enanthate being used as a
promising compounds.
standard. The biological results were
The preparation of the long-acting es- supplied to the various principal investi
gators. who frequently undertook the
thc acid chains—encompassing over 100 synthesis of additional esters based on
different chemical structures—had to be particularly promising biological leads.
synthesized, since most of them had not
been described in the chemical litera
ture. Their synthesis invariably involved
a number of steps, frequently with a vari
The synthesis and screening programs
ety of stereochemical problems. Another
problem was the esterification reaction, were reviewed in depth during consulta
which is difficult to perform on tertiary tions held in November 1977 (Geneva),
alcohols of the type present in NET and January 1979 (Geneva), and January
Icvo-norgestrel. In several instances, so 1980 (Jena. German Democratic Repub
phisticated techniques were used and lic) with participation of most principal
with certain acids a new esterification investigators, expert chemists, biolo
method had to be developed. A third gists, the coordinator, and WHO staff
problem, both time- and material-con members. Approximately 220 steroids
suming, was that of reaching the re had been synthesized in the 12 partici
pating laboratories, many of which had
quested high purity (about 99 percent).
had no previous steroid experience but
which arc now able and willing to extend
such work. The biological evaluation of
potential male contraceptives is being
After they were synthesized, all com discontinued for financial reasons (9).
pounds were shipped to the Department but six compounds of possible use in fe
of Chemistry of the City University. male contraception have now been se
London, for quality control and further lected for further development. The next
purification, when necessary. The com phase of research—testing in primates
pounds were then forwarded to the and preparation of larger amounts for
School of Pharmacy of the University of toxicology and for eventual phase 1 clini
London for formulation. Once satisfac cal studies in one of the WHO Clinical
tory stability was established, the micro Centers—has already been initialed, Un
crystalline suspensions were sent for
bioassay to the National Institute of formed outside the regular pharmaceuti
Child Health and Human Development cal industrial channels. If a promising
(NICHHD) of the U.S. Department of drug should emerge from such phase I
Health, Education, and Welfare in Be clinical studies, then it is anticipated that
thesda. This N1H unit under G. Bialy the large-scale synthesis would be com
handled both the funding and operational missioned with some chemical firm be
details of the biological evaluation in ro fore long-term toxicology and phase II
dents (and currently in primates). Esters and II! clinical studies are conducted.
not suitable for the preparation of aque
Excluding efforts by military estabous suspensions were bioassayed as oily lishmenisTnTJTtlils rs probably IM firs!
solutions. After leaving WHO headquar inslAnrr-io-whkh an international public
ters for quality control at the City Uni sector agency has launched successfully
versity. London, every sample was fol a program of this nature, and it is reason
lowed by the WHO Secretariat and by able to ask how economical the program
the coordinator (appropriate forms were is. In terms of time, the chemical synused at every stage of the program) until thesis has taken longer than it would
the biological results were relumed.
have in the steroid synthesis laboratory
every compound submitted by the cen
ters) and checking the data sheets (each
sample sent to WHO headquarters was
accompanied by a data sheet giving a full
description of the substance including its
physical, spectroscopic, and analytical
properties). The coordinator acted as a
genera] troubleshooter and was easily
available to the various principal investi
gators; together with the WHO Secretar
iat he reviewed all the manuscripts origi-
SCI
Science
_ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _
Dalum28. Juli1989P4^j
National Institutes of Health (NIH), and the WHO Also, whereas whereas many Asian women prefer steroid injectable
*
(U). wl^crf |
in die 1960s the overwhelming majority of American obstetricians tcnajn women’s health groups in the United States cuntinuAb
young practitioners in that subdisciplinc arc now women
development—from research and testing to delivery of the prod- pronounccd stagnation in the range of choices and the quality of ;
uct—their choices arc becoming more limited. This is primarily a birth control. Many people ignore the fad that incidence of abortion
consequence, again, of public, governmental, and media response to reflets the state of contraception. In the Sexier Union, die country
the complaints in the 1960s and 1970s of women who wanted a wjtyl
highest per capita abortion rate in the world (J/), the
perfectly “safe” pill or other contraceptive What do the profession- qiuhty of binh control is exceedingly poor and the pill is essentially
als in contraceptive research have to offer in that regard’
unavailable. Japan, die country with the third or fourth highest
still not approved for contraceptive use'IJ
*)
The United States, |
finaUY> h“ <** h’8h€St tccna8c Prc8nancv
abortion rate I
of any industrialized country (J6).
•
|
The fashionable area of human reproductive brfil^gy is now the | cjrc
cxamp|e5 to show that improvements in contra |
study of infertility rather than contraception. The lessened prestige CCptjve “hardware ” in addition to contraceptive! “software” (for 1
of the latter field is reflected by the paucity of new talent entering it cxamp|c> education, distribution, and hcaldi care), arc likely to have
This is partly because relatively less money is flow dedicated to unponant effect on rich as well as poor countries. And this bungs
contraception R&D than was die case 15 years ago (/0) Not only
lolhc i,ltuitivc desire of most people in the United State, tor
have industrial expenditures virtually ceased, but the principal U S ^proved contraception. So what, again, do the professionals have
government funding agencies, die NIH and the Agenev tor Interna- l0 offg,-)
.
•
cional Development, because of mandates initiated under the Rea|
gan Administration, are prevented from supporting many important
areas of contraception research. To convert promising laboratory
.
..
,
iKoverk, in mi reproduction mro v„bk mertiodx of hum™ Prognosis for New Developments
birth control is now so time-consuming, mil so dependent on the 11w 1982 OTA report Future Fmilitf 1‘hminx Il-yiei <-’<) ■
participation of the pharmaceutics! industry, that num- scientists mtroduca a list of filture contraceptive methods by saying that
have turned to other fields because of the lack of material and -between now and the end of this century, more than 20 new or |
societal support
significantly improved technologies for contraception are expected |
Another reason that scientific attention has turned away from Io become available” (21, p. 92). A similar article, published in 19K6
contraception research is that, since the late 1960s, country after u„dcr
77,, Ntx, Gnweplivr UnalMtn (31). gives vimullv I
country in the developing world has recognired the problems of the same list and cites a lackof financial support as thechiefobstacle I
uncontrolled population growth and has starred to implement birth w jD immediate realization.
!
control programs—some of them, such as the one in China, on a My own
(JJ, J9; „ much more pessimistic; regardless of die
huge scale. Health professionals dealing with the delivery rather amount of money available, none of the trulv revolutionary develop
than the creation of contraceptive methods then decided that the „„ luch „ annfertiliry vaccina or a male pill have a chance of
•mphasis in these countna should be placed on education, at the being used by the public in this century Tile rest of the cited I J?) I
creation of rhe appropriate infrastructure. on the integration of contracepnve improvements, which include another vaginal spemii- I
contraception with maternal and child health care, and on the aJal tablet, another copper IUD, and a cervical cap, although clock
optimum use of existing methods (rhe pill, IUD, condom, inerrable uxftl in a public health and demographic context, are not new or '
steroids, and sterilization) rather than on rhe search lor new „no|utiouary A delivery system for steroid contraccpriva, which !
contraceptive methods
replace, the daily ingestion of a tablet by steroid-loaded vaginal
This focus of Third World governments suggests how different is „„g, „ sllbdnnul implants, is no consolation to women wishing to
rhe perspective of women in the United States compared with that abandon continuous exposure to a potent steroid hormone, especial.
of women in poor countna. Here, IUDs have been rejected by |y
thrv
that these supposed novel developments have 1
many women, largely because of the defective Daikon Shield, been under way for nearly 20 years.
Makers of other IUDs—the Ortho Pharmaceutical Company with
the original Lippes loop and G. D. Searle with the (Topper Seven—
I
have also withdrawn them without any pressure from the FDA.
. .
.
....
IUDs never did play a role, in fact, in the single most
*
unponant A Pnonty List of New ContraccpDVC Methods
birth control issue in the United Stares, teenage pregnancy, because yVhat ncw contraceptive methods are needed and who would I
the device is unsuired to voung, nulbparous women. Yet in China at tbrir principal beneficiaria be? The following list is short, vet I
least 35 million women are anmated (II) to be wearing an IUD mbirojL
m „ Ofdcr of priority that I will justifv
developed in the 1960s, thus making ir the most prevalent contra- |, z
Thc AIDS epidemic I
cepove in that counnvJrLfilcxico, similarly, where rhe goverrenent
^rifie, putting this item on top of rhe list. Demonsrntu.g
twitched in 1974 from a laisscz hire pronaHCsr policy to an antiviral activity, however, is nor sufficient A drag ufclhmiiiliumj
increasingly aggressive population control program, steroid contra- 1x011 ■» devised that will be effective under conditions of normjL'
ccptivcs and IUDs arc the key components of that program (.12),
followed by abortion.
In some Larin American countries, such as Brazil, IUDs
hardly used, and the pill continues to be the method of choice (33) J
The Current Climate
SCI
28. Juli 1989. l g 4 g
Science
Datum
r
1 0
heavily in any risk assessment and in FDA approval.
other details of the menstrual cycle—informanon diat I believe ■
r... .j,
- pill widely lacking at present.
------------ -jrt If.
would have to be suitable for self-administration, in which case it
,,
S ..
could become the single most effccove method for reducing the 40 4>
Melons of men
to 50 million zboroons performed annually throughout the world. aP”1U’' th‘ Northern Hemisphere, now undergo varertoriua, ..
tn 1970 (11) I outlined the rechnwal steps required ro create such an
procedure that u sunpier md safer than tubal l.ga
„
agent and suggared why up ro 17 years (the present hfenme of a frnul,cs T1“ overwbelmsng ma|Oriry ofohesc vaseaom.red men a..
U.S parent) would be reqmred for such work. An expenditure of j'"
* 1’' fithcr5'
ro be guarameed resersilik
S100 ro S150 million now seem, a conservarive ortnare for such a
)ou"g
without children woild opt tor ,u< h a meth.u or
project.
fertility control. The reversibility would have to be relatively simpU
Instead of the current pill, which is taken dtilv for must of all of”*1
At P™
*"
1- ''“c™ny can only be, reversed
each month, the mensa-inducing pill would be taken by a woman
microsurgery («) Even wlym noniul sperm stnm. ,
only during .how months when tin: had unprontcred coitus. Theoimmunological reaction, frequkn-Jy lead to mlemlc qwnn
retically, she would have to rake only a single pill (containing a forty b
ab“ncc °[
ff^tced re.rorn.dn of tendin. pre
short-lived and rapidly menbolized drag) on the day she apecred !unubl1'. °n
°f cp'dcmrologwal stud..
her next mensa Instead of waiting to see whether she had missed mum ol tw° d‘c*aher period, a woman would take the pill ro induce rtMtstmal flow at v“c«omy reversals arc small, u
the expected rune Such a method would not be xceptabk or Pr?n" ta'Poon
.
suiuble for every woman, but to manv such a one.pill regimen , 4
'"“''7""'F'“- 1 8'
would represent an enormous improvement: at a maximum. a «dy because ot m long development time. In 1970,1 documenred
woman would be taking 12 pilb annually, rather than the present ("> dK
^clopmg a male pill would rak.
__ .1/u, _..t
■ .
...
.a
loneer—Drobabh' on the order of 20 vears—than work
j
‘ that has been insisted on by women for the female pill, is only
available through large, long-term epidemiological studies. Safety
may be more difficult to establish for men than for women, pnmarih
could be created. The steroidal anuprogesrin mifepristone (RU- because of the longer fertile lifetime of men.
486), developed by research workers at Roussel
*
Udaf in collabora- 6) Antifmilitf vaaine. In principle, tins would be the most
revolutionary development; it would radically change our percep
tion of human fertility if teenage males or females, or both, were
fertility control. Current clinical data (41) show that the drug’s vaccinated x> that they would be infertile until a conscious step was
effectiveness, especially when administered with a prostaglandin taken to achieve fertility. To accomplish prompt restoration ot
(42), is limited to initiating menstrual flow within 6 to 8 weeks after fertility, a method would be needed that actively reversed the
onset of the last menses; its administration mimics, a spontaneous immunological infertility—before vaccination wore off with time. '
miscarnage. Because RU-486 is likely to disturb subsequent periods search for such a method with a focus on the development <»l
*
gonadotropin has been
(43), induction of regular menses is probably not feasible with this antibodies to the female hormone chorionu
panicuhr drug. Anti-abortionists in the United States labeled RU" 9 486 the “French death pill” and then threatened boycotts and other
actions receiving front-page treatment in the A/ew York Times (44) controlled studies with large numbers of women volunteers u>
and ocher newspapers. The support that the Administration and determine how long it takes for the effect of die antifcrtility vaccine
present climate of fertility control in the United Sates. Neither babics, and whether therearc serious side effects after extensive
~*
Rousscl-Udaf nor a U.S. pharmaceutical company has so far applied of such vaccines.
for FDA approval of RU-486, even though hundreds of thousands
of women in the United States might benefit from it.
3) A reliable oeuiation predictor For couples practicing “natural Current Barriers to Contraceptive R&D
family planning” who are interested in more precise indicators of a
“safe” interval than “natural” methods available now can give, it is
- thcsc su
11x1 00
were completed success-1
much easier to detect (45) the time when ovulation has oocuned
the
for human fertility control would be vastly expand 1
(that is, the second half of the menstrual cycle) duA to predict
constituencies—poor and affluent, jwochoice and anti
accurately the onset of ovulation. As human sperm has a fertile life aboraoni ferule and mat. What are the chances that this can be
span in the women’s reproductive tract of up to 3 days, couples ^ortW^hed? The following analysis is presented primarily from a .
wishing to have unprotected intercourse during the first half of the US
but it has global ramifications lhe complexities ul I
menstrual cycle need to be able to predict the onset of ovulation by devcbP,n8
modem drug—contraceptive or therapeutic -reapproximately 3 days beforehand. Such precise prediction k now $mCT such
for all practical purposes to the United States,
technically feasible. What still remains to be done is to convert this
’ fundhjl of W”rem industrialized countries, and perhaps I
uifo a financially realistic and operationally practical method for cvcncuaUy 011,1111x1 India- But at present the United States still has :
routine birth control. This approach to contraception would be
overpowering influence, partly because it represents such an ■
equally attractive to prochoicc and anti-abortionist groupa. There is in’Pomn' market.
an additional educational bonus: for couples to depend on such a Two of
,u a8cnda
antiviral spermicide and a 1
Ingrid Schneider
Ulrike Schaz
ANTI- PREGNANCY- VACCINES
Contraceptive researchers and population planners all over the
world dream of "a perfect method", which controls population
growth by controlling women and their fertility with medicaltechnical interventions. Contraceptive vaccines are supposed to
be such a "perfect method". According to the announcements of
the researchers, birth-control vaccines should be easy to
administer, cheap, safe, effective and long-lasting.
Research in immunological methods of birth control has been
financ ,ed and coordinated from a very early stage onwards: In
1974, the WHO founded the "Task Force on Vaccines for Fertility
Regulation" as subunit of the HRP (WHO Special Programme of
Research, Development and Research Training in Human
Reproduction). This is due to the fact, that private companies
widely dropped out of contraceptive research because of rising
liability costs.
The most progressive approach is the development of a vaccine
against the human pregnancy hormone hCG (human chorionic
gonadothropin). The way it works is based on the principle of
auto-immunity: The immunological system of a woman's body
should be "trained" to react against the hCG-hormone - which is
produced by the early embryo a few days after conception - like
it reacts to a virus or a bacteria-infection. The mode of
action consists of playing a trick on the woman's normal
tolerance to hCG by combining the hCG-hormone with vaccines
against deseases e.g.tetanus or diphteria. So the woman
produces antibodies not only against tetanus e.g. but also
against hcg. Implantation of the fertilized egg is inhibited,
so the further development of pregnany is stopped: the woman
menstruates.
Several research groups all over the world are working to
develop immunological methods for controlling fertility. The
most advanced scientific group concerned with antifertility
vaccines is a team led by Prof. G.P. Talwar, director of the
National Institute of Immunology (Nil) in New Delhi.
Taiwar's research budget for anti-hCG-vaccines is sponsored by
the Indian Department of Biotechnology in the Ministry of
Science and Technology, the Population Cotfcil, USA, the
Rockefeller Foundation, USA, and the Canadian IDRC. The
development of birth control vaccines has top-priority for the
Indian government. India plans to introduce these vaccines as
part of their so-called family welfare programmes in the mid905.
The most competitive team to Taiwar's approach is a research
team formed by Vernon Stevens, Ohio State University, USA, and
Warren Jones, Flinders Medical Center, Australia. This research
team investigates under the umbrella of the WHO-HRP-Programme.
Their type of birth control vaccine is also directed to the
hCG-hormone. But the vaccine they develop is using a smaller
part of the hCG-molecule. Whereas Talwar is using the whole
beta-chain of the hCG-molecule, coupled with the alpha subunit
of ovine luteinizing hormone (or- oLH) and linked to tetanus or
diphteria toxoid as carrier molecule, the WHO-team uses only
the carboxy- terminal peptide of beta-hCG, linked with
diphteria-toxoid as carrier.
The WHO-team regards Taiwar's vaccine as dangerous because it
cross-reacts with the hormone LH, necessary for the maintenance
of the menstrual cycle. Serious hormonal disorders could
occure. The linkage between a mixture of tetanus and diphteria
toxoids is doubtful because allergical reactions are likely to
appear, too.
On the other hand, the "disadvantage" of the WHO-vaccine is a
much shorter period over which it is effective. While Taiwar's
vaccine is supposed to last for one year, the WHO-vaccine works
a maximum of 6 months. Talwar doubts that the WHO-vaccine
elicits enough antibodies to block the hCG effectively and thus
stopping pregnancy.
The WHO-team is now planning not to administer the vaccine as
an injection but as an implant - putting the components of the
vaccine into so-called "biodegradable" plastics. These implants
are meant to release the vaccine over a longer period (one year
or more after implantation).
HUMAN TRIALS - WOMEN AS GUINEA PIGS
Before a new contraceptive is admitted by the national drug
authorities, a long phase of animal experiments and human
trials is demanded. The hCG-vaccine was tested in mice, guineapigs, monkeys
and baboons.
The phase I human trials are done to prove the safety of the
vaccine and to find out the do sis and mixture of the vaccines.
Therefore it is carried out on surgically sterilized women.
Taiwar's team performed his phase I trials from 1974 to 1978 on
63 women in India, Finland, Sweden, Chilli and Braail, supported
by the International Committee for Contraceptive Research of
the Population Council, New York. In this phase I-trial they
found wide variations in the amount of antibodies produced and
little vaccine response in one quarter of the tested women.
Talwar, in a hurry to beat his competitors, in 1976 also tested
this former prototype vaccine without permission on six
unsterilized women, two of them became pregnant.
Afterwards Talwar employed a new mixture of the vaccine and
initiated another phase I of clinical trials in 1986 at five
centres in India on 105 women.
Taiwar's team claims the vaccine to be devoid of side-effects,
only some women having shown "mild hypersensitivity reactions".
The WHO-team carried out the phase I clinical trials on 30
women in Australia. According to the scientists it was free of
3
side effects and produced "contraceptive levels of antibodies".
The pharmaceutical firm Sandoz from Switzerland financially
supported these tests.
Phase II clinical trials are expected to show the contraceptive
efficacy (whether it really works to stop pregnancy).
Taiwar’s team initiated phase II trials in May 1990 at three
centres in India. The phase II shall be conducted on 180 women.
Preconditions for becoming part of the trials are "proven
fertility and an active sexual life". The women already have to
have two children - because of possible irreversibility of the
vaccine.
Those women participating at the trials get three injections of
the vaccine, the intervals between these injections being six
weeks. The first injection is a mixture of beta-hCG conjugated
to tetanus as well as diphteria, followed by one of diphteria
and one of tetanus. The women undergoing the trial have to
give a blood sample every two weeks. These samples are checked
at the Nil. If the antibody levels are considered to be too low
they receive a booster injection (beta-hCG conjugated to
diphteria or tetanus alternatively).
For the targeted mass production of the vaccine its genetically
engineered production is in progress.
Until now, the WHO-team has not yet started phase II trials of
their anti-hCG-vaccine.
MEDICAL CRITIQUE
So far side effects and long-term-effects are unpredictable. It
is entirely unknown whether the hCG-vaccine blocks hCG only or
whether it blocks other body functions, too. Severe health
hazards for the endocrinological and immunological system are
possible.
The linkage of hCG to other vaccines like tetanus or diphteria
toxoid as carrier-molecules can cause allergical reactions and
immunological disorders. Especially the "vaccine-cocktails"
Talwar is using runs potential health risks. Auto-immunediseases could occure.
The amount of antibodies sufficient for safe contraceptive
effect is not yet known. One single injection is not even
lasting for half a year or one year: After the first three
injections booster injections are necessary. But how can a
woman know if she has still got enough antibodies circulating
in her blood? Therefore the WHO intents to develop a diagnostic
kid (antibody-measuring blood-test) for self-use. But this
surely will be no easy and cheap technique.
Women's reactions towards the hCG vaccine show a great variety
of antibody levels. The duration of the vaccine's effect will
differ individually and can't be predicted precisely. What's
the use of a contraceptive method, when the woman doesn't know
whether it still works???
In addition, the hCG-vaccine has a so-called lag-period before
it is effective. Taiwar's vaccine doesn't work effectively
until three months after the first injection. For this period
of time, contraception with another non-hormonal-method (IUD
e.g.) is needed.
Nobody knows what will happen, if a woman who becomes
vaccinated is pregnant or gets pregnant within the first three
months after the injection; the anti-hCG-vaccine may work as an
abortifacient or the development of the fetus could be very
negatively affected.
When the effect of the vaccine drops - which the researchers
consider to happen not abruptly but slowly - the problem is the
same: a "safe", non-hormonal contraceptive method has to be
used. Possible interactions between the anti-hCG-vaccine and
hormonal contraceptives like the pill, injections etc. are not
yet investigated, but are feared.
On the other hand, the vaccine is at least temporarily
irreversible. It cannot be "switched off for the duration of
it's effect nor can it be reversed - even if severe health
disorders occure.
It’s not sure if the effect of the anti-hCG-vaccine can be
totally reversed at all. It's also possible that the vaccine
has to be regarded as a sterilization method. Even very small
amounts of antibodies remaining in the woman's body could lead
to permanent infertility.
According to the considerations of WHO the effect of the
vaccine on women with specific immune status due to e.g.
malnutrition, parasitic diseases or HIV infection should be
taken into account. But in the group targeted with the
vaccination - poor women in Third world- countries malnutrition and weakness of the immunological system can be
taken for granted! The immunological chaos the vaccination
might cause in these women is unforeseeable!
All this makes clear that the easiness and safety of
administration of the anti-hCG-vaccine which is promoted by the
researchers is definitely wrong.
GENERAL CRITIQUE
Besides these points of severe medical doubts there are lots of
principal critics against the anti-pregnancy-vaccine:
The mode of action of the anti-hCG-vaccine - based on the
coupling with vaccines against deseases like cholera, tetanus,
diphteria etc. - offers enormous possibilities for political
misuse: Women could get vaccinated without their knowledge or
consent. The anti-hCG-vaccine can be easily abused under social
circumstances where women can't choose their contraceptive
method themselves - like in coercive family planning programmes
5
or in psychiatric institutions. The vaccine is suitable for
compulsary measures.
The birth-control vaccine takes control from woman over their
body and their reproductive capacity, similarly to implants and
contraceptive injections. It could result in the control of
doctors and family planners over women.
Anti-pregnancy-vaccines are provider-dependant: Women need
health care services which administer the vaccine.
Paradoxically the principle of vaccines is, that it could also
be given by mobile teams without integration in general health
care services. What happens in such cases if side effects
arise?
Contraceptive researchers and population planners generally
identify woman's sexuality with fertility. But there are lots
of possibilities for woman to experience enjoyable, satisfying
sexuality without the danger of pregnancy. This is being
ignored by these stupid, techno-orientated men.
Like all modern contraceptives birth-control-vaccines separate
radically contraception and fertility from sexuality. There is
no need for an agreement on modes of contraception and forms of
sexuality between woman and man. Men remain free of taking
responsibility for their fathering-capacity and contraceptive
issues.
Unlike many researchers and familiy planners want to make us
believe, pregnancies are not only the result of contraceptive
failures. In many countries children are necessary for
sustaining the family and as an old-age-insurance. And they are
of emotional and social importance for their parents -e.g. as a
support and hope for the future. In many patriarchal societies,
only the birth of children (particularly sons) gives women
social acknowledgement.
Hence unwanted pregnancies are not only an expression of
lacking contraceptive techniques but can also simbolize the
social powerlessness and missing autodetermination of women.
Family planning programmes that really strive for the
strengthening of women's control over their bodies and their
lifes should support women to gain knowledge about their body
and their health. They should give women space to exchange
their experiences with men and sexuality und to share critics
and changes. This would be one step to overcome the
hierarchical gender-relations which are also reflected in
sexuality, procreation and all the questions concerning
children.
Family planning programmes in India and elsewhere have nothing
in common with feminist approaches. Even in so-called
progressive projects which integrate family planning into
mother-child-health programmes, sexuality and sensuous
bodyliness are taboos.
Many researchers concerned with anti-pregnancy vaccines
describe people and pregnancies as an epidemic: in a cynical
way this metaphorical vision interpretes women and their wombs
6
as a disease. And they declare them to be the target for
medical attacks. - We should attack this sexist, antihuman
vision!
Many researchers have the dream to give anti-pregnancy vaccines
as mass immunizations. This reveals their extremely
te^pocratic , reductionist and sexist attitude. The necessary
changes of the social, economical, political, patriarchal
structures is not in their focus of interest.
If women don't oppose to their plans, the researchers dream
will turn out as a nightmare.
LET'S START A POWERFUL INTERNATIONAL CAMPAIGN AGAINST
THE FURTHER DEVELOPMENT OF THE ANTI-PREGNANCY-VACCINE !!!
In Germany, the BUKO-Pharma-Campaign
. (member of the Health Action International - Network)
intents to start a campaign against
r the anti-pregnancy-vaccine.
Contact:
BUKO-Ph arm a-Kamp agne
August- Bebel- Str. 62
4800 Bielefeld
F.R. Germany
NATIONAL INSTITUTE OF IMMUNOLOGY, NEW DELHI
PHASE II CLINICAL TRIAL OF ANTI-hCG BIRTH CONTROL VACCINE
SCREENING FORM.
Inclusion Criteria
Yes
NATIONAL INSTITUTE OF IMMUNOLOGY, NEW DELHI
PHASE II CLINICAL TRIAL OF ANTI-hCG BIRTH CONTROL VACCINE
ADMISSION FORM
Name of woman______________________ __________________________________ __
Address ________________________________________________________________
No
IDENTIFICATION
MEDICAL HISTORY
I. ICMRJobNo.
20. Illness within last 6 months
01 No
If yes specify
2. Study No.
1. Healthy informed female volunteer with written consent
4. Confirmation of ovulation by estimating progesterone level at 18 and 24 day
of cycle and supplemented with ultrasonography whenever possible.
5. Exposed to the risk of pregnancy
(Cohabitating with husband)
□□□□□
d
□d
5. Study group
(cut off level of Antibody
titre for booster injection)
1. 150ng/ml
2. 75ng/ml
□d
d
6. Has at least two living children
Age of second child more than one yea'
8. Stabilized on IUD or non hormonal contraceptive (minimum 3
months)
9. Willing to get IUD removed or discontinue contraceptive method after 13-14
1. Illiterate
2. Read and Write
3. Primary
4. Middle
5. High School 6. Above High School
OBSTETRIC HISTORY
10. Ability to return for follow-up at required interval
21. Present complaints
01 No
If yes specify
22. Current medication
01 No
If yes specify
Menstrual Pattern
(last 3 months)
23. Usual cycle length (days)
24. Duration of bleeding (days)
25. Amount of bleeding
1. Scanty
2. Moderate
18-19
IF 1
8. No. of pregnancies
|
9. No. of live births
|~~]|J
12. Suspect pregnancy
10. No. of still births
F|
13. Currently breast feeding
11. No. of spontaneous abortions
U.D.-foTLMP
□□□□□□
EXAMINATION
Exclusion Criteria
28. Breast examination
1. Normal
if abnormal specify
12. No. of induced abortions
15.11/0 secondary infertility
16. H/O chronic allergy disorders (Eczema. Hay fever, asthma, skin rash, etc.)
17. Evidence of autoimmune disease (Rhcumatiod arthritis.)
18. Evidence of endocrine disorder (Diabetes, Grave’s disease, etc.)
19. Known or suspected malignancy of breast or pelvic organs
20. Hypertention (B.P. > 140/90 mm Hg)
21. lib <8 gm %
22. Cervical cytology not normal
The subject will be enrolled in the study, Ifanswers to questions 1-11 are
13. No. of living children
14. Age of second child (months)
15. Breast feeding
I. No
2. Yes
i]
|—|W
29. Blood Pressure (Systolic)
30. Blood Pressure (Diastolic)
|__ |
16. Date of last
pregnancy termination
31. Height (Cm)
32. Weight (Kg)
PELVIC EXAMINATION
17. Outcome of last pregnancy
1. Live birth
2. Still birth
3. Spontaneous abortion 4. Induced abortion
18. Current contraception
1. IUD
2. Nou Hormonal
Name and signature of the
27. Systemic examination
01. Normal
if abnormal specify
19. Duration of last contraceptive used
(mths)
I
— —’
33. Vagina
1. Normal
If abnormal specify
34. Vagina! discharge
1. None
2. Psysiologfcal
3. Pathological
! 1 H
Hill
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--------
’
■ NATIONAL INSTITUTE OF IMMUNOLOGY
BLOOD ANALYSIS
SUBJECT DETAILS
HAEMATOLOGICAL RESULTS
CLINICAL CHEMISTRY RESULTS
Study
Haemoglobin...................... ........... 1%
Alkaline Phosphatase....... .... I.U./lit.
Centre
Total Leucocyte Counts........
Bilirubin....................... -....mg%
Subject Name/Code
Differential Leucocyte Counts
Cholesterol........... ........
Date of Present Bleed
Neutrophils.............. .... .. ............... '/.
Creatinine............... ..... .......
Date Received
Lymphocytes..... ........ . .............. 7.
Glucose.............. .......... .......
Type of Specimen
Monocytes.............
a) Whole Blood in EDTA for Haematology
Eosinophils..... ....
b) Serum for Clinical Chemistry
Packed Cell Volume........... ............. %
Urea............................. ....... mg%
Date of Testing
*
Platelet Count.................. ...lakhs/mm
Total ‘Protein........................... <7.
Investigations Done
ESR..................................mm/lst hr.
(Wintrobe’s method)
Albumin................
..............%
SGOT........................... .....I.U./lit.
......... 8%
a) Haematology
Globulin........................ ...... -1%
b) Clinical Chemistry
A/G Ratio.....................
National Institute of immunology, New Delhi
Annual report, April 1989 to March 1990
Birth control vaccines
While an animal birth control injection. Talsur is near to the point of reaching
the public through industry, birth control vaccines for regulating human
fertility would be highly desirable as additional methods to the present
options for family planning. Vaccines are attractive propositions on several
grounds. They would require only periodic intake, will be free of "user
failure" nsk. A vaccine inducing the formation of antibodies against
pregnancy hormone, the human chorionic- gonadotropin (hCG) has been
described in previous reports. Extended Phase-l clinical trials on two alternate
formulations of the vaccines were completed this year in three clinics located
at the Postgraduate Institute of Medical Education & Research (PGIMER),
Chandigarh. All India Institute of Medical Sciences (AIIMS) and National
Institute of Health & Family Welfare (NIH4FW). New Delhi. Based on the
results of the trials, formulation A consisting of a heterospecies dimer (HSD).
BhCG associated with heterospecies a subunit of LH. linked to either tetanus
toxoid (TT) or diphtheria (DT) has been selected for Phase-II trial. The vaccine
used at 300 pg dose generated antibodies above the presumed threshold
required to prevent pregnancy The vaccine is now entering the crucial Phase
II studies, whereby its efficacy in women will be ascertained. The effect of the
vaccine is so far established in monkeys and baboons. Phase I trials have
cleared the safety of the vaccine and its reversibility. The trials would
determine if immunization can indeed prevent pregnancy and would also
provide information on the threshold titres of antibodies required to do so.
The protocol was submitted to the Drugs Controller of India on the
8lh January. 1990 for clearance to start the Phase n trials. Approval should
come in the next few months.
Another vaccine designed at the Institute induces antibodies against LHRH. a
key hormone made in the hypothalamus, an area of the brain, which regulate
*
the production of gametes and sex steroids in both male and female. The
vaccine is therefore usable in both sexes. We intend to make use of this
vaccine for therapeutic and preventive purposes. A possible therapeutic
action of the vaccine was indicated by studies in experimental animals
reported last year. Immunization of male rats with the vaccine produced a
vaccine as per the national guidelines and these were approved by the ICMR
Expert Committee. Permission was sought from the Drugs Controller of India.
and trials were started with this vaccine at the PGIMER and AHMS after due
approvals of the Drugs Controller and the Institutional Ethics Committees. By
the end of March 1990. nine patients of carcinoma of the prostate were
enrolled at PGIMER and thirteen at AIIMS. Immunization with the vaccine
has induced formation of antibodies against LHRH in patients, with
concomitant fall of LH. FSH and testosterone. Clinical improvement has been
reported in some patients. Similar trials with this vaccine in prostate
carcinoma patients have started in two centres abroad - at Salzburg, Austria
The LHRH vaccine has also the potential of use as a poat-partum method for
Neonatal teratology studies were undertaken in monkeys. Mothers were
immunized soon after delivery. The effect of immunization on breast-feeding
and growth of the progeny was observed. Immunization did not influence
lactation or nursing behaviour and the weight gain of the progeny was similar
to that of the controls. No LHRH antibodies were detectable in the mothers'
milk or in infants' blood. These studies have cleared the ground for
development of a protocol for studying the utility of the vaccine In
A highly interesting new observation has been made this year on the
become infertile without any observable ill-effects. Normal ovarian function
and libido are maintained. The action is brought about by cells mobilised
in situ by instillation of the oiL The effect is reversible and rats rendered
infertile regain fertility after 4-6 months. This novel use of a traditional plant
product, has the potential of serving as a "vacation" contraceptive. It will also
be extremely useful to cover the latent period in appearance of antibodies in
women immunized with our birth control vaccines. Preliminary studies also
indicate the contraceptive action of neem oil used intra-vaginally in monkeys.
A desirable requirement in birth control vaccines is their ability to generate
high antibody titres after a single injection, which could be sustained by a
boomw for prolong^ period,. In quest for ■ racdn, with thl, property, a live
recombinant vaccine was developed using vaccinia as vector. The gene for
phCG alongwith an anchor sequence was inserted in the virus at a
non-detrimental' locus. Monkeys immunized with this vaccine produced
high titres of antibodies with high affinity for binding to hCG and capacity for ’
neutralising its bioactivity. The efficacy of immunization with this vaccine for
prevention of pregnancy will now be determined as also the reversibility and
safety of the procedure.
Gena expression
Successful expression of luciferase has been achieved in baculovirus
expression system. The gene has been expressed both in insect cells as well as
in insect larvae paving the way for undertaking the preparation of human
proteins of utility in this system. Promising headway has been made for
expression of a and 0hCG in this system.
Probes
A synthetic probe, has been developed, which Is specific for the human Y
chromosome and characterizes without ambiguity, the male from the female.
in small samples of DNA. Two independent, yet complementary approaches
of research have led to generation of different probes for use in DNA
fingerprinting, paternity testing and identification of individuality.
Refinements have been made on the probe for tuberculosis. The tetramer
probe for HBV is putting in evidence clinical cases picked up by this probe
that are negative to traditional serological markers for hepatitis B. These
investigations suggest the existence of hepatitis caused by variants of HBV.
Publications
The work carried out by scientists of the Institute was the subject of 49
publications in recognized journals, monographs and proceedings of
symposia. The Institute also applied for eight patents in India. U.K.. Canada
and U.S.A.
Designations
The Institute continues to be a WHO Collaborating Centre for Research and
Training in Immunology for India and the South East Asia. It has also been
designated as a centre for UNESCO’s 'International Network for Molecular
and Call Biology' and as a centre for the 'Asian Network for Biotechnology
Applied to Animal Production and Health
*
of the FAO. ND is a recognized
node of the International Hybridoma Databank.
International collaboration
The Institute has ongoing collaborative programmes with the Inslitut Pasteur.
Paris. Centre for Biomedical Research, the Rockefeller University and the
International Committee on Contraception Research of the Population
Council. New York A new US-A1D CD * RI grant links projects of the
Institute with the Harvard Medical School and the Centres for Disease
Control, Atlanta. Nil is also involved in collaborative projects with
institutions in the USSR under the ILTP programme and with Bulgaria and
Hungary under programmes of cooperation in science and technology.
•
Clinical trials with the counter human chorionic gonadotropin
vaccine
G.P To/»ror. Om Singh. Indira Kha mt. Rahul Pal. KArunan and Subash Sad
*ith clinical collaboration of K. Dhall of the Postgraduate Institute of Medical
Education and Research (PCMER}. Chandigarh. K. Buckshee of the All India
Institute of Medical Sciences (AIMS} and A.K Banerjee of the National
Institute of Health and Family Welfare (NIH&FW), New Delhi.
Human chorionic gonadotropin (hCG) has an Important role in implantation
anti sustenance of early pregnancy. One of the birth control vaccines under
development at the Institute has the rationale to induce the formation of
antibody inactivating hCG. The vaccine employs the entire 0 subunit of hCG
linked to carriers such as tetanus toxoid (TT) and diphtheria toxoid (DT). In
an earlier study it was observed that 0hCG • TT (formulation B) induced the
formation of anti-hCG and antl-TT antibodies in women. However, the
response was variable and some women bad only low antibody titres. To
enhance the antibody response, an adjuvant. SPJ-PS was added to the first
doseof the vaccine. The intrinsic immunogenicity of the vaccine was further
raised by employing two other strategies — in one of them 0hCG was
annealed to heterospecies alpha subunit (aoLH) to generate heterospecies
dimer (HSD) (Talwar et al. J. Reprod. Immunol. 14, 203-212.19881. This dimer
had a conformation recognized by the target tissue receptors. It did not induce
antibodies cross-reactive with hFSH and hTSH. The bloneutrallzation
ospacity of antibodies made by HSD was superior to those induced by 0hCG
[Pal et al. AmJ.Reprod. ImmunoLMicrobioL in press). It was also observed
that the mixed formulation of 0hCG and fioLH linked to carriers (M) had
higher immunogenicity in monkeys than 0hCG alone (Talwar et al. Fertil.
Steril. 52. 739-744, 1989|. After due toxicology study and approval of Drug
Authority and Institutional Ethics Committees, phase 1 clinical trials were
conducted in 101 women to determine the safety and relative immunogenicity
of the three formulations. These studies reported in the previous years
demonstrated that formulation M had a comparative low immunogenicity
than formulation B or HSD (formulation A henceforth) (Talwar et al.
Contraception. 41. 301-316. 1990 and Kharat et al. Contraception. 41. 293-299.
1990). No dear cut conclusions could be made on the relative
immunogenicity of B and A formulations. It was also observed that there were
a few incidents of hypersensitivity reactions encountered in women who had
repeated immunizations with the single carrier based vaccine.
An Extended Phase I study was conducted to determine whether alternating
carriers could obviate hypersensitivity reactions. In addition to confirming the
findings of the Phase I trials, the Extended Phase I trial was also designed to
select the best formulation for phase efficacy trials.
Thirty six women in the fertile age group (25 - 35 yrs.) who had undergone
tubal ligation, were recruited for the study at AIIMS. PGIMER and N1H4FW.
They were administered 33 pg. 100 pg or 300 pg dose of either phCG-TT/DT or
aoLH. phCG-TT/DT formulation. The first Injection had TT as carrier, second
and third injections had DT as carrier and the fourth injection again had TT as
carrier. Six control subjects were concurrently administered the vehicle alone.
Two cycles of each subject were studied for basal values prior to
immunization. The clinical chemistry and hematological parameters were
recorded at six-monthly intervals and clinical examinations conducted every
4 to 8 weeks. None of the vaccine recipients demonstrated hypersensitivity
reactions following the revised schedule of alternate carriers, thus
demonstrating the advantage of the 'alternate carrier approach’.
Menstrual cycles were grouped into normal (22-35 days), short ( < 22 days)
and long (>35 days) categories based on cycle-length, tn recipients of
formulation A. 83.5% cycles were of normal duration. 8% were of shorter
duration and 8.5% of longer duration. The corresponding figures in the
recipients of formulation B were 83.6%. 8.2% and 8.2% respectively, and in
control subjects, 82.6%. 7.3% and 10.1% respectively.
Sex steroid glucuronides in the urine of subjects were determined, one cycle
prior to immunization and two cycles during the phase of circulating
antibody titres. Pregnanedlol-3-glucuronide (PDG) levels in all urine samples
analyzed Indicated that the cycles were ovulatory. Adequate corpus luteal
function was evident, but in some cases the area under the PDG curve was
E'TL'’?pi,nl 01 lh’ ’•can. genaralgd uU-bCC mUbodlx. Tbs pmk Ubw
reported hCG levels in early pregnancy, was 11 months’'In recipients of
lormulabon B and 12 months in formulation A recipients. Antibody titre*
cont
for 7 mont^3 in women receiving formulatioh A. in
Duration of Antibody titres
(in months)
4 dose (gg)
>20ng
>75ng
>l50ng
>2
9.0
7.0
B-300
A-300________
The antisera showing peak anti-hCG titre
*
were analyzed for cross-reactivity
with hLH. hFSH 4 hTSH. No cross-reaction was observed with hFSH or hTSH
tn any case. Croas-reectivity to a varying degree (15 ■ 75%) was observed with
4. Antibodies had a high affinity for hCG. the association constant was Ka«
Leydig cell competitive inhibition assay. Antibodies prevented
hQ3-stimulated testosterone production. Binding of radiolabeled hCG to
Leydig ceil receptors was also inhibited by the antisera.
immunized women were administered increasing doses of exogenous hCG
(500. 1000. 1500. 3000, 6000. 10000. and 15000 (Us of hCG) from day 9
analyzed for hCG. Serum progesterone levels were also monitored. It was
observed that no hCG Immunoreactivity was detectable in the urine of women
Expression of a and flhCG in insect cells using bacu Iovirus
expression vector
Bila Nakhai and Sayed EHasnain
Hind IB fragments of a and fihCG were provided Bgl
linkers and
independently cloned into the Hine U site of pUC18. The two genes were
excised out as Bgl II fragments and cloned into a baculovirus transfer vector.
The recombinant plasmids pAcohCG and pVCphCG were characterized by
restriction analyses and sequencing to verify the orientation of the insert with
plasmids were used to cotransfect Spodoptera frugiperda (Sf9) cells alongwith
wild type AcNPV DNA. The extracellular virus particles were serially diluted
and used for seeding Sf9 cells. Recombinant plaques were isolated and
amplified and will be used to infect Sf9 cells. Recombinant [JhCG will
The purified ahCG recombinant was used to infect Sf-9 cells and the infected
cell supernate was aliquoted at 48. 60 and 72 hrs after infection. The
expression levels were quantitated by RIA. Maximal amounts of hCG (10 - 12
pg/ 2x10
*
cells) was produced at 72 hrs post-infection. A significant amount
55S-methionlne labeling. The recombinant hCG was able to combine with
purified 0hCG to form functional hCG. This semi-recombinant hormone could
could also stimulate the production of testosterone in a mouse Leydig cell
In order to enhance the expression level of ahCG. a translational
amplification was made by constructing a recombinant pAC ahCC-T plasmid
which had a trimer of ahCG ligated in tandem in the correct orientation. This
was used to cotransfect Sf9 celb alongwith AcNPV DNA and purified vAca-T
virus was obtained. The expression leveb of ahCG by vAc ahCG and vAca-T
are being quantitated for comparison.
Molecular cloning of placenta
*speciflc
antigens
Construction of a human placenta cDNA library and bolatlon of a clone using
monoclonal antibodies generated against the placenta-specific heat-stable
have ths capacity to neutralize
was further characterized and was observed to be of about 2.3 kb size
synthesizing a 43 k£) protein. This protein has biological activity. Similar
celb. and the amount of hCG inactivated varied with the prevailing titres.
i and the appearance of antibodies was shorter with formulation
submitted to the Drugs Controller of India for approval. The trials are
expected to commence in May. 1990.
Teratology studies on hCG vaccines
PGIMER. Chandigarh.
and skeletal) abnormalities.
immunized with the hCG vaccine. In every case, the antibody response was
reversible. With declining antibodies, the animals regain fertility. 12 baboons.
and 64 bonnet monkeys rendered pregnant under these conditions, had
A monoclonal FD0181G evaluated in a WHO workshop earlier, as a potential
candidate for conlragestational studies, was used to screen the Xgtll lysate for
suitable clones. The MoAb identified a clone expressing a 45 kD protein. This
protein was isolated on PAGE and used to immunize rats. Thb would
generate monospecific polyclonal sera needed for further studies. Other
monoclonal antibodies such as T15 (courtesy Dr.B.L Hsi. Univ, of Nice. Pans)
to screen the library with the aim of identifying antigens that are potential
candidates for antifertility vaccines.
Clinical trials with LHRH vaccine in prostate cancer patients
GPTalwar. Rahul Pal. Radhika fayashankar. Subash Sad. Hema Malini
Gupta and Dinakar Salunkt with clinical collaboration of SJC Shanna of tht
Postgraduate Institute of Medical Education and Research. Chandigarh,
S.N Wadhwa of the All India Institute of Medical Sciences. New Delhi and J.
Frick, of the Urologiseis Abteilung Landatrankenanstalen. Salzburg. Austria
and V Bruche and F.Alvam of Association Dotrunicana Pro Blanestar de la
Familia. Santa Domingo.
A semisynthetlc vaccine for LHRH that consistently induces bioeffective
antibodies was reported the previous year. Extensive toxicology studies with
the vaccina were conducted in both male and female animab, including
sub-human primates. The vaccine blocked ovulation in females and impaired
prostate gland in all male animab. With the approval of the Drug regulatory
measurements and developmental land marks. The infants were kept under
observation till they attained maturity and two of these have also delivered
under the South-to-South cooperative programme in population sciences and
Recombinant hCG vaccine
safety of immunization and absence of harmful side-effects. The vaccine is
being employed at two dose-levels. 200 or 400 jig. The immunization
A recombinant vaccinia virus carrying the gene for (JhCG along with a
immunization, followed by a booster at 6 - 8 months and later as and when
Early results of these trials demonstrate the lack of side-effects of
immunization in patients. The vaccine was effective in inducing antioodies
reactive with LHRH. With ’he elevation of antibodies, a fall in LH. FSH and
Immunogcnetic studies on the LHRH vaccine
Raj Raghupathyand Subash Sad
Immunization of male rats wich LHRH conjugated Io foreign carriers (such as
diphtheria toxoid (DT) and tetanus toxoid (TT)I results in the generation of
anti-LHRH antibodies and a subsequent decline tn fertility in males and
Expression of a chimaeric phCG-HBsAg fusion protein in
mammalian cells
Construction of a chimaertc gene by fusion of [JhCG cDNA and HBsAg was
described earlier. This fusion cassette was cloned tn two mammalian
ihe human 0 actin gene promoter The two constructs were transiently
transfected into mouse LMtk' cells and their expression levels compared It
two-fold of that obtained with the SV40 construct. Different mammalian
cell-lines to express (JhCC. were explored. CHO cell-line was established as
the most efficient. Stable clones obtained from one of the constructs were
cassette had undergone no further recombination. Studies on the expression
of the cloned gene product is in progress.
cases of hormone-dependent prostalic hyperplasia.
It is now well known that immunogenetic factors can influence an
individuals' immune responses to various antigens. In order to investigate the
immunogenetic Influences on responses to the LHRH vaccine (LHRH-DT).
mice of different MHC haplotypes were immunized with the vaccine.
Anti-LHRH antibody titres were estimated by a radioimmunoassay and
anti-DT antibodies were estimated by ELISA Substantial anti-LHRH antibody
found to be a low responder to LHRH. Interestingly enough, the C57BL/6
strain which carries Ihe same MHC haplotype (H-2b) as 129. turned out to be
high responders la 'he LHRH vaccine. By changing the carrier in the vaccine
from DT to TT, it was possible to convert the initially hyporesponsive 129
strain to a high responder. The success of this “alternate carrier approach"
suggests that the hyporesponsiveness in the 129 mice is due to the earner
IDTI. Experiments are now underway to ascertain whether 129 mice lack the
ability to recognize helper epitopes that direct anti-LHRH responses or
whether putative suppressor epitopes on DT down-regulate anti-LHRH
Pepi.d.
(n,m DT ’
'
““
unmuoog.oMla o( rapddJes ,0 LHRHome,
comugite <i lb. .ftKt th., pmeuuarion ,0
h
touted.
r«poa,» ,o <ht h.p>.0 iLHRH) O( U» .wo ,muB of
„udied S I
mouse of one strain CA7Rt'fil h.
studied (BALB/c). This findin
Structural studies on gonadotropin releasing hormone
of Son«do>n,pia relmin, hormon.
’ h''h'"°,n°' b"n
Tbi. infom.cion will
undemanding of molecular interaction ot GnRH w.th anlibodie.
?„i?„w'L'P"S"
Th'"
approaches are being
louowed in order to determine the structure of this molecule. These are. (a)
S
rh
1°??
Pdi!fereOt ?yn,hetic ana10®3 of GnRH (b) crystallography of
GnRH-anti-GnRH Fab complex and (c) computer modelling of GnRH arnd its
analogs employing a knowledge based approach.
•Due, GnRH[analog were synthesized and crystallization experiments were
aM10SS Sh°w 5ma11 cry3,a13 wh,ch an clearly
fSX^JZ reU btr’t?n8aQa’ P«>P«n‘M- ‘n a parallel approach crystal, of
[’b fragment, of monoclonal antibody have been prepared which will serve
u template for structural studies on GnRH. Appropriate size crystal, of Fab
dSdv tin “£^“2
* M^Ab SU*t,bIe f°r X‘™y diffr’,c,ion "“dies have
??
and experiments are in progress to diffuse the
decapeptide in these crystal, for co-crystallization.
compute modelling on lb, bui. o( sequenc.
corre«Sirii?,U,1CaI ““Iy,“ “d eQergy "tinunization. A sequence data base
GnRH seque
themselves. A
En.w muunuaauoo a»d .uteequeei uulyrn of.u.UUc.1 diairibulIoQ of lb.
oootonwuoiu of .equeeoa wlectte tern tbi, librwry. „ cummtly io orottreu
Aoylog,
for 30 other te.ll bioactiv. popt.tte ™ abd ojrite Xte
prelumttey aoalyee, ,tew, u,,,
p.pUdM
q( ™ “J
’"‘““'Sally coowmrf three ditnetuteul rtrecture. to
Immunization studies with sperm-specific antigen
Chandrima Shaha. T. Seshadri and Anil Suri
between their glycosylated and deglycosylated forms. These MoAbs will find
utility in characterizing the role of ZP3 in the fertilization process and for
definition of the smallest immunogen capable of inducing infertility.
Antifertility effect of neem oil in female rats
Shakti N.Upadhyay. Charu Kaushik. M.G. Sharma and G.P Talwar
The oil of neem (Azadimchta indicaf was investigated as an antifertility agent
in rats. Female rat, of proven fertility were administered 100 pl of neem oil by
the intra-uterine route. The control rats were administered peanut oil.
Animals from both the groups were put for continuous mating with males of
proven fertility after administration of neem oil.
Animals immunized with neem oil remained infertile despite repeated matings
for periods upto 180 days, in contrast to control animals that became pregnant
Fertility in the former group could be regained and the litter size as well as the
health of the delivered animals indicate that neem oU is not teratogenic
Application of neem oil to only one uterine horn led to a fertilization block in
that horn and the contralateral uterine horn was spared from this effect. There
was no sign of implantation or fetal resorption in the uterine hom subjected to
the treatment. The treatment did not alter responsiveness of the uterus to
estradiol as evidenced by weight gain of the organ in ovariectomized animal,.
The uterine epithelium of all animal, subjected to neem treatment exhibited
leukocytic infiltration around day five post-coitum. the day corresponding to
implantation of the embryo. The precise mechanism(s) responsible for
inducing sterility, whether it is a cellular immune response against the sperm
or against the embryo is not defined yet. Investigations are in progress.
Meanwhile, experiment, with neem oil have started in rabbit,, oonnet
monkey, and baboon,. Preliminary results obtained from rabbits following a
single intra-ulerine administration of 200 pl of neem oil seem to confirm the
Intravaginal application of neem oil in bonnet monkeys induces
transient infertility
MG.Sharma. S./ayaraman and G.P.Talwar
..
UK3 VI nccm arc documented in literature. Neem oil
has also been reported to be used as a vaginal contraceptive by different tribal
populations. Sinha et al. and Rlar et al. have reported the spermicidal /
anti-implantational and early abortifacient activities of neem oil and some of
its active principles in rats, monkeys and women.
Investigations were undertaken in 14 (nine experimental and five control)
colony acclimatized, fertile, regularly cycling female bonnet monkeys, to
Study the contraceptive OOtential nf n~>rn nil
: 11..
.....
..... . .cvo.tcvi I mi OI nrem on administered
■ntravaginally through a catheter. 10 minutes before they were set for mating
the animals were allowed to mate daily for 5 menstrual cycles or till the
females became pregnant, whichever was earlier. The cyclicity of the females.
yariou. b.m.lolpglc.1 .od blood bioeh.mi<al p.nm.Lr. u indicate, of
lyit.m.c loxiaty wen earned out. tefor. aid durieg th. dudy Dolly
;X™^.dTd,ra °'irai
L*
•
, .luuaiiug me siuay. one female in the experimental group
became pregnant while the others remained infertile during the study (1
conception in 40 cycles ).
There were neither disturbances in cyclicity nor systemic or local adverse
reactions during the study. The female from the experimental group that
became pregnant following an accidental exposure to the male, delivered a
normal, healthy infant at term. Three of the experimental female,, on
discontinuation of neem oil. became pregnant within 2 cycle,. Observations
suggest that neem oil has potential as a vaginal contraceptive.
Effect of intra-epididymal or intratesticular injections of neem
oil in rat testes
Shakti Upadhyay. Charu Kaushik and G.P.Talwar
Neem oil was Investigated as a candidate contraceptive for male animals. Two
groups of adult male WISTAR rats were injected with 50 jil of neem oil,
intratesticularly or intra-eoididvriMl nn •■rh
Fertility regulation by 55 kD glycoprotein of the porcine oocyte
SJC.Gupta. Harini Bagavant and G.P.Talwar
bonnet monkeys with porcine zona peUudda-3 (ZP3). a highly purified 55 kD
glycoprotein, either alone or conjugated to phCG. High titres of circulating
anti-ZP3 antibodies were observed. Immunization did not. however, impair
cyclicity or ovulation as monitored by progesterone and estradiol profiles and
laparoacoDic examination of the
a
subsequent to decline in anti-ZP3 antibody titres.
C000«. bbtol^ ofTte tete 7^"'.=
XTpXiX!" dKSt to’Xd^
diXrim'id0 and P0”1?
* reVerMl 10 fertile a,a,ua’ once inunSizat^J are
discontinued, are presently under investigation.
x,Qd“ inlK,i'” wilh neem °u lnducM *2"”"n,u‘1,1
Anil Suri, Sunil Chhabra and G.P Talwar
",
(Previous reponl. Neem oU wa.
f°nn
r ,nduc
awospermia
in monkeys.
AU monkeys
10 S‘P®
-C0“'nta8 wilhin
on® month
of administering
the
m0Dk8y’ ,ubiec,ed (0
nMm oil “l®«ion WM sperm
fimrtianinS
’’T
* 'e3,O3,Bron® '»V®1« did not decline, showing noraial
functioning of Leydig cell,. Further investigations are being carried out
Hini™£n
MonodoMl uiUbodiM wen, g>omite .gwut th. ZP3 glycoprol.m to
S!K’
,US8*U that
n’co«ai2- • drte^nfon^ a
subunit which may be buried deeper within the zona peiludda. Some of the
MoAbs spwnfiolly reacted to a or 3-ZP3 and some were able to distinguish
?
U\J
Ho : I2tse,acd.
G-e-^izzk
IWo
|/<( (40 'H RP~ Steering Committee of the Task Force on
Vaccines for Fertility Regulation
Anderson. D
Baslen, A
de loannes, A
Ibeziako. P.
Isahakra. M.
Izquierdo. L.
Johnson. P.
* Mitchison. N.
Sehgal. S.
Talwar. G.
Wang Yi Fei
Webb. C.
Wick. G.
Harvard Medical School. Boston, MA, USA
University of Sydney. Sydney. Australia
Catholic University of Chile. Santiago, Chile
University of Ibadan. Ibadan. Nigeria
Institute of Primate Research. Nairobi. Kenya
University of Chile. Santiago. Chile
University ol Liverpool, Liverpool, UK
University College London. London. UK
Postgraduate Institute of Medical Education
and Research. Chandigarh, India
National Institute of Immunology. New Delhi,
India
Shanghai Second Medical University.
Shanghai. People's Republic of China
Weizmann Institute ol Science. Rehovot.
Israel
University of Innsbruck. Innsbruck. Austria
Coilnhnrnling Agency Scientists
Alexander. N
McClure. M
Thau. R
Contraceptive Research and Development
Program (CONRAD). Norfolk. VA. USA
National Institute of Child Health and Human
Development. Bethesda. MD, USA
Population Council. New York, NY, USA
Birth control
vaccines
The central role played by
vaccines in providing
protection against many
infectious diseases is now
well accepted, and few
people would disagree
that vaccines have had a
major positive impact on
the health status of all the
populations into which
they have been introduced
or that vaccination
programmes form an
essential part of any
health care system The
use of vaccines to protect
against unwanted
pregnancy, however, is a
comparatively new
concept Such vaccines
would be particularly
attractive for a number of
reasons For example:
they would have a longlasting protective effect
after a single course of
■ immunization; they would
not cause menstrual-cycle
disturbances and other
hormone-dependent side
effects; they would be
easy to administer by a
well-accepted procedure;
and they could be
manufactured at low unit
• Chairperson
The three main criteria of
drug development - safety.
efficacy and acceptability
- are particularly important
in (he development of anti
fertility vaccines, which
are designed to work by
generating immunity to
one or more of the
molecules involved in the
reproductive process. To
ensure that this immunity
does not cause
unacceptable metabolic
disturbances and
potentially hazardous side
effects, the Programme
Tias decided to restrict its
research activities to the
development of vaccines
based on molecules
present only in. or on. or
produced by. the sperm.
the ovum (egg) and the
pre-implantalion embryo.
Anti-hCG vaccines
During 1988 and 1989
work has been concerned
mainly with the further
development and clinical
testing of a vaccine
directed against the
hormone human chorionic
gonadotrophin (hCG).
This hormone, which is
necessary for the
establishment of
pregnancy, is produced
by the pre-implantation
embryo perhaps as early
as lour days after
fertilization. The purpose
of the vaccine is Io inhibit
the function of hCG. thus
preventing implantation of
the embryo, which is
expelled, together with the
lining of the uterus, at the
next menstruation, an
event which occurs
naturally.
During 1988, a
Phase I clinical
trial was
completed on the
safety of the
prototype antihCG vaccine in
previously
sterilized women
volunteers, and
the results were
analysed and
published. The
vaccine was
apparently
capable of
producing
immunity well in
excess of that
estimated to be
needed to
neutralize the
biological activity
of hCG.
suggesting that
this prototype
may be capable
of preventing
pregnancy in
fertile women.
A Phase II clinical trial is
now planned to assess the
vaccine's efficacy.
Before such a clinical trial
can start, animal studies
have to be done to
determine whether any
fetal abnormalities occur
in the offspring of
immunized animals, in
order to assess the risks
to the fetus should an
unexpected pregnancy
ggienbia
>. *
,
,
-- -------------------------- ---
«doenca
1 -irA,mddica e femmiua Ana,Regina ^'Jcudpeo Norplant-^afinnaque a yadna ',.
*fize a mulber para jct|ipn:. J^e o Elsinxu
I G^ttjfcs’Reu/asseao'fa’da CotrusUo ‘.-r anticodxpdoaaj d mna rcvolm^io, pots ^Coutinho jSzero talc an muibcres {&.| dos pirCTjt^.Pxprddutqos'da Asimbldia'! <)wu do campo ^ounonal (odas pflulas ppc / 'jru j daqui. i^’digamj^’IQ^nos," nJ a
J LifgMlatryaz do. Rx^'fc, Jaociro/cricknu 'JVesetnplo). para J ^nninoldgico. '“Mas f '.},;3e[asqutser <mgravi£??pode aabar tounokaLatDcnicauitCD^pdo md^obaia-'Y 'f tuna revotu^iaperversa, o pnndpio fflo- -xobiiidq'que Dav^^cnivelmente ds.1 do EJsi^'C^uunbo dc^tcslar era mulhe-z7,'sdficn’dessa cotsa'd perverse, aberranu, ;(drill Acbo que par‘bso que de quer
" da condmd.'um hormfijrio que d'produ-
induidas num programa da OMS — Or• pnindo Muxiialde Sai
oar oma da outra?", pergunta. A mAlka
tmhra nn<- rrhtdrirKria AMS mn<iV A.
^Ana^egma Umbdn quabotu o taro s para tsso e as mulbcrcs prindpalmcntc. 0 *; V *, ln“ 4 0 prdpno uUgeno '/-'de 0 banoo Fhrmar Coutinho anundar / bonndgip cpolra o qoal querem'nos vadiOM'aprpdyjdpdynbcorpoi. H® •' que vai taur I'nqna-cm mulhcres vpax djcsuHajiteda mtrrarloda mulbcr’c
oidcoocepooul, Orandgcnq d a y crerjlfradii' Segundo Cootaibd.Vobjc- £'ida''tmbnVM‘^c“S5 ranou'^xpnia
ana cqrwmca, quedetona a thnndodsdxrse avadna funooaa, mas '^inrerpcncJra^lo,Sc tc^ii'<cIi
*£le c do
de aanporpos que yai combatd- determine 6 tempo rteduxaqao'rfairaurii- Pt^Y'Umiuaujon^’ifeg^oTaaSyla'd
n
V • * ■ >za^p/que serd [eiw atraYdsde ciama Irq'ttd'&^de'qlqrpjaBmo^^ESjt?1
poasdwl fxla ...de ungue'nas'rnutteres vaonadas para ^aaiu’o^.drpnismo'in^^w'xy.
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Contraceptive Research
a long and winding road to safety..
RING
Although to date there have been no studies
that compare the WHO vaginal ring with other
hormonal contraceptives, data arc available
from several large-scale studies on various ste
roidal preparations that have been carried out by contraceptives. Fourth, the total amount of ste
WHO over the past years. These data indicate roid released by the ring over, for example, a
that the WHO vaginal ring has a method failure period of one month is lower than any other
rale comparable to the low-duse combination hormonal method, being approximately 600 pg.
pill and the progcsturone-releasing IUD.
Finally, the vaginal absorption of the steroid
The vaginal route of administration of contra avoids the "first pass” effect of the liver, which
ceptive steroids oilers a number of advantages means that the drug reaches the target organ
oyer the oral or injectable steroidal preparations. without having first entered the entcrohepalic
First, the device can be inserted, removed and circulation, thus reducing the risk of loss of the
replaced by the user herself. Second, its position drug due to it being metabolized in the liver.
in situ can be checked easily, and corrected if
The Special Programme is also collaborating
necessary, by the user, which is not possible with with the Population Council in the development
IUDs. Third, since the ring has a constant release and testing of a progestcrone-releasing vaginal
rate of the drug, a steady blood level of the steroid ring. It is expected that this ring will be particu
is maintained, which is not the case with oral larly useful for post-partum contraception.
Phase I Clinical
Trials start with an
Antifertility Vaccine
Potential advantages of an antifertility
vaccine
• Ifand when safe and effective antifertiliiy vac
a decade of research and develop cines become available, they are expected to
After
ment, the first clinical trials of a WHO revolutionize family planning programmes. One
obvious advantage will be that an antifertiliiy
anijfeirility vaccine started in Adelaide,
Australia, at the beginning of 1986. The elicet ofa fairly long duration (at least I yearjwill
achieved without the need for continuous •
active principle in this vaccine is a peptide be
administration of a pharmacologically active
immunogen that was specifically designed to agent. Second, since they will be administered by
elicit immunization against the hormone, injection, which is a well accepted and a simple
human chorionic gonadotrophin (hCG). procedure, it may be possible to distribute the
1
his hormone, which plays a crucial role invaccines using paiamedicul personnel. Third,
the establishment and maintenance of early although they will be long-acting, it is likely that
pregnancy, is a particularly attractive target their clfci't will be reversible. Finally, such vac
for an antifertiliiy vaccine because during cines are expected to lend themselves well to
the non-pregnant state it is not produced in large scale synthesis and manufacture al a low
cost. If all goes well the first antifertiliiy vaccine
detectable amounts. *
should become available in the next five to ten
Although it is still caily to say with certainty years.
how successful this approach will be, preliminary
In addition to the WHO bcta-hCG peptide
data fiom the study have been quite promising. vaccine, a number ofothcr vaccines based on the
In the majority of women who have received this whole beta subunit of the hormone human cho
vaccine, including those in the lowest dose group, rionic gonadotrophin arc currently undergoing
antibodies to hCG have been elicited, confirming Phase I clinical trials. These preparations include
the immunogenic properties of the synthetic pep a bcta-hCG tetanus toxoid formulation deve
tide being tested. While, no unacceptable side loped by the Population Council, New York,
effects have so far been detected, some technical
USA, and several bcta-hCG and alpha-ovine LH
problems have been encountered with the for formulations, coupled to or mixed with tetanus
mulation of the emulsion vehicle of the vaccine.
toxoid and cholera chai^^ developed by the
Scientists are now trying to overcome these pro National Institute of Im^Bology, New Delhi,
blems by developing alternative macromolecular India. The Special Programme is assisting with
carriers, adjuvants and delivery systems.
the coordination of research efforts in this urea.
Ia/
occur in a woman
receiving the vaccine.
The vaccine has been
prepared and packed in
accordance with Good
Manufacturing Practice
(GMP) requirements lor
materials intended lor
human use, and teratology
studies - in rats, rabbits
and baboons - are being
conducted according to
protocols approved by
national drug regulatory
authorities. In anticipation
of a successful outcome.
a protocol has been drawn
trial and centres have
been identified at which
the trial might be
conducted.
The prototype anti-hCG
vaccine is a complex
formulation unlikely to be
suitable lor large-scale
production and use. The
Programme has continued.
therefore, with the
development of better antihCG vaccines which could
prove suitable for final
product development.
This work has included
incorporating the
immunogen and adjuvant
components of the vaccine
into microspheres formed
from biodegradable/
biocompatible polymers.
which are capable of
releasing the vaccine over
a long period and have
the potential to confer
effective immunity lasting
one year or more after a
single injection In
addition, further work has
been done on the design
components of improved
potency, specificity and
clinical acceptability.
Anti-trophoblast vaccines
The Programme is also
supporting studies to
identify molecules that
form part of the surface of
the trophoblast of the pre
implantation embryo and
might be suitable
candidates for anti
trophoblast vaccines.
Most previous studies in
this area have used
biochemical extraction
procedures to isolate
molecules that occur in
relatively large amounts in
the membrane of placental
tissue Molecules isolated
in this way are then
analysed Io determine
tneir amino-acid sequence.
and from this information
synthetic peptides can be
made. The analytical
procedures used are
relatively harsh and
unsuitable for isolating the
molecules of most interest
for vaccine development,
namely those expressed
for very short periods and/
or in low concentrations
during the pre-implantalion
stage of embryonic
development.
To overcome this problem,
the Programme has taken
advantage of recent
advances in the fields of
immunology and molecular
biology including
monoclonal antibodies
(MAbs). These MAbs can
be used in a highly
specific manner to detect
and isolate molecules on
the surface of trophoblast
cells, which can then be
assessed as candidates
for vaccine development.
Recombinant
DNA technology
is being used to
determine the
structure of these
molecules so that
they can be
synthesized in
the relatively
large quantities
needed for
vaccine
development.
number of baboons is now
planned with the more
potent of the materials.
Additional MAbs are being
generated and used to
identify other trophoblast
specific molecules that
might be suitable lor
vaccine development.
In order Io manage the
large amount of novel data
being generated as a
result of the Programme’s ‘
studies in this area, a
nomenclature system has
been developed which will
permit the establishment
of a computerized data
base containing
information on trophoblast
specific MAbs and the
molecules with which they
react. A similar data base
is also being developed
for sperm-specific MAbs
« and the molecules with
which they react on the
sperm surface. These two
nomenclature systems are
being integrated into a
joint data bank, the
contents of which will be
published at regular
intervals and made
available to investigators
working in these areas.
Two proteins expressed on
the surface of the
trophoblast have been
identified in this way and
small amounts of these
proteins have been
prepared and tested for
their ability to elicit a
trophoblast-specific
immune response capable
of inhibiting fertility in
female baboons. Some
evidence of a partial
reduction in fertility was
obtained in this
preliminary experiment and
a further study in a larger
'Freedom to choose means knowing all the choices.'
RESEARCH IN HUMAN REPRODUCTION
desired slow and prolonged release of vaccine,
it was likely that a rapid and transient release
had occurred, producing the reported myalgia
and arthralgia and the poor anti-hCG antibody
responses.
It was decided, therefore, to form two additional
treatment groups, Groups IVa and Va, of eight
more volunteers who would receive the same
vaccine doses as the subjects in Groups IV and
V but this lime in an emulsion vehicle which
had been made more stable by minor changes to
the relative proportions of its constituents. This
plan was approved by the appropriate drug regu
latory committees and authorities, the subjects
recruited and the immunizations carried out.
The incidence and severity of the myalgia and
arthralgia reported by the subjects in Groups
IVa and Va were significantly less than
those reported by their predecessors in Groups
IV and V and were most evident in Group Va.
These observations would suggest that the
amount of MDP to be used, in this particular
vaccine formulation, should be limited to the
Group IV/lVa dose of 250 pg or less. The antihCG antibody responses in Groups IVa and Va
were considerably improved and formed with
the Groups I, II and III data, a clear dose
response pattern (Fig. 1). both in terms of anti
body dues and, to a lesser extent, duration of
anuliody production.
Because of known species differences in the
structures of baboon and human chorionic gonadouophins and the time-course and mechanism
of implantation in these two species, it is diffi
cult to determine, from previous baboon antifertility studies, what levels of anti-hCG antibody
will confer antifertility efficacy in the human.
However, on the basis of the concentration of
hCG in the maternal circulation al the lime of
implantation, it is estimated that an antibody
level of approximately 0.5 nanomoles of hCG
binding capacity would prevent implantation
and thereby confer antifertility efficacy in
women. As can be seen in Figure 1, this titre
threshold has been exceeded in all of the five
dose groups receiving the complete vaccine.
As pan of the intensive analysis of the serum
samples obtained in the course of this Phase I
184
trial, immunofluorescent staining studies have
been carried out to determine the incidence and
nature of any tissue cross-reactivity exhibited by
these sera (Burek et al, 1986a; Rose et al, 1988).
A total of four serum samples were obtained
from each of the 30 volunteers, in weeks 5, 7
and 26 after injection of the vaccine, with a pre
immunization sample serving as an individual
specific control in each case. These sera have
been tested against a panel of rat, baboon and
human tissues prepared as fresh cryostat sections
(Burek et al, 1986b).
Virtually all sera exhibited reactivity against rat
cardiac, skeletal and smooth muscle. However,
the frequency and intensity of these reactions
were essentially the same in the pre-immune
sera as in the post-immunization samples and
these results were not considered to be clinically
significant.
**
Weak reactions against baboon pancreas were
observed with samples from four individuals.
These reactions were transient, appearing in
samples taken five weeks after injection of the
vaccine and disappearing by week 26. A closer
examination of the stained sections indicated
that the antisera were binding to' somatostatin
secreting cells in the pancreatic islets. However,
this reactivity could not be absorbed out using
purified somatostatin, in either the natural or
straight-chain forms. Although no signs of pan
creatic dysfunction and damage were seen in the
preclinical baboon efficacy and safely studies,
nor detected in the detailed histopathological
examinations that were carried out on these
animals postmortem, further studies are under
way to identify the antigen involved and the
long-term sequelae of this reaction.
Two of the 30 sets of sera exhibited binding with
human pituitary sections. In the first case this
activity was present only in the week 26 serum
sample and not in any of the other samples from
this individual; in the second case the reactivity
was observed in all of the samples with the most
intense reaction being exhibited by the preimmune serum. A closer examination of the
stained tissue indicated that binding was not spe
cific to any one cell type and appeared to be
randomly distributed and restricted to the
VACCINES FOR FERTUJTY REGULATION
intracellular compartment. In view of the diffi
culties involved in obtaining fresh human tissues
for definitive immunofluorescence studies, and
the known artefacts that can occur as the result
of non-specific reactions and postmortem
changes in the tissue substrates, these results are
not considered significant. However, studies are
underway to characterize further the reactions
observed, to identify the cell types and the anti
gen involved, and to determine the long-term
sequelae of this apparent antibody binding.
With the successful completion of this first clini
cal trial of a synthetic peptide based antifertility
vaccine, it is important to review the objectives
of the trial, how well these objectives have been
met, and the other information that has been
obtained during the course of this study.
The results obtained in the Phase I clinical trial
indicate that the Task Force's primary objective
has been successfully achieved, in that the
desired type of immunity has been elicited in
most of the vaccine recipients without the pro
duction of unacceptable side effects. Further
more, the antibody levels attained in all respond
ers are estimated to be in excess of those
expected to confer antifertility efficacy.
In view of these encouraging results, the Task
Force is proposing to carry out a limited study
with the current B-hCG-CTP vaccine formula
tion, in a small number of fertile women volun
teers, to determine if anti-hCG antibody levels
in excess of 0.5 nanomoles of hCG binding
capacity will provide an antifertility effect.
However, before seeking approval to conduct
this study in women it will be necessary to carry
out further animal experiments in order to deter
mine if any fetal abnormalities are associated
with the vaccine’s use. This will involve both
an assessment of "chemical teratology" in
rodents and rabbits as well as a concurrent
assessment of "immunoteratology" in baboons or
another relevant primate model. The latter study
is particularly difficult to carry out in view of
, the paucity of background information in this
area and the need to use a large number of ani
mals in order to obtain statistically significant
data. Although negative data will not be conclu
sive, the Task Force considers it important to
attempt to obtain as much information as pos
sible before conducting an efficacy evaluation of
the cunent vaccine formulation in women.
Protocols for these animal experiments and for
the clinical study have been drafted in consulta
tion with Task Force scientists and clinicians
and with representatives of the pharmaceutical
industry and national drug regulatory authorities.
A further supply of the B-hCG-CTP vaccine,
needed for these additional animal and clinical
studies, is currently being prepared, under the
appropriate GMP conditions.
Valuable additional information has been
obtained in the Phase I clinical trial, relevant to
the development of a safe, effective and accept
able anti-hCG vaccine suitable for wide-scale
application, particularly in the developing
countries. This important information concerns
all components of the current B-hCG-peptide
prototype vaccine formulation.
HCG Peptide: The 109-145 B-hCG-peptide used
in the current vaccine appears to be capable of
eliciting antibody levels estimated to be several
fold higher than that needed to confer antifertil
ity efficacy. However, future, vaccine produc
tion would be greatly facilitated if one or more
short peptides of B-hCG could be identified
which retained the ability to elicit high lev
els of specific immunity to hCG and which
were cheaper and easier to manufacture and
characterize than the long peptide in the current
formulation.
DT carrier. Out of a total of approximately 80
injections with the B-hCG-CTP vaccine that
were made during the course of the trial, adverse
reactions to the DT component were seen in two
instances. Whilst this may appear to be a very
low incidence, it would probably be regarded as
an unacceptably high level when large-scale use
of the vaccine is considered.
Adjuvant: Comparison of the clinical trial data
with those derived in the preclinical animal stud
ies would suggest that the human dose of the
MDP adjuvant need not exceed 200-250 pg in
order to elicit adequate anti-hCG immunity.
Limiting the MDP dose to this level would
greatly reduce, and perhaps even eliminate, the
185
RESEARCH IN HUMAN REPRODUCTION
VACCINES FOR FERTILITY REGULATION
occassional and transient arthralgia and myalgia
reported by some of the trial volunteers in the
high-dose groups.
Last but not least, this approach offers the added
advantage of long-term vaccine stability under a
wide range of climatic and storage conditions.
of totally novel peptide immunogens, selected
and engineered to provide enhanced immuno
genicity whilst retaining specificity for hCG.
Vehicle: The complex and highly viscous emul
sion used as the vehicle for the current vaccine
is obviously not suitable for use beyond the pre
liminary stages of clinical testing. Although it
may prove possible, by mechanical means, to
produce a stable emulsion in a reliable and
repeatable manner, the short duration of the
immune response elicited by the B-hCG-CTP
vaccine delivered in this vehicle, necessitating
frequent booster injections, would argue against
its use in further vaccine development.
During the reporting period, a large number of
microsphercs, consisting of different ratios of
polylactic and polyglycolic acid, have been pre
pared and evaluated in terms of their ability to
elicit anti-hCG antibody titres of the required
magnitude and duration. Four of these formula
tions produced titres which persisted, for at least
six monihs, at levels in excess of those produced
by the emulsion delivery system, and additional
studies with the more promising of these formu
lations have indicated that anti-hCG antibodies
can be elicited for a period in excess of twelve
monihs. Additional supplies of the more prom
ising preparations have been produced in larger
quantities for further studies and a number of
new formulations are also being prepared for
comparative evaluations.
In natural B-hCG, the amino acid residues form
ing the 38-57 region of the molecule exist as a
loop structure formed by a disulfide linkage
between the cysteine residues at each end of this
pepude. Since previous studies with other mole
cules have demonstrated that such loop struc
tures are potent immunogens, perhaps because
of their prominent surface presentation on the
molecule, a 38-57 loop peptide was synthesized
and evaluated in rabbits. Although this loop
peptide proved to be highly immunogenic, the
antibodies raised to it cross-reacted with hLH.
Further studies were carried out, therefore,
with a number of intermediates of both straight
chain and loop versions of the 38-57 peptide in
order to develop an analogue capable of eliciting
high levels of antibodies devoid of hLH cross
reactivity.
These findings justify the decision taken by the
Task Force to evaluate a number of alternative
formulations, as well as additional immunogens,
immunostiniulants and vaccine delivery systems,
in order to produce improved vaccine prepara
tions that will be suitable for eventual product
development
Development of improved and optimized antihCG vaccines
This work is being carried out in two phases.
The first phase involves an evaluation of alterna
tive delivery systems for the existing B-hCGCT'PiDT immunogen and MDP adjuvant in order
to find a replacement for the squalene-arlacelwater emulsion. In this area, the Task Force has
continued with its studies on microsphere deliv
ery systems, prepared with biocompatible and
biodegradable polymers. The advantages of this
particular approach to vaccine delivery are that
microspheres can be individually engineered to
meet the varied physico-chemical requirements
of the different vaccine components, thus per
mitting the sustained release of the encapsulated
vaccine over long periods of lime and at pre
determined release rales. It would be possible,
therefore, io prepare vaccine formulations with
pre-set durations of action ranging from a few
monihs io several years. Furthermore, these
preparations appear to be capable of eliciting
high levels of anti-hCG immunity of long dura
tion following a single injection of vaccine.
186
The second phase of this work is concerned with
optimizing the anti-hCG vaccine to the point
where it represents a safe, effective and accept
able pre-product formulation suitable for
large-scale clinical trials. The studies being car
ried out in this area involve optimization of all
components of the vaccine.
HCG peptide: The B-hCG-CTP component of
the immunogen in the current vaccine formula
tion, consists of a synthetic peptide 37 amino
acids long. In spile of recent advances in chemi
cal and biological peptide production methods,
the preparation of a peptide of this length is still
an expensive and difficult undertaking if the
product is to meet the stringent specifications
demanded by drug regulatory authorities. The
Task Force has been conducting studies, there
fore, to identify and subsequently evaluate a
variety of additional peptides representing both
sequential and conformational immunogenic
determinants (epitopes) on the B-hCG molecule
(Stevens, 1986d).
The following summary of the studies carried
out in this area over the reporting period, illus
trates the complexity of this work and the poten
tial offered by this approach for the development
Comparative mapping studies have identified
the 43-50 sequence as the hCG-specific epitope
within the 38-57 peptide. An analogue of this
epitope, consisting of the 43-50 straight chain
peptide linked at its amino-terminal residue to a
hexa-proline spacer, proved to be more immuno
genic in generating hCG-specific antibodies than
the 43-50 peptide alone but not as immunogenic
as the 38-57 loop peptide.
Complementary studies were carried out to
define the regions within the 38-57 loop peptide
that were responsible for eliciting antibodies
crossreacting with hLH. These activities were
found to reside in the regions, 30-42,45-57 and
50-62 of the molecule. On the basis of the infor
mation gained from these studies, three experi
mental loop peptides have been prepared with
amino acid substitutions designed to remove the
hLH crossreactivity and to confer some degree
of a helical structure on the peptide. One of
these"helical" peptides has been found to be
more immunogenic than its straight chain
counterpart, and whilst it is not as immunogenic
as the native 38-57 loop, it does produce anti
bodies specific for hCG. When this peptide is
given, as a combined immunogen with the 109-
145
B-hCG-CTP, antibodies are elicited at levels
much higher than those produced by either of
the peptides alone. In addition, other surface
epitopes on the beta-hCG molecule have been
identified using predictive rules for molecular
structure or by the binding properties of B-hCG
specific monoclonal antibodies. Peptides repre
senting some of these epitopes have been syn
thesized and evaluated and a number of regions
on the B-hCG molecule have been identified
which could form the basis for the development
of new anti-hCG immunogens. These data indi
cate that immunogens consisting of a number of
short and novel peptides, selected on the basis of
their immunogenicity and hCG specificity, could
form the basis of a prototype second generation
anti-hCG vaccine meeting the Task Force’s
requirements.
New carriers: The carrier molecule used in the
first generation anti-hCG vaccine is a purified
form of clinical grade diphtheria toxoid (DT).
Although this DT is a single molecular weight
fraction, it is still a chemically ill-defined and
heterogeneous preparation. Furthermore, the
repeated use of a vaccine incorporating this
material produces a low but significant inci
dence of delayed type hypersensitivity (DTH)
reactions. As slated earlier, such DTH reactions
were observed in two out of 30 women receiving
the complete vaccine formulation in the Phase
I trial. Although this incidence of DTH reac
tions presents no difficulties in the context of a
small-scale clinical trial, it is almost certainly
loo
high to permit a DT-containing vaccine to be
considered for wide-scale clinical use.
The Task Force has continued, therefore, with
its search for clinically acceptable molecules to
evaluate as alternative carriers for the hCG pep
tide immunogens. In studies carried out with
B-hCG peptides conjugated to a purified protein
derivative (PPD), obtained originally from My
cobacterium tuberculosis, good anti-hCG anti
body responses were elicited and the frequency
and intensity of DTH reactions were found to be
much lower than those produced by conjugates
containing DT. Further studies are planned with
single molecular weight species of M. leprae
PPD obtained by recombinant DNA procedures.
187
RESEARCH IN HUMAN REPRODUCTION
The principal advantage of these materials is
that their chemical structures are known. How
ever, they do have a major disadvantage in that
they will not confer protection against tuberculo
sis but will render recipients skin test positive on
subsequent challenge. The clinical and epidemi
ological implications of this "false positivity"
would need to be carefully discussed before
embarking on a major research programme to
develop an anti-hCG vaccine, or any other vac
cine, incorporating these materials as the carrier
component of the immunogen.
New adjuvants: Although the MDP analogue in
the current vaccine formulation has been
approved for use in clinical trials, it may not be
suitable for inclusion in a vaccine for wide-scale
clinical use except at lower doses which may not
confer immunity of sufficient magnitude or
length in all recipients. There are a large num
ber of additional MDP analogues and other
experimental immunostimulants available, but
the amount of immunological, pharmacological
and toxicological information on these com
pounds is limited and is not sufficient to permit
the selection of an alternative preparation suit
able for clinical trials. The Task Force is con
tinuing, therefore, with its studies to compare
the properues of alternative immunostimulants
that might be suitable for clinical use.
A number of thiol compounds have been tested
during the reporting period in an effort to iden
tify a clinically acceptable alternative to MDP,
but none was found to be suitable for this pur
pose. Although no further studies are planned
with these particular compounds, these studies
did allow the confirmation of earlier findings
that an adjuvant may be needed only in the first
injection for a vaccine to elicit an adequate
immune response.
New delivery systems: As indicated earlier in
this chapter, the vehicle used in the prototype
hCG vaccine is a high-viscosity water-in-oil
emulsion which requires careful preparation
immediately prior to injection. Although it is
possible that the in vitro and in vivo instability
problems encountered in the Phase 1 clinical trial
might be overcome by preparing the emulsion
using a machine capable of achieving high shear
188
forces, it is unlikely that a vaccine for wide
spread clinical application will be administered
in this form in view of the limited duration of
the immune response elicited by preparations
administered in this vehicle. The Task Force
has continued, therefore, with its studies to
develop and evaluate alternative delivery sys
tems capable of producing an effective level of
anti-hCG immunity of long duration, preferably
following a single injection of vaccine. In addi
tion to the work with copolymer microspheres
referred to earlier, the Task Force has also car
ried out experiments in rabbits with a number of
liposome and iscom (immunostimulating com
plexes) preparations, incorporating various com
binations of the B-hCG-CTP:DT conjugate and
MDP adjuvant.
Both of these vaccine delivery systems appear to
be well tolerated by the experimental animals
and elicit substantial levels of anti-hCG immu
nity. However, in terms of duration of effect,
neither liposomes nor iscoms proved to be
as effective as the microspheres.
Development of a baboon CG vaccine
Although the primate chorionic gonadotrophins
appear to have the same physiological functions,
there arc substantial species differences in the
chemical structures of these hormones and in
their secretion profiles throughout gestation. As
a result of these species differences, antibodies
raised in baboons to the heterologous B-hCGCI'P vaccine cross-reaci with endogenous
baboon CG (bCG) by approximately 5% com
pared to hCG. Whilst this comparatively low
level of crossreaction is sufficient to produce an
antifertility effect in the immunized baboons, it
may not be sufficient to stimulate, either qualita
tively or quantitatively, all of the acute or
chronic side effects that might occur when the
homologous B-hCG-CTP vaccine preparation is
used in women.
The Task Force has continued, therefore, with
its programme to develop a baboon model sys
tem in which a vaccine based on the animal's
own CG can be used to evaluate extensively
these safely issues. These studies have proved
VACCINES FOR FERTILITY REGULATION
technically difficult and costly and have not yet
been satisfactorily completed. If solutions can be
found to the technical problems encountered, it
may prove possible to develop a B-bCG-CTP
vaccine that is equivalent to the B-hCG-CTP
preparation. This anti-bCG vaccine would
enable more meaningful data to be generated in
baboons concerning the safely of this novel
approach to fertility regulation.
The fust step in the development of a B-bCGCTP vaccine is the elucidation of the amino acid
sequence of the baboon hormone in order that
the appropriate peptide can be synthesized.
These studies have followed two separate but
complementary approaches.
In the first set of studies, bCG is isolated from
baboon pregnancy urine and purified for subse
quent classical protein sequence analysis. Major
unforeseen problems and delays have been
encountered in this programme, resulting from
the transient nature of the secretion of the
baboon hormone, its inherent lability, and the
difficulties of collecting sufficient quantities of
baboon pregnancy urine in an uncontaminated
form. Improvements have been made continu
ously by Task Force scientists in the procedures
used for the collection of baboon pregnancy
urine and its subsequent processing to obtain uri
nary bCG. Recendy, several milligrams of puri
fied bCG have been prepared with a biological
activity corresponding to 10,000 1U of hCG per
mg from which the B subunit has been isolated
for amino acid sequence analysis. In accordance
with established protein sequencing procedures,
the B-bCG has been subjected to enzymatic
digestion in order to obtain fragments of the
molecule that can be analyzed using automated
equipment. These fragments have been purified
and separated by reverse-phase HPLC to yield
6-8 fractions with different physicochemical
properties reflecting their location in the B-bCG
molecule. Preliminary amino acid analyses on
these fractions are currently underway and it is
anticipated that a tentative structure for part or
all of this molecule might be available early in
1988.
In the second set of studies, recombinant DNA
techniques have been used to determine the
nucleotide sequence of the bCG gene, from
which the amino acid sequence of the hormone
can be deduced. These studies have identified
several genes coding for CG in the baboon pla
centa, and it is not clear how many of these
genes there are, how closely related they are to
each other, or which one is responsible for pro
ducing the physiologically and immunologically
important form of bCG. In an attempt to resolve
these issues, the Task Force has carried out stud
ies to assess the biopotency and immunological
reactivity of heterodimers, consisting of the a
subunit of bovine LH and the alleged B subunit
of bCG, produced using a mammalian cell
expression system. The gonadotrophic poten
cies of the expressed products have been deter
mined using the Leydig cell bioassay, and their
immunological reactivities have been assessed
in radioimmunoassay (RIA) using monoclonal
and polyclonal antisera to B-hCG-CTP and the
proposed baboon counterpart. To verify the
authenticity of the expressed materials, auto
radiographic studies have been carried out to
determine their presence and location in
human and baboon placentae.
None of the expressed heterodimer products
obtained so far has exhibited the appropriate
activities in all of these systems. From the
available data, it is not clear if the expressed
material is a gonadotrophin or another, irrele
vant, gene product. Comparative studies are
underway to determine if one of the other bCG
genes in the baboon placenta codes for a more
relevant material than that already studied, and
further RIA studies are also underway to deter
mine the tissue specificity and localization of
the putative antigenic material.
It is anticipated that a definitive answer to the
bCG sequence question will be provided from
the purified baboon pregnancy urine material
(Bambra, 1987), either directly by total amino
acid sequence analysis, or indirectly by using
partial amino acid sequence data to prepare
oligonucleotide probes for screening gene librar
ies prepared from baboon placentae at the peak
of bCG secretion. The relative molecular sizes
of the naturally occurring and expressed materi
als will be compared using electrophoresis,
immunoblot procedures and autoradiography.
189
RESEARCH IN HUMAN REPRODUCTION
From ihe dam generated in these two comple
mentary research activities, it should prove pos
sible to detect and characterize the C-terminal
region of B-bCG and to synthesize the appropri
ate peptide for formulation into a B-bCG-CTP
vaccine.
Once a relevant B-bCG-CTP vaccine has been
prepared, meaningful studies can be carried out
in the baboon to assess the efficacy and safety of
this homologous preparation. A successful out
come to these studies will provide greater confi
dence for proceeding to a clinical evaluation of
the antifertility efficacy of the the current BhCG-CTP vaccine as well as for the develop
ment of improved anti-hCG vaccine formula
tions suitable for wide-scale clinical application.
interest for vaccine development. The Task
Force has decided, therefore, to use a combina
tion of monoclonal antibodies (MABs) and
molecular genetics techniques to identify, isolate
and characterize trophoblast membrane antigens
that might represent suitable candidates for
development into anti-trophoblast vaccines.
The research strategy being employed by the
Task Force in this area involves the use of
MABs that satisfy the following three criteria:
— tissue-specificity for human trophoblast;
- cross-reactivity with similar or equivalent
tissues in other mammalian species;
- ability to disrupt or inhibit the function of
trophoblast in vitro and/or in vivo.
Development of an anti-trophoblast vaccine
At its meeting in September 1985, the Special
Programme's Scientific and Technical Advisory
Group (STAG) recommended that the Task
Force should expand its activities to include
studies on additional targets for FRV develop
ment. In order not to duplicate the work of
other agencies in this area, which is largely
restricted to the development of ami-gamete
vaccines, the Task Force has initiated studies on
a vaccine based on membrane antigens of the
early trophoblast. Although there are many
investigators working on the immunobiology of
lhe early trophoblast, this is largely in terms of
its role in preventing immunological rejection of
the "fetal allograft", and lhe Task Force studies
are the only international, multidisciplinary col
laborative vaccine development programme in
this area.
Previous studies carried out, both by Task Force
scientists and other investigators, had focused on
lhe identification of membrane expressed mol
ecules that could be isolated from lhe trophob
last using classical mechanical and biochemi
cal extraction procedures (Johnson. 1985; Stem
et al, 1987). The comparative harshness of this
approach can result in the partial or complete
destruction of lhe more labile membrane compo
nents, many of which may be molecules of
190
By establishing these three criteria at lhe outset
of its studies, lhe Task Force is aiming to
develop anti-trophoblast vaccines which will not
produce cross-reactions to other non-target tis
sues; which can be evaluated for safety and effi
cacy in a relevant animal model; and which will
be directed against antigens expressed on lhe
cell surface, and which arc accessible, therefore,
to antibodies and immune cells in lhe maternal
circulation. MABs satisfying these three crite
ria can then be used to isolate antigens expressed
on lhe surface of the trophoblast membrane and
to screen the products of expression systems in
which genes coding for trophoblast antigens
have been inserted. The data generated in these
studies will permit a range of synthetic peptide
immunogens to be prepared for comparative
evaluations of their potencies as anti-trophoblast
vaccine components.
As an initial step in this new research pro
gramme, the Task Force has carried out a
systematic evaluation of a large number of anti
trophoblast monoclonal antibodies that had
already been produced by investigators in lhe
field. The data generated in these studies were
reviewed and discussed at a workshop
(Anderson et al, 1987), jointly organized by
WHO and Family Health International (FHI).
and held in Toronto, Canada, in June 1986
in conjunction with lhe third International
VACCINES FOR FERTTUTT REGULATION
Congress on Reproductive Immunology and lhe
sixth International Congress of Immunology. A
total of 44 such antibodies alleged to satisfy the
primary criterion of trophoblast specificity were
obtained from 15 investigators and further char
acterized, in coded form, in terms of the
types of tissue with which they reacted, lhe loca
tion of these reactions within the tissue, and the
nature of the putative antigenic material. The
results obtained in these preliminary studies are
summarized in Table 2.
Table 2. Tissue reactivities of anti-trophoblast
monoclonal antibodies
Species cross-reactivity was assessed against
baboon, marmoset, donkey, horse, cow, pig and
rodent placentae. Five of lhe 44 MABs exhib
ited tissue-specific cross-reactivity with baboon
placental tissue and many exhibited a variable
degree of cross-reactivity with rodent placental
or embryonic tissues. However, the data gener
ated with rodent tissues showed poor correlation
between investigating laboratories.
Tissue location and antigen characterization
studies were carried out on detergent-solubilized
isolated human placental syncytiotrophoblast
plasma membranes using immunoblot and radio
immunoprecipitation techniques. In lhe im
munoblot studies, five of lhe 44 MABs reacted
with clearly defined bands of solubilized mat
erial with molecular weights of approximately
115 kDa, and 14 MABs identified protein anti
gens in lhe radioimmunoprecipitation studies.
Further immunohistological studies and enzyme
capture assays indicated that four out of lhe five
MABS that reacted with solubilized material in
lhe immunoblot experiments were directed
against heat-stable placental-like alkaline
phosphatase (PLAP) and an additional four
MABs appeared to be directed against the cell
surface receptor for transferrin. However, five
other MABs appeared to react to novel solubil
ized components of placental syncytiotrophoblast plasma membrane and two of these MABs
also reacted with baboon placental tissue. These
two MABs appeared to be directed against two
glycoprotein antigens with molecular weights of
’ 43 kDa and 76 kDa, respectively.
These preliminary studies have identified, there
fore, at least two and perhaps as many as five
MABs, out of lhe original group of 44, that
appear to satisfy two of lhe three criteria estab
lished by lhe Task Force. Further studies are
underway and planned with these high priority
reagents in order to isolate and characterize the
trophoblast membrane protein antigens with
which they react as a prelude to the synthesis of
these materials for evaluation in prototype anti
trophoblast vaccines. The Task Force is main
taining contacts with investigators working in
this field and further MABs, meeting lhe same
stringent requirements, will be added to this
panel of reagents as they become available.
Progress has been made also in the recombinant
DNA project which is being carried out to com
plement the MAB studies. A human placental
gene library has been established and vectors
containing cDNA coding for human placental
proteins have been inserted into cloned mam
malian host cells. The high priority MABs will
be used to screen these host cells for the pres
ence of relevant human placental gene products
expressed on their plasma membranes. Clones
exhibiting the desired expression products will
be expanded to obtain sufficient quantities of
genetic material, or expressed protein, for the
sequence analyses needed prior to lhe synthesis
of peptides for subsequent evaluation as candi
date immunogens for anti-trophoblast vaccines.
191
RESEARCH IN HUMAN REPRODUCTION
VACCINES FOR FERTILITY REGULATION
Table 3. Tissue reactivities of anti-sperm monoclonal antibodies (MABs)
Tissue and other
reactivities observed
Number of
MABs tested
Number of
MABs reacting
Live human sperm surface,
beforc/after washing, and
before/after capacitation
66
Human testis, seminiferous
tubules only
66
9
Human testis, interstitial
compartment only/also
66
24
49
11
60
33
LDH-C4 neutralizing
activity
Cross-reactivities with
other human tissues
Development of an anti-sperm vaccine
Studies on anti-gamete vaccines, which are
likely to be effective prior to fertilization, have
been supported by the Task Force in the past
(Hjort and Griffin, 1985; Hjort et al, 1985; Mori
el al, 1985; Shelton and Goldberg, 1985; Wang
et al, 1986) and are being supported currently by
several national and international funding agen
cies (Bronson et al, 1985; Czuppon, 1985;
Lehmann et al, 1985; Mathur et al, 1985;
Mettler et al, 1985). In order to avoid duplica
tion of effort, the Task Force is not funding a
major research programme in this area. How
ever, it is conducting a systematic evaluation of
anti-sperm MABs in order to characterize these
reagents in terms of their abilities to:
- react specifically with human late spermat
ids and mature spermatozoa;
— cross-react with similar or equivalent cel
lular stages of spermatogenesis in other mam
malian species;
- interfere with sperm motility or inhibit
32
sperm-ovum attachment and fertilization in vitro
and/or in vivo.
The overall objectives of these studies are simi
lar to those described for anti-trophoblast MABs
in the preceding section of this report, namely to
identify MABs that can be used to isolate and
characterize sperm membrane antigens that rep
resent appropriate candidates for development
into anti-sperm vaccines.
Again, as the initial step in this new research
programme, the Task Force has carried out a
systematic evaluation of a large number of anti
sperm MABs that had already been produced by
investigators in the field. The data generated in
these studies were reviewed and discussed at the
workshop (Anderson et al, 1987), jointly organ
ized by WHO and Family Health International
(FHI), and held in Toronto, Canada, in June
1986 in conjunction with the third International
Congress on Reproductive Immunology and the
sixth International Congress of Immunology. A
total of 66 such antibodies, alleged to satisfy the
primary criterion of sperm specificity, were
obtained from 17 investigators and further char
acterized, in coded form, in terms of the types of
tissue with which they reacted, the location of
these reactions within the tissue, and the nature
of the putative antigenic material.
Tissue location studies were carried out, by
immunofluorescence and immunoperoxidase
staining procedures, on human testis sections (to
distinguish between reactions with components
of the seminiferous tubules and the interstitial
compartment of this organ), and on a large num
ber of other normal human tissues and fluids.
Some of the MABs were assessed for their
abilities to neutralize the enzymic action of
the sperm-specific lactate dehydrogenase
isozyme, LDH-C4. The results obtained in these
preliminary studies are summarized in Table 3.
Species cross-reactivity was assessed against a
variety of primates (gorilla, orangutan, rhesus
monkey, baboon, chimpanzee, marmoset) and
other species (elephant, hamster, rat, mouse,
horse, mountain sheep, dog). Eighteen MABs
cross-reacted with sperm from at least one non
human primate species and 21 cross-reacted
with mouse sperm in at least one laboratory.
Wide species cross-reactivities were exhibited
by four MABs.
A variety of tests were carried out to assess
the inhibitory activity of the MABs on sperm
function. These included inhibition of sperm
motility, sperm agglutination, sperm immobi
lization, inhibition of cervical mucus penetra
tion, and inhibition of the penetration of ham
ster ova by human sperm. The results obtained
in these functional tests are summarized in
Table 4.
Four laboratories have carried out studies in
an attempt to derive information on the physico
chemical properties of the human sperm anti
gens identified by selected sperm-specific
MABs. Although the results obtained by these
laboratories did not correlate well, the more
relevant materials identified in this way have
molecular weights in the range 15-30 kDa.
These preliminary studies have identified six
MABs, out of the original group of 66, that
appear to satisfy the criteria established by the
Task Force. In addition, these studies have dem
onstrated a considerable variability in surface
expression of most sperm antigens identified by
sperm-specific MABs. This variability may be a
product of the wide variation of immunizing
materials used by different investigators as well
as a reflection of the inherent polymorphism of
these antigens. In addition, antigenic expression
on the sperm surface can be affected by the
known and suspected changes that occur as a
result of passive coaling with seminal plasma
Tabla 4. Activities ol antl-sparm monoclonal antibodies In sperm function tests
Number of MABs tested
Number of MABs active
Inhibition of sperm
motility
62
22
Sperm agglutination
55
15
Sperm immobilization
55
8
Inhibition of cervical
mucus penetration
35
8
Inhibition of hamster
ovum penetration
53
25
Functional test
•
193
RESEARCH IN HUMAN REPRODUCTION
components, enzymatic modification as well as
the stage-specific structural changes associated
with maturation, capacitation and the acrosome
reaction.
In view of the confusing and often conflicting
data being generated in this area, the Task Force
has initiated a sperm antigen classification proj
ect. This project is modelled on other WHOsponsored nomenclature programmes in other
fields (for example leucocyte and parasite anti
gens) and will establish an organized data base
and nomenclature system specifically for human
sperm antigens. Initially, the work to be carried
out will form an extension of the studies already
conducted by the Task Force and will involve
the collection, banking, distribution and charac
terization of anti-sperm MABs with a final
objective of producing a computerized data base
in which each sperm-specific antigen will be
identified by a project-assigned WHO code
number.
animals to evaluate prototype anti-trophoblast
vaccines. The antigens to be used in these vac
cines will have been identified by characteriza
tion of trophoblast membrane extracts and by
screening gene libraries from human placen
tae, using selected anti-trophoblast MABs that
satisfy the Task Force’s criteria of tissue-speci
ficity, lack of species-specificity, and a function
inhibiting or disrupting action.
The Task Force will continue with its recently
initiated programme to classify sperm-specific
MABs, with a view to characterizing sperm
membrane antigens that might represent suit
able candidates for development into anti-sperm
vaccines. It is envisaged that this work will
be conducted in close collaboration with the
Task Force on Methods for the Regulation of
Male Fertility and with other agencies active in
this area. In addition, developments in the field
of zona pellucida immunobiology, local (secre
tory) immunity and ‘basic vaccinology’ will be
monitored in terms of their relevance to the
development of antiferiiliiy vaccines..
FUTURE DIRECTIONS
The Task Force is proposing to carry out the
following activities during the 1988/89 bien
nium.
Subject to a satisfactory outcome of animal tera
tology studies, approval will be sought to carry
out a limited efficacy evaluation of the current
anti-hCG vaccine formulation in fertile women
volunteers. In addition, the Task Force will con-.
linue with the development of an improved ver
sion of this vaccine, using a slow-release deliv
ery system designed to elicit long-lasting immu
nity from a single course of immunization, as
well as the development of a second generation
of anti-hCG vaccine that will represent a viable
product prototype. This latter work will involve
the systematic development and comparative
evaluation of additional synthetic peptide immu
nogens, carrier molecules, adjuvants and deliv
ery systems in order to produce a vaccine that is
clinically acceptable, appropriate for product
development, and suitable for wide-scale appli
cation in family planning programmes.
Antiferiiliiy studies will be carried out in
194
The Task Force is planning to convene a meet
ing on vaccine safety in order to develop guide
lines for the preclinical and clinical"safety evalu
ations of vaccines in general and for antifertility
vaccines in particular. It is envisaged that this
meeting will be organized in conjunction with
other vaccine development programmes within
WHO and with other agencies interested in the
development of antiferiiliiy vaccines. Basic and
clinical scientists, representatives of national
drug regulatory authorities, the pharmaceutical
industry and consumer groups will be invited to
participate in this meeting.
The Task Force will continue with its coordina
tion activities in the field of fertility regulating
vaccines. As in the past, this coordination will
include participation in Task Force Steering
Committee meetings by representatives of
CONRAD, the Population Council, the Indian
National Institute of Immunology and the US
National Institute of Child Health and Human
Development; the convening of inter-agency
consultations; organization of symposia; and the
joint funding of research projects of mutual
interest
VACCINES FOR FERTILITY REGULATION
REFERENCES
(* Denotes publication resulting from studies supported by the Special Programme)
Ada, G.L., Basten, A. and Jones, W.R. (1986) Prospects for developing vaccines to control fertility. Nature,
317: 288-289
Anderson, D.J.. Johnson, P.M., Alexander, N.J., Jones, W.R. et al. (1987) Monoclonal antibodies to human
trophoblast and sperm antigens. Report of two WHO-Family Health International Workshops, 30 June 1986,
Toronto, Canada. Journal ofReproductive Immunology, 10: 231-257
Bambra, C.S. (1987) Purification and properties of baboon chorionic gonadotrophin. Journal of Reproduction
and Fertility, 79: 421-430
Bronson, R., Cooper, G., Hjort, T., Ing, R. et al. (1985) Anti-sperm antibodies, detected by agglutination, im
mobilization, microcytotox icily and immunobead-binding assays. Journal of Reproductive Immunology, 8:
279-299
Burek, C.L., Smith, J.P. and Rose, N.R. (1986a) Immunosafety studies with the WHO hCG vaccine. In:
Reproductive Immunology 1986. Elsevier Science Publishers B.V. (Biomedical Division), Amsterdam, pp.170177
Burek, C.L., Smith, J.P. and Rose, N.R. (1986b) Detection of autoantibodies in baboons following immuniza
tion with a human choriogonadotrophin (hCG) vaccine. Federation Proceedings, 45: 260
Czuppon, AJB. (1985) Detection of anti-spermatozoal antibodies by a “I-protein-A radioimmunobinding assay.
Journal of Reproductive Immunology, 8: 313-319
Griffin, P.D. (1985) A fertility regulating vaccine based on the carboxyl-terminal peptide of the beta subunit of
human chorionic gonadotrophin. In: Immunological Approaches to Contraception and Promotion of Fertility.
Plenum Press, New York and London, pp.43-60
Griffin, P.D. (1986) Development of a fertility regulating vaccine using synthetic peptide antigens. In:
Proceedings ofXXXIV Colloquium on Protides of the Biological Fluids, 1-3 May 1986, Brussels, Belgium (in
press)
Gupta. S.K., Mountain. L. and Alexander, N.J. (1988) Seminal plasma antigens detected by immunoblotting
with human sera from vasectomized males. Journal ofReproductive Immunology, 12:263-276
’ Hjort, T. and Griffin, P.D. (1985) The identification of candidate antigens for the development of birth control
vaccines. An international multi-centre study on antibodies to reproductive tract antigens, using clinically
defined sera. Journal ofReproductive Immunology, 8:271-278
• Hjort, T., Johnson, P.M. and Mori, T. (1985) An overview of the WHO international multi-centre study on
antibodies to reproductive tract antigens in clinically defined sera. Journal of Reproductive Immunology, 8:
359-362
Johnson, P.M. (1985) Antibody reactivity against trophoblast and trophoblast products. Journal of Reproduc
tive Immunology, 8: 347-352
•'Jones, W.R. (1986a) Phase I clinical trial of an anti-hCG contraceptive vaccine. In: Reproductive Immunology
1986. Elsevier Science Publishers B.V. (Biomedical Division). Amsterdam, pp.184-187
’ Jones, W.R. (1986b) HCG immunization for contraception. Healthright, 6: 17-20
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VACCINES FOR FERTILITY REGULATION
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Lehmann, D., Temmdsck. D., Da Rugna, D.. Leibundgut, B. et al. (1985) Blot-immunobinding test for the
detection of anti-sperm antibodies. Journal ofReproductive Immunology, 8: 329-336
Mahony, M.C., Alexander, N.J. and Swanson, R.J. (1988) Evaluation of semen parameters by means of auto
mated sperm motion analyzers. Fertility and Sterility (in press)
Mathur, S„ Genco, P.V., Moller, B. and Mardh, P.H. (1985) Antibodies to microbial, leukocyte and organ
antigens. Journal ofReproductive Immunology, 8. 353-358
T,. RB WmsoH, C.B.. Sunoakam. K.. PlllLLffS. D. ET AL. (1987) Long-lerm tmmumza.ion against Ihe beu*»
XJof'ovine luteinizing honnonc (oLH beta) has no adverse effeeta on pt.ut.-y funcuon m rhesus
monkeys. American Journal ofReproductive Immunology. 15:92-98
.V r„n RMY
Heleroimmunizalion against human male reproductive
antibody pauents. Aria A Oceania Journal of Olrste.rtce dr Gynae-
ano Jones, W.R. (1986)
cology, 12: 523-528
Mettler, L, Czuppon, A.B., Alexander. N.J., D
* Almeida, M. et al. (1985) Antibodies to spermatozoa and
seminal plasma antigens detected by various enzyme-linked immunosorbent (ELISA) assays. Journal of
Reproductive Immunology, 8: 301-312
Mori, T„ Kamada, M., Hasebe, H., Irahara, M. et al. (1985) Antibody reactivity with porcine zona pellucida.
Journal of Reproductive Immunology, 8: 337-345
' Rose, N.R., Burek, C.L. and Smith, J.P. (1988) Safety evaluation of hCG vaccine in primates: Autoantibody
production. In: Progress in Vaccinology, Contraception Research for Today and the Nineties. G.P. Talwar, ED.
Springer Vcrlag Publishers, New York, pp.231-239
Shaiia, C., Suri, A.K. and Talwar, G.P. (1988) Identification of a specific antigen on human sperm acrosome
with potential of regulating fertility. International Journal ofAndrology. (in press)
Shelton, J. and Goldbero, E. (1985) Serum antibodies to LDH-CV Journal of Reproductive Immunology, 8:
321-327
Stern, P.L., Beresiord, N.. Friedman, C.L, Stevens, V.C. et al. (1987) Class I-likc MHC molecules expressed
by baboon placental syncytiotrophoblast. Journal of Immunology, 138: 1088-1091
' Stevens, V.C. (1986a) Development of a vaccine against human chorionic gonadotropin using a synthetic
peptide as the immunogen. In: Reproductive Immunology 1986. Elsevier Science Publishers B.V. (Biomedical
Division), Amsterdam, pp.162-169.
Stevens, V.C. (1986b) Current status of antifertility vaccines using gonadotropin immunogens. Immunology
Today, 7: 369-374
' Stevens, V.C. (1986c) A synthetic peptide vaccine against human chorionic gonadotropin. In: Vaccines 86 New Approaches to Immunization. Cold Spring Harbor Laboratory, New York, pp.39-44
' Stevens, V.C. (1986d) The identification of peptide sequences of human chorionic gonadotropin containing a
conformational epitope. Immunology Leiters, 12: 11-18
Talwar, G.P., Singh, O., Bamezai, A.K., Gufta, S.K. et al. (1986) Potential of new technologies for develop
ment of fertility regulating vaccines. In: Reproductive Immunology 1986. Elsevier Science Publishers B.V.
(Biomedical Division), Amsterdam, pp.178-183
Talwar, G.P., Singh, O. and Singh, V. (1987) Birth control vaccines. In: Fertility Regulation Today and
Tomorrow. E. Diczfalusy, M. Bygdeman, Eds. Raven Press, New York, pp.43-54
Thau, R.B., Bond, M.G., Witkin, S.S., Sundaram, K. et al. (1985) Lack of toxicological effects following
seven years of active immunization of rhesus monkeys with the beta-subunit of ovine luteinizing hormone. In:
Immunological Approaches to Contraception and Promotion of Fertility. Plenum Press, New York and
London.pp. 25-33
196
197
Govemment policy and planning
Biotechnology in India
85) was the first policy document to cover biotechnology
development in the country. In the sphere of Science and
Technology (S & T) sector, the Plan had indicated that 'the
effort would be to strengthen and develop capabilities in
new areas such as immunology, genetics including molecu
lar biology and genetic engineering for control of intracta
ble communicable diseases viz. Malaria, leprosy, filarisis
and kalaazar.' Furthermore in respect of the Council of Sci-
and make them self-sufficient in their energy needs.
Biotechnological breeding techniques such as embryo
transfer can help in achieving fast growth of dairying and
pmiltry farming. The milk production can also be boosted
with the help of growth hormones produced through
biotechnology In the sphere of health, bio-diagnostic kits
The potential
Indians advantages in biotechnology
Among the developing countries India is perhaps one of
the inost_uniquglyj>laced to tap.the.poienligi of biotechno
in biotechnology, funding of R & D projects and program-
The Seventh Plan in the area of biotechnology gives em
phasis on programmes connected with manpower develop
ment; initiation of new projects and programmes involving
together with necessary linkages with industry, involving
techno-eonomic feasibility studies; providing seed and risk
project!sat ion and making an impact through close coordiand infrastructure
*
in major areas including biotechnol
ogy. Programmes in the area of biotechnologies included:
tissue culture application for medicinal and economic
plants; fermentation technology and enzyme engineering
house wastes utilisation, emerging areas like genetic en
gineering and molecular biology.6 Though the existing na
tional laboratories under the S & T agencies such as Indian
Council of Medical Research (ICMR) and CSIR had in
itiated research programmes to fulfill the above Plan objec-
manufacture (and associated R & D) of products based on
moderm biotechnology. The necessary infrastructure like
genn plasma banks, pilot plant and other bio-engineenng
scale-up-facilities, network of biotechnology information
systems, animal house facilities etc. would also be set up. In
panded Programmes of Immunisation would be produced
indigenously on a large-scale, using modem techniques.’
Besides the CSIR proposed to complete the establishment
• of the Institute of Microbial Technology, Chandigarh;
Board (NBTB) was set up in I9$Z_1Q spearhead develop
ment ol biotechnology, fhe NBTB was chaired by Member
(Science) of the Indian Planning Commission and had rep
viz. Department of Science and Technology, CSIR, Indian
Council of Agricultural Research (IC££), ICMR, Depart
ment of Atomic Energy (DAE) andthe University Grants
Commision (UGC). NBTB was formed with the specific pur-
Table 1 - Priorities for Blotcchnolonr In India
a long term plan for the country in biotechnology as well as
to initiate and promote such activities as conducive for
further development of various areas in biotechnology. The
one ot the tropical countries. India is endowed with rich
oped and diversified industrial base including a
industry in India has, in recent years, shown a growing in
clination towards scientific entrepreneurship, as reflected
ely IpiMcc than in Western countries. For instance, work
the country allows it to undertake ambitious research prog
rammes on viable basis. Besides, biotechnologies by nature
for biotechnology in India in view of the national objectives
such as self sufficiency in food, clothing, and housing,
adequate health and hygiene, provision of adequate energy
and transportation, protection of environment, gainful
employment, industrial growth and balance in interna
tional trade. These priorities in seven broad areas viz.
health, industry, agriculture, energy, environment, com
munication and informatics, and education and training
jects to fulfil the priorities with time horizons ranging from
3 to 10 years (Table II). The emphasis In the area of health
is on production of vaccines, hormones and antibodies for a
variety of tropical diseases and population control. In ag
riculture, it is biological nitrogen fixation and biofertilisers, biological control of insects, development of disease re
sistant and stress tolerant varieties of crops using tissue
culture, somatic hybridisation and selection technology.
propagation of high yielding vegetables and frails.7.
Besides formulating the long term plan, the NBTB
technologies such as microelectronics.
Devetopmont: Seeds ol Change 1987-
Industry
bSJh'C Ac,dS)
Food and Feed
Metallurgy and Mining
Soil Fertiility
Quick Propogation through
’"SealthandProductivity
Afforestation
through somatic embryogenesis in vitro. Currently work on
perfecting in vitro technology is being implemented at the
Central Plantation Crops Research Institute, Kasaragod;
National Chemical Laboratory (NCL), Pune; and Jawahar|3| Nehru University. New Delhi A major S & T project on
cattle herd improvement for improved productivity
through Embryo Transfer Technology (ETT) has been taken
up for implementation by DBT involving several institu
tions such as National Dairy Development Board, National
Institute of Immunology. National Dairy Research Insti
tute. Indian Veterinary Research Institute, and Indian Ag
ricultural Research Institute In addition, a project on De
velopment and Production of Immunodiagnostic kits and
another for development of contraceptive vaccines using
iinmunulogical approaches have been taken up at the Na
tional Institute of Immunology.19
Besides the above programmes initiated under the
framework of DBT, ICAR is setting up three biotechnology
centres to work on the livestock and crop improvement in
the country at National Dairy Research Institute. Kamal;
Indian Veterinary Research Institute, Izatnagar. and In
dian Agricultural Research Institute.70
The industrial policy of the Government has also
responded to the emerging developments in biotechnology.
The production of hybrid and high yielding varieties based
on high and sophisticated technology have been included in
the appendix 1 of the Industrial Licensing Policy 1973 with
effect from May I986?1 This means that MNCs and local
monopoly houses cap operate in ibis.area
International cooperation
India hosts one of the two chapters of the UNIDO's Inter
national Centre for Genetic Engineering and Biotechnology
(ICGEB) for which interim facilities are being arranged by
the DBT al one of the national institutes.77 ICGEB (New
Delhi chapter) is to be involved in basic research in health
and agriculture relevant for developing countries and train
ing of S & T manpower from developing countries in
biotechnology.
India also hosts a CG1AR institute viz. International Crop
Research Institute for the Semi-Arid Tropics (ICRISAT) at
Hyderabad. ICRISAT at the moment is in the process of deVrtOJSmga biotechnology facility. ICRISAT is already using
molecular techniques to identify virus pathogens in crops,
and aflatoxins on groundnuts, and on gene transfer across
sterility barriers in sorghum and groundnut.
The Research and Information System (RIS) for the NonAligned and Other Developing Countries based in New
Delhi has undertaken a project on Biotechnology Revolu
tion and the Third World. This project intends to examine
the issues posed by the advances in biotechnology for de
veloping countries and identifying the suitable package of
strategies to meet these emerging challenges. A number of
noted experts in the field are contributing to the project.
Besides, India would be hosting an Intergover nmental Cpnsu 11ive Conference of Experts on New and High '
Tethnologies of Developing Countries during ^iaV W88. »
Biotechnology will be"oneofthe new and high technologies
to be discussed at the Conference.
At the bilateral level. India has concluded R & D collaboration agreements tn the area of biotechnology with a
number of countries viz. USA. USSR, UK. FRG. France,
Switzerland, Sweden, Japan, Vietnam and Mexico.
Biotechnology industry
Industry in India is gradually becoming aware of the po
tential of biotechnology for their business and are gearing
themselves to enter into the field. Hindustan Lever Ltd tf
(HLL), an Indian subsidiary of multinational Unilever has II
perhaps the most intensive interest in bidlecfinology ||
among the businesses in India. HLL has a strong in house R
& D base active in application of new technology to agri-
tent skilled S & T personnel in India a few MNCs like^Ajira,
AB.. Sweden are setting up biotechnology R & D centres in
India.”
scientists working in the United States and other Western
ogy. The Indian government should devise ways and means
to attract them back. In biotechnology die distinction bet
ween basic and applied research is almost non^existent.
Hence, setting up of Biotechnology Entrepreneurship Parks
have reportedly achieved considerable success in the use of
chemicajs and explored producing edible quality oil and ’
glycerine 1
for industrial use by using genetically modified
bacteria. Through protoplast fusion of two edible varieties
• of yeast they have been able to produce a hybrid cell capable of producing and accumulating high amounts of fats
and of utilising sugar at high rates. The newly engineered
species of yeast has been successfully grown in pilot fer
menters and used for extracting edible fat from biomass.
They were working on tissue culture for coconuts and
palms and on biological nitrogen fixation. They have disco
vered organic compounds which greatly increase photosyn
thesis in plant and have succeeded in synthesizing certain
pheromones (bio-insecticides).23 HLL has commercially
launched a plant growth nutrient Paras2* and has got per- 1
mission to produce 20,000 tonnes of hybrid and high yield- 1
ing variety seeds using high technology per annum.25
*+•
Hoechst India Ltd, the Indian subsidiary of another mul- 9)
tinational was test ing a drug for the treatment of glaucoma - .
Ranbaxy, an Indian drug company is ready to go in for the
production of an intermediate used in the manufacture of
semi-synthetic penicillin.26 Some other Indian companies
are entering the field on the basis of technology borrowed
from Western sources e.g. Orkay is teaming up with Cetus,
USA. for production of biotechnology based anti/cancer
drugs,27 United Brewaries is entering the field of diagnos
tics. hormones and other chemicals.28 Southern Petrochem
icals Industries Corporation (SPIC) was setting up an R & D
centre to develop the process know-how for drugs of known
structure and was collaborating with Cytozyme, USA, for
marketing of a plant growth stimulant.29 Some companies
involved in breweries were introdocing energy saving
methods of alcohol fermentation and distillation using new
yeast strains e.g. DCM in collaboration with a Japanese
firm.30 A joint venture between Beardsell of Madras and
Satec Ltd. UK is to introduce new biotechnology In indust
rial waste treatment in India particularly aerobic fermen
tation of strong wastes to produce single, cell prjtfgins.31
Tatas have set up a joint venture PlJmtecITmrSingapore
with Native Plants International, US, to develop new
strains of plantation crops such as tea and oil palm through
tissue culture.32 TOMCO (Tata Oil) is producing fats from
molasses 33 Tata Energy Research Institute has set up a
biotechnology laboratory.34 Hindustan Insecticides Ltd, a
public sector firm, was involved in development of micro
bial insecticides in cooperation with DBT.35 five multina
tionals viz Seed tec International. Cargil Inc., QsbJgjgn
Inc., Northrup King and Sandoz (through their local sub- \
sidiary) have been shortlisted by the Indian government for
production of hybrid
in colleborauon-vith Indian
companies * T«> tap the availability of cheap and compe- <
Development: Seeds of Change >987: 4 55
India ought to be different than in the West. Like in the
Western countries, the Indian biotechnology programmes ;
appear to be dominated by health an medicinal related re- j
search. But it is in agriculture where most of the potential
being outside the Ministry of Science and Technology
where DBT is located may perhaps be responsible for rela
tively low priority given to biotechnology in agricultural
research. There is, therefore, need for galvanising ICAR into
biotechnology research and its greater coordination with
DBT.
Programmes and implementation
NtfTBT The DBT would be responsible lor evolving integin biotechnology, identifying
nitteejSAC) consisting of
The DBT has initiated various schemes under integrated
Development: Seeds of Change 1907:
54 Development: Seeds of Change 1907: 4
6
5
:h hormones
NEW CONTRACEPTIVE TECHNOLOGIES: LONG-ACTING AND PROVIDER DEPENDENT
'b\ Anita Harden
WEMOS/HAI Komen and Pharmaceuticals Group
Contraceptive researchers have over the past decade been developing
meet the criteria of
a number ot new contraceptive technology
long-acting and supposedly easy to administer. Examples of these
technologies are hormone releasing IUD’s, implants and more recently
contraceptive vaccines. These technologies are meant to increase the
family planning programmes: because they are longacting and easy to administer less user and provider failure is
expected to occur. In this article I will view these methods from a
women's perspective and raise some questions on the approprlateness of
the developments. I will discuss in some detail the latest development
ion. A number of
:ilit» m june 19P9 one
mg on time bomb., there
las a different inode of
1 however onlv one is
anti-HCG
HCG, a hormone (human chorionic gonadotropin)
jrtilization of the female ovum. The vaccine t,
of pregnancy, and
these methods will have a numbei
requirements (diagnosi
>roper use. With respect to safety it is important (
:his vaccine antibodies against a 'natural hormone’ c
induced,
* of this serious immunological disorders can
.----------------- . -------ir (this will be explained in more detail below). In
order to provoce an immune reaction against a 'self hormone’ a part c
vaccines)
'provider dependent' . Women depend on providers to have them
administered and in the case of implants and IUD's also to have
taken out. They can be abused in situations in which providers do not
give women free choice out of the available contraceptive methods (in
anning programmes, and in psychiatric institutions
for example), and for this reason many women and health groups have
opposed the introduction ano marketing of the methods. Some safety
issues of these drugs, for example the effect on the unborn child (if a
woman accidently does become pregnant) and the long term effects remain
unresolved. Women are very aware of the common side effects of hormonal
methods, such as headache, menstrual disorders and weight changes.
These side effects are however not taken serious in clinical research
:he safety and efficacy of these methods.
method. Long-acting hormonal implants such
known to cause menstrual disorders because
disrupted. This can lead to amenorrhoea (lack of menstruation),
spotting and excessive bleeding. Studies show that 60% of the Norplant
users suffer from such disorders. The long term effects of this
disruption of the menstrual cycle are not known, nor are immediate
effects on libido and general wellbeing of women studied
systematically.
Women need to know about what is not known about the contraceptives
that they are taking. Contraceptive researchers tend to be complacent,
arguing that if it’s risks have not been proven, then the drug is
probably safe. The risk of breast cancer due to the use of hormonal
contraceptives has for example only recently become a concern. Before
researchers affirmed that the issue was unresolved and that the pill in
fact was shown to have a ’protective effect’ against breast cancer. The
use of the term protective effects by contraceptive researchers
reflects the complacency of researchers. The term suggests that
contraceptives can be used to protect a woman against certain
disorders. This is not appropriate, as the drugs simultaneously
increase the risk of other disorders. They should be used for
contraceptive purposes not as a preventive measure against all kinds of
reproductive and other disorders.
Recently researchers are promoting contraceptive vaccines as a safer
alternative to hormonal contraceptives. During a WHO Symposium on the
:he drug cannot be ’switched off'
woman becomes pregnant or
the effect of HCG). If
does no
i is pregnan
the cnild.
important
responde
against HCG) are probably needed to define when
longer effective. The vaccines that are being developed at presen
a so called ’lag period' before the^ are effective. This means that in
the non-effective period women still need to use another method.
Although the contraceptive researchers promote the vaccines as easy to
case. Vaccine use will need to be accompanied by the use of other
methods and diagnostic tests.
The researchers justify the development of these (temporarily)
the ease of administration of vaccines and the continuing population
growth, especially in Third World countries.
In India the government’s five year development plan already
mentions the future introduction of vaccines into the family planning
programmem and the Indian Council for Medical Resarch has give top
were started fifteen years ago when an Indian researcher (Dr. Talwar)
eager to test the principle of antibody reaction against HCG in human
beings vaccinated six unsterilized women. Two became pregnant. The
vaccine developed by the Indian Council for Medical research provoces C
an antibody response to one of the two chains (the so called B-subunit)G
of the HCG hormone. The problem is that some of the chemical components~f
on this subunit also occur in other natural occurring hormones, such as"LH (luteinizing hormone). HCG is only present during early pregnancy,
but LH is one of the hormones that controls the menstrual cycle.
Serious immunological and hormonal disorders could occurr if the
7
8
consultat ion kith women and health groups tvim Thailand, India,
Bangladesh, Brazil and Indonesia. WEMoS also ini end:. !.»,» stimulate
discussion and research on the t^pes of Contraceptives that women do
-desire (tor example a method lo measure o\ulaiioh, t»i a male
contraceptive), as a guidance for contraceptive researchers. With
respect to this last point it is interesting that the above mentioned
vaccine researchers are looking into the possibility of developing an
anti-sperm vaccine. However according to them it is safest if this
dangerous as it produces antibodies against a natural body tissue
(sperm). In women the sperm is only present ’transiently
.
*
Perhaps the
researchers also worry chat there will not be enough men interested in
participating in a trial for such a vaccine, and industries may doubt
the potential market for such a drug. It seems unlikely that a male
vaccine will be developed.
( From: MEMOS, ' Bevolleingsbele id en het welbevinden van vrouwen: een
wankel evenwicht
.
*
6 Nov.1989, Amsterdam)
(Taken from Uechselwirkung, no.41, ’lay 1939, a journal froSwitzerland - the picture is a reproduction of a poster
put up on an Vest Indian island^
i sers yes io hormone-based contraceptives
- '(D
- O
W'
From^RAVl R. PRASAD _
'.
'<£?'■:;
/Continued ^rom page 1 col. 6)
minor.surgery. In case of NorDuring the trials, each of the ,
plant a small incision is made on .12 women who have opted for
ganda about.. hormone-based
the left upper arm of the women Norplant, have 'to ------report- to
contraceptives.- A. total of 186
and’the six capsules are inserted 'hospital one" week after the
chose Copper'-T, 96 decided in
through the incision. The con insertion is done and then after a '•
favour of. tubectomy. and 42
traceptive is . effective, . for .a month. Then, she has to come to
wanted oral pills,.according to
period of.. five years. -These hospital every three months for
DrKodkany.. .iu... , . . .,
capsules are removed after this one year and, later, twice a year
-..Refuting the argument of wo
period and if the woman wants for a thorough. Check-up. "This
men health advocates that it, . fresh capsules can , be gives us an opportunity to test
hormone-based contraceptives
implanted,” Dr Kodkany said.
the woman for other problems
like Depo provera, Net En- and
Dr Kodkany said the HRRC also, besides looking for the side
" -Norplant-1 should not be used had not come across any serious effects of Norplant," Dr Geetha
• because these need immediate
problem among the women who Pangi, a research officer at the
medical help in case of comp had chosen Norplant-2, the first HRRC, said.
.
lications, Dr Kodkany said none
version of. this contraceptive,
Interestingly, while women's
■ of ~ these contraceptives ■ cause
when it was tried out in 1986. organizations have been raising
any major problem. “Oral pills
One of those women, Mrs Jahi- a hue and cry against Norplant
are • also; hormonal contracep rabi, has volunteered to become and other hormone-based con
tives, complications caused by a,part,,of this experiment She traceptives all over the country
these are the same as those of the-------had disappeared after 1986 and and at New Delhi, their counter
te back
last month when »uo
she parts in Belgaum have been clo
new ones. :Like a women dis- .came
—
continues'.? pills if ' she has
came to know about Norplant-1. sely working with the HRRC
problems,.Norplant can also be ,'.The
ru* ‘
-»»•
—i__. - here. So far no protest has been
two capsules of
Noiplant-2
removed," he said.
which.werq. inserted in her left held against the,,trials and the
"As far as the need of a doctor arm 'eight years back were re office bearers of these organiza
in concerned even insertion and moved early this month and she tions have been given a detailed
removal of Copper-T requires had no complaints.
explanation
...
urn
' BELGAUM (Karnataka). May
tors hope that these will also be / removed as the women gained • lent:
lent:'’• She opted for Norplant-1 - successfully without
without . any negani
fers
—
!J-,~------■--■ *
-by
-- ---------17. — Inspite of misgivings over
widely
accepted
women de-- three kg of weight in three because she had’ developed' a tove results, Prof B.S; Kodkany,
hormone-based contraceptives
spite ,the; doubts and furore
---------months.
...
.-. ----complication
r-------------------------while using
„a.con-- head of the department,
r_
, Gynaecreated
by;
voluntary
organ!
Of
the
12
women
who
have
■
ventipnal
contraceptive.
.
“
Cct
'cology,
JLN
medical
College
and
Ind protestsby women’s.organinot. a” pper.jT
me--------------------------------------• trouble and " Chief Investigator
zations.
:
. . opted
—-j for: Norplant-1,
. -—
—-n gave
1--------------------of
* the
<■
’- HRRC,
zations against the introduction
"of these new birth -control
Contrary to” the' claims of single one-complained of any., when I consulted the doctors' said.''
serious side-effects. Rather, they' /they told me about Norplant. So
. “We are not pushing Norplant:
measures, the.Indian Council of several women health advocates
Medical Research (ICMR) is con "and social workers — who are' claim to be satisfied with the -1. decided to. become a part of. There is no fixed target. Women
tinuing Ivith Phase-III.’trials of; opposed to the introduction of contraceptive and were willing this experiment," she told The are advised. about the various
to
continue
as'
a
part
of
the,
Statesman.
'
birth-controlmethods'when
Norplant-1 at 10 centres frrthe , hormone-based contraceptives
ICMR’s experiment despite proMrs Shakira switched, over ' they come to the hospital.'They
country and heading towards a
in the country — women who
tests made by women's organ!-' from oral pills to Norplant as she, are offered a complete range of
have v
been
using
Norplant-1 -as
success.'
-, .
-------'
The Human Reproduction Re
zations at'New Delhi a few days' ‘ had pr'dblems with the tablets. “I contraceptives' like'.lubectomy,
serted that they neither had any
back.
:'
... .
was told1 about the complied- -IUD, Oral Pills, etc. and they
search'Centre here,(.one of the .^problemynor had they suffered
“We have been told'about the
tiohs that'can be 'caused by have to choose. AU those who
10, has been very successful in
from any complications after the
side effects and also the aim of.?' Norplant 'before kbpted for- it..popularizing this new birth con contraceptive was implanted in
-.
the
experiment
being
conducted
Now I sometimes fee] dizzy and ■ 'Informed consent-1 form' after
trol measure and women: using
their arm.
_1.—l_g the contraceptive,
my hair has started falling:- choosing
the contraceptive say they: are
The ICMR • itself has listed a ■ by ■ the • doctors. We have not
whether !:
it is Norplant or pills," .
Doctors.had told me that this v.L.'J...
satisfied with it. /
•
number’ of . side effects in the been kept in the dark-and made
for the
could happen and will be there ' he said. •
circular issued to the HRRCs . guinea pigs lur
me trials,
dials, ” says
L.-A significant .number of wo
Out of 3'
515 women who were
for aLyear so" I" am'not much.' , G-',
about the phase’ ’ III trials of Mrs SandhyaJ ""
Vijay Tamiiche,
men have opted for Norplant-1,
about the
worried about-it,?. she said.-.- :advised by
uj the
u.c HRRC ----—
Norplant-1 and instructed that, who chose, to .use Norplant-1:Norplant-1
which is effective for five years,
the contraceptive , should be ’ after trOT
'r' officials briefed her
cis' .- Phase-Ill trials of Norplant-1^ .contraceptives,.only 13 ..opted
HRRC
instead of conventional methods
. will last for seven years and any • -for Norplant, a major success
being offered to them at the civil
removedfrom the woman’s about the new contraceptive.
hospital. The uijectible' con body in case' of any compli /■*■■ Mrs Tamuche said the doctors -‘ decision regarding the adoption ■; considering its recent introductraceptives, Depo Provera and
cation. But sd fair the HRRC here had told, her about'the'side-'’ of' this contraceptive, in the,, tion and the. negative' propo- .
but so far she had-noP: family-welfare policy will-be .
Net En, are likely . to -be in- has not come across any serious effects,
-------- -----------------------------------'
J any seripu?'pfo6■ ■ v.
-taken?only if the trial conclude^1- ^(Continued on page 9 col-13)
side effect; In one case it was experienced,
i traduced here shortly and doc-
users? yes to Hormone-based contraceptives '
..
. FromRAVI R. PRASAD
'
■ ®
U'
BELGAUM (Karnataka)^ May
□ved as tl
tors hope that these will also be : removed
the women gained- ■ lemr- She opted for Norplant-1- successfully without any negawidely accepted by women de-- three- kg of weight in three because she had'developed a' tove results, Prof B.S. Kodkany,
17. — Inspite of misgivings over
spite the
the-doubts
; doubts and furore
months. . y
.4 complication while using a.con-<• -head of the department, Gynaehormone-based - contraceptives
created by. voluntary organi-,, . Of the 12 women who have ■ ventipnal contraceptive. . “Co? cology, JLN medical College and
arid protests by women’s .organi
opted
me•■--Al-r■ trouble—and
*-.-r
zations.
“"'“C1
—*‘J rfor:
--‘ Norplant-1, not a ' 'pper.jT
------ ■— gave
-- ----------- of
.<■-v.
zations against the introduction
Chief --------Investigator
the rm™'.
HRRC,
when I consulted the doctors ' said."
"of ■ these new birth --control
Contrary to? the claims of single one- complained of any
serious side-effects. Rather, they- Tthey told me about Norplant,-So
“We are not pushing Norplant
measures, the Indian Council of several women health advocates
claim to be satisfied with the -I. decided to.become a part of. there is no fixed target'Women
Medical Research (ICMR) is con "and social workers — who are
ILL experiment," she told The' are advised. about the various
this
tinuing with Phase-Iir trials ’ of opposed to the introduction of;: contraceptive and were willing
Norplant-1 at 10 centres'in: the . hormone-based contraceptives
|
birth • control- methods • when
to continue as' a part of the, Statesman.
’
ICMR's experiment despite proMrs Shakira switched; over ' they come to the hospital/They
country and heading towards a
in, the country — women who
tests
made
by
women
’
s
organi-'
from
oral pills to Norplant as she.- are offered a complete range of
'*-■■■'
----- '
'
'
have been using Norplant-1 as
success..'
zations at'New Delhi a few'days; ' ha'd problems
with
the tablets. “I contraceptives'likel tubectomy,
v-----The Human Reproduction Re
serted that they neither had any
back.
.
was told'about
told- about the complica- IUD, Oral Pills, etc. and .they
search' Centre here,_one of the ... problems nor had they suffered
“We have been told about the ; tion's that 'can be'''caused by have to choose. All-those who
10, has been very successful in
from any complications after the
side effects and also the aim of.?? Norplant I before kbpted for- it.- -come
■come to the HRRC'have to sign a
.popularizing this new birth con contraceptive was implanted in
trol measure and women: using
their arm.
“■
-■-• . the experiment being conducted ■ Now
......I sometimes feel dizzy and . .'Informed consent-- form’ after
----The. ICMR itself has listed a ■■ by ■ the ■ doctors. We have not -my hair’ has started falling:- choosing the contraceptive,
the contraceptive say they are
—
—
-<r
—
<_
.v_
k
—
-I
—
-.':.1
—
i
—
i.
„
j
—
i—
i
—
j
.-ij
—
.k_.
.k:„
it is Norplant or pills," ;
number‘of: side effects in the been kept in the dark and made
Doctors.had told me that this whether
v
satisfied with it. ?
;
l_
J
•
I
circular issued to the HRRCs guinea pigs for the trials,",
trials," says
could happen and will be there" he said. ■
--A significant .number of wo
Out‘ of
about the phase'III trials of Mrs Sandhyai Vijay .Tamuche,
for a?year so'F'am'not much’ ; ”
-r 515 women who were
men have opted for Norplant-1,
about-it,?, sue
she scuu.r
said.-.- :;::wumeu uuwui-iivj
advised by the HRRC about the
which is effective for five years, Norplant-1 • and instructed that, who chose, to .use Norplant-1- worried
_ briefed her'
Phase-Ill trials of
the contraceptive .should be after HRRC officials
-r Norplant-1^
*■ ’—>---- ..contraceptives, .only 13 ..opted ?
instead of conventional methods
about
the
new contraceptive. .
will last for seven years and any - ?fbr Norplant' a major success
removed-from the woman’s j]
—
------------being offered to them at the civil
Mrs Tamuche said the doctors ■ decision regarding the adoption • considering its recent introduchospital. The injectible' con body in case ; of any compli
traceptives, Depo Provera and
cation. But so far the HRRC here had told, her about4 the ’side?’' of' this contraceptive in the^ tiori and the. negative propo- .
...•
Net En, are likely to .be in- has not come-across, any serious effects.but so far she had'noPr family-welfare policy will-be
*
^(Continued on page9 colt 3)
| troduced here shortly and doc- side effect In one case it was experienced, any serious''prob,-xf taken? only if the trial concludes
(Cqntinued ^rvin page 1 col. 6)
minor; surgery. In case of Nor
During the trials, each of the ,
plant a small incision is made on .12 women who have opted for
ganda about hormone-based
the left upper arm of the women Norplant, have to report to
contraceptives. A-total of 186 .ahcTthe six capsules are inserted ' hospital one' week after the
chose Copper-T, 96 decided in
through the incision. The con insertion is done and then after a '
favour of-ptubectomy. -and 42
traceptive is , effective, .for .a month. Then, she has to come to
wanted oral pills,,according to
period of., five ' years?: These hospital every three months for
DrKodkany. .,,,,.
capsules are removed after this one year and, later, twice a year
...Refuting the. argument of wo .'period and if the woman wants for a thorough. Check-up. "This
men health advocates that • it,.. fresh capsules can ., be gives us an opportunity to test
implanted,
"—
Dr. kodkany
hormone-based contraceptives —
,
} said.
the woman for other problems
• like Depo provera, Net En- and ,. Dr Kodkany said the HRRC also, besides looking for the side
' -Norplant-1 should not be used
•had■ not• come across any serious effects of Norplant," Dr Geetha
■ because these need immediate
problem among the women who Pangi, a research officer at the
medical help in case of comp had chosen Norplant-2, the first HRRC, said.
lications, Dr Kodkany said none
version of. this contraceptive,
. Interestingly, while women’s
■' of '■ these contraceptives • cause
when it was tried out in 1986. organizations have been raising
any major problem. “Oral pills
One of those women, Mrs Jahi- a hue and cry against Norplant
are - also; hormonal contracep rabi, has volunteered to become and other hormone-based con
tives, complications caused by a.part,,of this experiment She traceptives all over the country
these are the same as those of thehad disappeared after 1986 and and at New Delhi, their counter
new ones.;Like a women dis- .cameback last month when she parts in Belgaum have been clo
continues .'.' pills ' if " she has ■ came to know about Norplant-1. sely'working with the HRRC
. problems,. Norplant can also be .The two capsules of Norplant-2 here. So far no protest has been
removed," he said.
'.
'
which ,werq. inserted in her left held against the,,trials and the '
‘As far as the need of a doctor arm 'eight years back were re office bearers of these organiza
in concerned even insertion and
moved early this month and she tions have been given a detailed
removal of Copper-T requires had no complaints.
explanation
_ ----------- ~
. •
_____
_, a-
IP
<-O VA O' 18
_____ Vr
Reversible vaccine for
plan birth control soon
ice
Om Praa
secretary
Monday
sial Disned in
>uld promployed
irate re-
•neyland
.■sh Pilot
Delhi on
laid the
ainchild
ment in
Bhajan
inly de: JD (S)
mment
hrough
ensure
/as acimuseultural
tdequven to
d.
nment
roject
it.it is
rbjecm the
d will
:ment
Express News Service
New Delhi, Dec. 4: A safe and
reversible vaccine for birth control
among human beings could soon
be a reality, if the crucial clinical
trials now under way in the country
prove successful.
The vaccine, heterospecies dim
er (HSD). for women, developed
by scientists at the National Insti
tute for Immunology (Nil), here.
has already passed the first stage of
the trials, both in India and
abroad. Tentative results from the
second stage of trials, in which 180
fertile women are involved, are ex
pected to be out by next March.
The studies are being under
taken at the Post-graduate Insti
tute ol Medical Education and Re
search, Chandigarh. AH-India In
stitute of Medical Sciences and the
Safdarjung Hospital. New Delhi.
In the trials which began in Au
gust. 51 women with proven fertil
ity and having at least two chil
dren. have been enrolled, and 130
more are to be added in due
course.
NO SIDE-EFFECTS.
During the first stage of the
trials, conducted on 140 sterile
women in India. Sweden, Finland
and some other countries, the vac
cine has proved that it can iducc
the formation of antibodies against
the pregnancy hormone and is
completely free from side-effects.
ppa denies
Based on the results of the trials.
involving two different formula
tions. the scientists have chosen a
formulation consisting of hetcrospecies dimer, linked to either teta
nus toxoid or diphtheria.
According to Dr. G. P. Taiwan
director of Nil. who has played a
leading role in developing the vac
cine. the effect of the vaccine has
already been established among
monkeys and baboons. The phase
1 trials (on human beings) have
cleared (he safety of the vaccine
and its reversibility. I be phase II
trials will determine if immunisa
tion can indeed prevent pregnancy
and provide information on the
threshold level of antibodies- re
quired to do so.
I'he injection, as a method, of
family planning, has several attrac-.
tive propositions in that it will re
quire only a periodic intake, with
the effect lasting one or two years,
and it will be free from “user fai
lure" risk.
Another vaccine designed at the
institute
induces
antibodies
against LHRH, a key hormone
made m an area of the brain, which
regulates the production of ga
metes ana sex steroids m both, the
male and female. The vaccine is
therefore usable by both sexes.
The vaccine is intended to be used
for therapeutic and preventive
purposes, akin to “immunological
surgery".*
Call for ban on
H 2,-^
Pros and Cons of
Contraceptives Available in India
^MUNITy H£a
V Main, I S(ock
A range of contraceptives are now available in India,
8®n9«,or9-560034
particularly for women. Some of these methods are being
actively propagated by the Family Planning Programme in
India. Many of them are at the centre of raging controversy and
debate, especially as they are being questioned by health
activists and women's groups across the country.
CONTRACEPTIVES FOR WOMEN
Disadvantages
Advantages
Methods
REVERSIBLE
Temporary and reversible, useful in
spacing children
•
It is provider-controlled, as it needs to
be inserted and removed by trained
medical professionals
•
Does not interfere with the sexual act
•
•
High success rate, if positioned
properly in the uterus
It can get dislodged from its correct
position, thus causing unwanted
pregnancies, haemorrhage, etc.
®
It
leads
to
heavy/extended
menstrual periods, something which
adversely effects already anaemic
women
®
Often there are complaints of chronic
back pain
O
It is likely to lead to pelvic infections,
or
intensify
already
existing
infections
(this
is
especially
significant as almost 50 per cent of
Indian women have been found to
suffer
from
some
form of
reproductive tract infection).
1.
Intrauterine devices (IUDs)
•
a.
The Copper-T is so-called because it
resembles the English alphabet T. It
is made up of a 200 mm copper wire
shaped spirally, with a T-shape on
top.
b.
The Loop is an S-shaped copper wire
and its functions are much the same
as copper-T.
IUDs are positioned in the uterus. The
copper content in them destroy the
sperms and thus prevent conception.
2
2.
Hormonal contraceptives
•
No interference during coitus
a.
The oral pill acts to introduce the
hormone estrogen into the woman's
body. This prevents the ova from
maturing
and
thus
prevents
conception. The pill is available in
various forms. Some contain both
estrogen and progestin, some have
only progestin and some come in the
form of separate estrogen and
progestin pills, administered in
sequence during each menstrual
cycle.
O
Reversible
Its adverse effects may be overt or
less obvious, and include
®
Disturbances in the menstrual cycle,
usually heavy bleeding/irregular
periods
O
Mental depression
•
Migraine headaches, associated with
heavy blood loss
•
Vagfinal and urinary tract infections 4
•
Blood pressure
•
Weakening of the immune system,
exposing women to various common
infections
• •
Sterility
•
Ovarian cysts
•
Skin allergies
•
Malfunctioning of the liver, jaundice
•
Pregnancy may occur if even one
dose is missed
•
May be difficult for illiterate women
to keep track of menstrual cycle.
________ Methods
b.
Injectables
The hormone progestin is injected in
doses of 200 mg. and is effective for
three to six months. The two
currently
available
injectable
contraceptives come under the brand
names Depo Provera and Norigest
(Net-En).
Advantages
•
Long acting
•
High success rate
Disadvantages
•
•
•
•
•
O
C.
.
Implants
Six capsules or rods, containing the
hormone
levenogestral,
are
implanted under the skin of the
woman's forearm. The drug is
released slowly over a period of five
years. The capsules need to be
removed after this.
®
Long acting
®
High success rate
•
©
O
•
•
•
•
Advantages
Methods
TERMINAL
1
3a.
Sterilisation (tubectomy) involves
one of two surgical procedures.
*
Laparotomy, the older method, is
done under general anaethesia,
wherein the fallopian tubes are cut
and the free ends sutured or
cauterized. This prevents the union
of ova and sperm, thus avoiding
conception.
»
Laparoscopy involves the use of a
laparoscope (a tube-shaped optical
instrument
which
permits
examination of the internal organs
from outside) by which the fallopian
tubes are drawn up and bound by a
plastic ring, which has the same
effect as laparotomy.
•
A permanent and effective method
for couples who havehad the desired
number of children
Creates hormonal imbalances
Causes menstrual irregularities,
induding amenorrhoea, excessive
bleeding and spotting
Chances of breast-fed infants
receiving a small percentage of the
maternal dose
Not reversible until the period of
efficacy is complete
Full-fledged studies on all possible
side-effects have not been carried out
Provider-controlled
method
(administration and follow-up has to
be done by medical professionals)
Requires a medical professional for
insertion and removal. This takes
away a woman's right over her body
and reproductive functions
The poor health facilities in our
country are unlikely to provide
proper m’edical care before and after
insertion
Problems in removal occur when the
rods have not been inserted properly
The device should be removed
before the expiry period (as it could
otherwise cause ectopic pregnancy,
which is life- threatening)
Studies on side-effects not completed
No research to establish that fertility
will return after removal
Interferes with normal body
functions, including the menstrual
cycle
Disadvantages
1
•
•
•
Sterile operating facilities are
pre-requisites not readily available
in our health system
Since the tubes are deep-seated,
bringing them to the surface during
the surgery may injure other organs.
Two incisions are made during
surgery; improper care may lead to
infection
Improper placement of the ring may
result in ectopic pregnancy
Being an irreversible method, opting
for sterilisation assumes:
* joint responsibility on the part
of the couple
* accepting it out of one's free will
and not because of any pressures
or compulsions
* willingness to take necessary
precautions/care
following
surgery, such as rest, medication,
preventing infection, etc.
3
Methods
b.
C.
Abortion (Medical Termination of
Pregnancy, MTP)
The various methods for indue- ing
abortion are:
* Suction
* Dilatation and curettage (D&C)
* Combination of the above
* Induced abortion (injection and
abortifacients)
* Surgical removal
The method used depends on the
stage of pregnancy. Suction or D&C
are preferred in the initial (upto 16)
weeks; methods 4 and 5 are used
between 16 to 24 weeks.
The abortion pill
Mifepristone, commonly known as
the French Abortion Pill, consists of
the chemical compound, RU 486. It
needs to be administered along with
a small dose of prostaglandin. This
increases the frequency and strength
of the uterine contractions needed to
expel the embryo.
Disadvantages
Advantages
MTP can be used to terminate an
unwanted or unplanned pregnancy
o
O
Chances of infection in the vagina,
cervix or buttocks. If unattended, this
may result in sterility in the woman.
©
Chances of excessive blood loss,
leading to anaemia
0
Possibility of injury during the
process of D & C
O
Improper removal of the embryo
from the uterus may lead to toxicity,
often fatal to the mother
0
Due to lack of trained personnel, or
proper hospital facilities, often
dangerous and unscientific methods
are used. This should be avoided at
all costs.
®
Effective in the early weeks of
pregnancy
®
®
®
Surgical procedures are avoided
*
0
Possibility of excessive blood loss
leading to anaemia
Requires medical attention and
follow-up, which is not possible
given the poor medical infrastructure
in our country
This is still under trial, with neither
the government nor the scientific
community taking responsibility to
inform women about the method, its
proper use and impact.
Is effective only when administered
in the first 7 or 8 weeks of pregnancy.
Translated from Hindi by Nargis Sanjivini Satyapal,from the book 'Prajanan Niyantran Ki Koshishen — Sannvad Ke Prayas', written
by three women activists in Bombay — Chayanika, Swathija and Kamakshi.
'Prajanan Niyantran Ki Koshishen — Samwad Ke Prayas', a joint venture by three
women activists in Bombay — Chayanika, Swathija and Kamakshi — explains very
clearly the meaning of Prajanan (reproduction/procreation) and the efforts being
made to control it, as the title suggests. This work is an excellent effort, especially
towards portrayal of the social and political pressures under which it is mostly the
women who have to adopt some of the various birth control methods. The book deals
at length with both merits and demerits of each contraceptive method as well.
4
THE LANCET,JUNE II, 1988
emulsion acquired antibodies to hCG as assessed by a
semiquanntative radiobinding method (table II, fig I).
blastocyst, a putative contraceptive effect was obtained in all
second injection) and it persisted for almost six months. In
contraceptive threshold by the 5th week and remained above
it after six months. Longer term follow-up of two subjects in
In selected sera with relatively high peak antibody levels
hCG-P 109-145. Examples are shown in table ill.
Fig 2 shows the levels of anti-diphtheria toxoid (DT)
antibody in subjects receiving the complete vaccine. All
Amongst subjects receiving the full vaccine, twelve out of
twenty showed a significant rise in antibody and the
remaining eight showed no response. Three out of four
pronounced antibody response to DT. It is noteworthy tha
myalgia within 48 h of the injection. This was similar to,
(later replaced) who received injections in which the
emulsion was unstable. There were no immediate local
reactions to the injection. Two subjects reported pruritus
Several subjects had sporadic abnormalities in blood and
cortisol, but the only other endocrine abnormalities were
raised follicle stimulating hormone and hLH levels in
subject 28 (group 5, "placebo" injection, adjuvant and
vehicle alone) who had an early menopause during the trial
Medical disorders thought to be unrelated to the vaccine
were diagnosed in five of the total of forty-three subjects
initially entering the tnal. They were acute cholecystitis,
Wolf-Parkinson-White syndrome, iron-deficiency anaemia,
acute pyelonephritis, and colonic diverticulitis.
In twenty-five of the thirty women who composed the
definitive (rial subjects the menstrual panem was
menopause, three test subjects reported inrermcnstrual
tissues will be reported elsewhere. In summary, however,
there was no evidenfc of reactivity with follicle stimulating
hormone or hLH in any of the sera. There were minor and
transient positive reactions of some sera in a routine tissue
autoantibody screen. Some sera reacted with indeterminate
cells in the islets of Langerhans of baboon pancreas. The
meaning of these reactions is unknown.
The anti-hCG vaccine reported here gives promise of
antigen is present transiently in the reproductive process,
the immune response appears specific to the target
hormone, and the effect is potentially reversible. Data in
non-human primates indicate that, after antibody litres
wane, pregnancies can be achieved without untoward
*
consequences.
The vaccine is based on a synthetic antigen
that would al|pw quality control and economy in large scale
production. It is the first synthetic (peptide) vaccine to be
developed for systemic use in man. One previous clinical
trial involved the oral administration of a synthetic vaccine
directed against Escherichia coli enterotoxin.
*
2
the two response patterns with different vaccine doses
possible histocompatibility type restriction of the immune
whole P subunit of this hormone14 indicated the potential of
the approach to contraception but raised concerns about
specificity since the subfects acquired antibodies which,
although they were capable of neutralising hCG, cross
reacted with hLH.
*
’ Immunosafety studies of the current
vaccine in baboons and in the present clinical tnal revealed
no such cross-reactivity and gave evidence ofserological and
clinical safety sufficient to justify further trials of efficacy
and acceptability. This trial has also facilitated the
establishment of drug-regulatory assessment criteria and
general and will provide an impetus to further approaches
based on other target antigens in the reproductive tract such
cell membrane.
existing delivery system, a small synthetic molecule such as
release from an intramuscular depot maintains an antibody
was myalgia, and the fact that this was especially
long cycles (> 31 days) in test and control groups either
Apart from the ten subjects who were withdrawn and
replaced after receiving unstable emulsions, there were three
injection. One had domestic problems; a second, recently
Safety Aspects
intestinal disorder, and a third had convened to DT skin test
positive when screened before the scheduled second
effects. Several women in group 5 had mild and transient
The details of assays for cross-reactive autoimmune
reactions with pitutary hormones and with various body
systems. The reactions were presumably due to rapid release
laboratory animals suggest that the answer may tie in
into biodegradable microcapsules (Stevens V C, unpub
lished).
0-26 nmol/l of anti-hCG binding in vitro equates
approximately to an in-vivo hCG concentration of
135 mlU/ml—a value found in the second half of a
concepoonal cycle. Ifwe allow for the fact that the biological
neutralising activity of the antibodies formed in response to
the vaccine is about 50% of their in-vitro binding
(unpublished data from WHO file), an amount of antibody
capable of neutralising 270 mlU/ml of hCG in vivo might
peri-implantation stage. This equates to an anti-hCG
more than 6 months in groups 4 and 5. The mean antibody
pattern. Calculations will be tested when the vaccine is
subjected to phase 2 clinical trials.
The antibody results for the carrier protein, diphtheria
immunity to diphtheria. Antibody levels were bcxisted by
suggests that an escalating immune response to DT with
ranations in the antibody response
REFERENCES
I HE I jKNC.ET. JUNE 11, I9R8
This report describes the characteristics of lhe immune
response elicited by this vaccine with particular reference to
its potential efficacy and safety as a fertility regulating
method.
The Lancet • Saturday 11 June 1988
(CT) region of the P subunit of hCG which is absent in
P-hLH. Adequate immunogenicity was achieved by
conjugating the antigen to diphtheria toxoid to form a
hapten-carrier complex.
*
Systemic immunisation of
baboons with this complex was effective in inhibiting
fertility despite the fact that there is only 3-15% cross-
and baboon CG
* Further immunogenicity studies in inbred
strains of mice, and in rabbits and baboons, led to the
formulation of a vaccine incorporating an adjuvant and a
vehicle that was suitable for use in man.’
PHASE I CLINICAL TRIAL OF A WO^JA
HEALTH ORGANISATION BIRTH CONTROL
VACCINE
Introduction
SINCE W4. rhe Task Force on Birth Control Vaccines of
the World Heaim Organisation (WHO) Sp™al Programme
of Research, Development and Research Training tn
Homan Reproduction has promoted me development ofa
__ acrainM the DltiUiancy
several possible mechanisms oy
----exert annferohry effects. One is me stimulation of
mat neutralise the luteotropic action of me
u
in rrcressioa of the COFOUS
credible action ts by a aireci
--------mediated cytotoxiceffect on dte hCG-produdng cells of the
Summary
A mnn control
---- r•
synthetic pepude anngen representing me
sminoaod sequence KW-HSoT the C/emnnal repon of me
0 subunit of human ehononie gonadotropin (hCG-IS t™
sobmined to a phase 1 dmical Inal Th.ny surgically
sterilised female volunteers, divided into five equal groups
for different vectne doses, received nvo
contraceptive levels of antib.xdies to hCU aeveiopcy
wbjmJn lhe highest exone dose group.
promise of a eomracepiiee effect of six months duration.
Whatever the mode ot action 01 >uu. y
marmoset1 and the baboon
*
established the principle that
immunity to hCG is capable of blocking fertility at an early
stage of pregnancy with no discernible alteranons m the
menstrual cycle. This method,
acceptable birth control strategy m bom developed ano
su<~nn of human lu.emiT.^^LH>,^»^
109-145, produced by the solid phase procedure of Tregear
et al" (Peninsula Laboratories, Belmont, California),
conjugated to a protein carrier, diphtheria toxoid
(Connaught Laboratories, Swiftwater, Pennsylvania). The
composition and purity of the peptide antigen was
confirmed by high voltage electrophoresis, thin-layer
chromatography, and high performance liquid
chromatographic analysis. The remaining components
of the vaccine were a water-soluble synthetic adjuvant,
N-acctyl-glucosaminc-3yl-acvtyl-L-alanyl-D-isogluiamine
(CGP-11637)(Ciba-Gcigy, Basle) and a saline-oil emulsion
vehicle (Ciba-Gcigy, Basle) with an oil phase consisting of4
as an emulsifying agent. New conjugation methods were
established to produce a highly stable peptide-camer
N-hydroxy succimide ester (MCS) which couples to free
amino groups. After purification, the modified diphtheria
toxoid was reacted with the hCG-fl CT peptide in a reduced
coupled to the maleimido group of the MCS/carrier
complex. This reaction is virtually 100% effective and is
very specific under the conditions adopted. The conjugate
was constructed with a pcptide/carrier ratio of 24-28
peptides to 10' Daltons carrier.
after routine toxicological studies in laboratory animals and
authorities in the USA and Australia gave permission for its
use in a phase I clinical tnal for safety and immunogenicity.
at
Laboratories
have
the National Institute
could
in
used
be
birth
approaches to achieve this
1)
of
identification
antigens
of
Identification
vaccines.
antigens
egg-antigens
thereby rendering it 'non-self' or 'foreign' and provoke
of
2)
sperms,
block
can
fertilization either by masking sperm receptor sites
by building up a physical barrier that the sperm
Hormonal
interception
gonadotropin
releasing
hormone can be
bring
about
both
males
that
hormone
or
to
neutralization
is
the
essential
for
of
sustenance
most
these and will be the matter of
in
process
females and 4) by
The fourth approach is the
pregnancy.
amongst
cannot
intercepted
as
cessation of the reproductive
s
or
LHRH
such
penetrate,3)
toxoid
is
Four
capable
that
tetanus
like
to a carrier molecule
that
have been adopted. These are
sperm
that can immobilize
antibodies
generating
control
Immunology
of
been working to identify potential
a
of
advanced
discussion
in
this article.
linked
the
immune
system.
carriers
stimulate
a
Director, of the National Institute
of
Immunology and his associates first proposed the use
of
The
also
stronger response against these molecules.
Prof.G.P.Taiwan
/S-hCG
linked
tetanus toxoid as
to
a
birth
candidate
control vaccine (BCV). Studies conducted on 65 women
five
different
countries had demonstrated the
of side-effects of the vaccine. However,it also showed a
variation in response to the vaccine from one individual
to
another .prompting investigators to look
formulations
levels
with
better efficacy,sinee
that
the woman was
meant
pregnancy.
not
Experiments revealed that a
other
for
antibody
low
protected
from
formulation
of
alpha subunit of ovine luteinizing hormone (<x-oLH)
the
Human chorionic gonadotropin (hCG) is a hormone that
is
annealed
by the fertilized egg. It acts as a signal
to
immune response, yet had virtually no side-effects.
released
inform the body that conception has occurred and thereby
prevents
the
degeneration of the corpus luteum thereby ensuring
high
prepares
levels
the body for pregnancy. It also
of progesterone.
implantation
which
Progesterone
facilitates
of the embryo in the uterus.
The
uses only the fl subunit (hCG has two, alpha
beta) generates antibodies that neutralize the
the
vaccine
and
hormone,
thus intercepting the signal midway. The hormone subunit
in
absence
to
was able to
fl -hCG-TT
elicit
a
greater
vaccines
Phase
I clinical trials employing the
were
initiated in May,86 (using three formulations)
105
volunteers
centres
5
at
in
fl -hCG
India.
on
trials
The
demonstrated that the vaccine was well tolerated, had no
adverse
side-effects
levels
of
immunized
and generated
sufficiently
high
level
in
all
decline to near zero level
by
the
antibodies.
subjects
The
antibody
54th
week confirming the reversibility of the
vaccine.
The
vaccine
IV
will go sequentially upto Phase
after
(iaS/iAj/c
/jw«vxUlno/O'
Mw
health-hazards like cholera, tetanus
other
diphtheria
AN INDIAN BIRTH CONTROL VACCINE
In
a
world survey by the Population
Committee
Crisis
towards the end of 1986, it was revealed that 80X of the
population
the developing
from
has
world
access
to birth control. That eventhough
nearly
U.S.$550
millions per year
on
inadequate
India
spends
family
welfare
etc..
-
also suited for low-cost
is
It
and
delivery
easy
through existing health infrastructure.
- Finally, such a vaccine is expected to lend Itself
programmes, the results have not been commensurate
with
It is
Bureaucratic constraints together
with
that are essential for and highly specific to
the emphasis on sterilization to the exclusion of
other
events
in
of
release
of gametes, fertilization, development
family
embryo,
its
the investment.
contraceptive
couples
options have resulted in only a third
the
in
reproductive
age
practising
planning.
A
birth
control vaccine (BCV)
family
planning
programme
revolutionize
may
due
to
the
the
following
-It
will
have an anti-fertility effect
(a
year
or
more)
administration
continuous
of
without
for
a
the
need
longer
for
pharmacologically
any
The
effect of this vaccine will
Presently
be
to
the
inhibition
or
neutralization
of
a
function,
very
often
accompanied
by
physiological
undesirable side-effects.
Vaccines can be tailormade so
pregnancy
molecules
for
an
etc.
By
different
production
and
of
the
implantation In the uterus,
of
initiation
targeting
’immune-attack’, the
&
these
reproductive
process could be impaired. By modifying these
attacking
molecules
vaccine employs carrier molecules to
immune response which also
afford
elicit
prophylaxis
these
molecules which would
have
otherwise
been
spared by the immune system for being ’one of
own’.
The
not
criteria followed to select
such
a
our
target
that would be a potential BCV is (a) one
present
present
only
Several
such
characterized
hormones,
as not to affect other body functions adversely.
The
eg.
that
is essential to the process of reproduction (b) which is
reversible.
available contraceptives lead either
alteration,
-
the reproductive cycle
sustenance
molecule
active agent.
-
well known that there exist a number of molecules
the immunologist succeeds to fool the immune system into
advantages:
duration
to
large-scale synthesis and manufacture at very low cost.
an
against
in
other body tissues or
fluids,
or
transiently
and
low
amounts.
molecules
or
antigens
have
include
several
reproductive
which
very
several antigens of the sperm,
(zona pellucida), embryonic and
etc.
in
if
been
egg
antigens
foetal tissue
antigens
RESEARCH IN HUMAN REPRODUCTION
immunity, persisting for periods in excess of 12
months, can be elicited with such preparations in
experimental animals. The second phase of this
work is concerned with optimizing the anti-hCG
vaccine to the point where it represents a safe,
effective and acceptable pre-product formula
tion. Preliminary results indicate that the use of
a combination of carefully selected and engi
neered hCG peptides greatly enhances the antihCG antibody response and that alternative car
riers, adjuvants and delivery systems, offer
promise in terms of producing an anti-hCG vac
cine with enhanced efficacy, safely and a pro
longed duration of activity following a single
injection.
During the reporting period, the Task Force has
implemented a new research programme to
develop a vaccine directed against the trophob
last of the peri-implantation embryo. In contrast
to earlier studies carried out in this area, in
which classical biochemical approaches were
used to isolate trophoblast membrane protein
antigens of potential interest for vaccine devel
opment, the Task Force is employing monoclo
nal antibodies (MABs) and recently developed
biotechnological procedures in order to identify,
isolate, characterize and select relevant mole
cules more precisely. A sperm antigen classifi
cation system has also been initiated by the Task
Force, using the same techniques and procedures
as for the trophoblast antigen work, in an effort
to standardize and rationalize the information
being generated by the large number of investi
gators working in this area with support from
THE RATIONALE FOR FERTILITY
REGULATING VACCINE DEVELOPMENT
other international and national funding agen
cies. This antigen classification project is con
sidered by the majority of the investigators in
the field to be an essential aid to vaccine
development.
In preparation for these new activities, the Task
Force carried out an international, multicentrc
collaborative project to evaluate and assess the
large number of anti-trophoblast and anti-sperm
MABs that were already available. A total of
111 MABs. 29 providing laboratories and 42
evaluating laboratories were involved in this
project, the results of which were reviewed in a
WHO-sponsored workshop held in conjunction
with the sixth International Congress of Immu
nology in Toronto, Canada, in July 1986. As
a result of these initial studies, a number of amitrophoblast and anti-sperm MABs have been
selected as reagents for the identification, isola
tion. characterization and selection of molecules
for evaluation as components of prototype
anti-trophoblast and anti-sperm vaccines.
The Task Force has continued to coordinate its
research activities with other vaccine develop
ment programmes within WHO and with other
international and national programmes engaged
in the development of fertility regulating vac
cines. This coordination has involved participa
tion by representatives of other programmes and
agencies in Steering Committee meetings of
the Task Force and by Special Programme
representatives in relevant meetings of other
agencies.
the alteration or inhibition of a physiological
function and resulting in an antifertility effect.
This desired effect is often accompanied by less
desirable side effects of varying types and inten
sity, which, together with the increasing concern
being expressed about the sequelae of long-term
use of many of these preparations, is having a
major influence on their acceptability and
continued use.
Although the number of fertility regulating
methods currently available is probably greater
now than at any time in the past, it is still not
adequate to meet the widely varying cultural,
religious, personal and service needs of all popu
lations, particularly of those in the developing
countries. Many of these methods act by exert
ing a pharmacological action at one or more
points in the reproductive process, leading to
If vaccines could be developed which would
safely and effectively inhibit fertility, without
178
VACCINES FOR FERTILITY REGULATION
producing unacceptable side effects, they
would bean attractive addition to the present
armamentarium of fertility regulating methods
and would be likely to have a significant impact
on family planning programmes. The theoreti
cal advantages that a fertility regulating vaccine
(FRV) would have over currently available
methods of fertility regulation include: (a) lack
of pharmacological activity and the often atten
dant side effects; (b) long-lasting action follow
ing only one or two injections; (c) administra
tion by a procedure associated with positive
health benefits; and (d) low manufacturing
cost and ease of delivery within existing health
services.
Essential to the development of FRVs is the
identification of components of the reproductive
system whose neutralization by immunological
means will result in a safe?effective and accept
able antifertility effect, as well as the identifica
tion of appropriate animal models in which rele
vant preclinical studies of vaccine safety and
efficacy can be carried oul
OPTIONS FOR FERTILITY REGULATING
VACCINE DEVELOPMENT
Mammalian reproduction is a highly complex
biological process involving diverse and special
ized molecular systems and our knowledge of
the number and type of molecules that are both
specific to and essential for successful reproduc
tion is rapidly increasing as the result of both
clinical and basic research in the reproductive
sciences. Immunization studies have demon
strated that many of these chemical entities,
when suitably modified, are capable of eliciting
an immune response which will neutralize the
biological activity or destroy the structural
integrity of the parent molecule, thereby reduc
ing or inhibiting fertility in the immunized ani
mal. Furthermore, there is a substantial body of
information linking naturally occurring immu
nity to some of these molecules with certain
types of infertility. These experiments of man
and of nature indicate that there are many com
ponents of the reproductive tissues that could
form the basis of antifertility immunogens for
use in the development of FRVs.
Whilst virtually every step in the reproductive
process is accessible to immune attack, not all
represent attractive targets for FRV develop
ment. Immunization to some of these target mol
ecules can result in a low level of antifertility
efficacy and/or can produce unacceptable side
effects, ranging from minor disturbances in
endocrine function through to the more serious
immunopathological sequelae of auto-immunity
and immune-complex disease. In order to avoid
these potential side effects and hazards, it is nec
essary to select carefully those immunogens that
will produce safe, effective and acceptable anti
fertility effects. Ideally, such candidates for FRV
development, would need to be: essential for the
success of the reproductive process; accessible
to immune attack; specific to the intended target
and not represented in other body tissues or
fluids; located in a site where a specific and con
trolled immune reaction will have no immunopathological or other undesirable consequences;
and present only transiently or in small concen
trations. These criteria are met by some mole
cules in the sperm membrane, the zona pellucida
of the ovum, the trophoblast cell membrane of
the peri-implantation blastocyst, and in the early
placenta. In addition, some secreted products of
these tissues, such as hCG from the trophoblast,
also appear to be promising candidates. Proto
type vaccines, incorporating natural and syn
thetic preparations based on several of these
tissue-specific immunogens, have been produced
and evaluated in animal and clinical studies.
CURRENT RESEARCH ON FERTILITY
REGULATING VACCINES
There is currently a major interest in FRVs in
many countries and several national and interna
tional agencies are funding work in this area.
These studies cover virtually all aspects of basic
research on the molecular events involved in
gametogenesis, comparative evaluation of inter
actions between monoclonal antibodies, biosyn
thesis of antigens using recombinant DNA tech
niques, and clinical trials of prototype vaccine
formulations.
The National Institute of Child Health and
Human Development (N1CHD) in Bethesda,
179
In the interests of safely, necessitated by the
novelty of the vaccine and the lack of previous
clinical information with this type of formula
tion, the trial was conducted in a modified
"dose-finding" manner in one centre. Six of the
30 women volunteers were assigned to each of
the five dose groups indicated in Table 1, the
highest of which. Group V, being the dose
expected to elicit a level of immunity sufficient
to confer antifertility efficacy, based on the
182
In view of these unexpected results, a close
inspection was made of the patient records and
laboratory data and a positive correlation was
found between the intensity of the reported side
effects and poor anti-hCG antibody responses in
some of the vaccine recipients. In all cases,
these phenomena were associated with apparent
or suspected instability of the emulsion vehicle.
Because of the difficulty of developing, manu
ally, the high shear forces needed to generate
adequate emulsification, the vehicles of some of
the vaccine doses formulated were probably
unstable and separated into their oil and water
phases soon after injection. Thus, instead of the
I
A total of 30 previously electively sterilized
women volunteers were needed for the trial and
recruitment was initiated in November 1985,
following receipt of the necessary WHO, institu
tional and government approvals (Jones, 1986ab). Telephone inquiries, requesting additional
information about the trial, were received from a
total of 185 potential volunteers of whom 93
were considered suitable candidates. Of these,
6! expressed an interest in taking part in the trial
and 47 were subsequendy selected for screening.
A total of 13 women were excluded at the
screening stage, for a variety of social, psycho
logical and medical reasons, leaving the required
30 with four replacements, should these be
needed.
The majority of vaccine recipients in all dose
groups produced antibodies to hCG as well as to
the DT carrier component of the vaccine. The
anti-hCG antibody levels in Groups I, II and III
exhibited only small dose-dependent increments
whereas those in Groups IV and V did not fol
low this pattern and were much lower than
Groups I-I1I. The only side effects considered
significant by the resident physician, were tran
sient muscle and joint pains reported by a few
subjects. These symptoms, believed to be pro
duced by the MDP component of the vaccine,
were most marked in subjects in Groups IV and
V but were satisfactorily controlled with analge
sics and did not cause any of the volunteers to
withdraw from the trial. Recovery in all cases
was complete and there were no associated rele
vant serological abnormalities. Two subjects
withdrew from the study after the first injection
for reasons unrelated to the trial. A third sub
ject was excluded after she converted to DT skin
lest positive following the first injection of the
vaccine.
U itb .h C G varxrin .d o«grou p . 8, th. Phase clinical trial
Although no adverse side effects had been
detected in the extensive preclinical toxicity,
safety and efficacy studies carried out with this
vaccine formulation in mice, rats, rabbits and
baboons, no information had been obtained on
the tolerance to, and immunogenicity of, this
formulation in humans. Therefore, the principal
objective of this Phase I clinical trial was to
determine what, if any, side effects were pro
duced by this vaccine. In addition, the levels of
anti-hCG antibodies elicited by the vaccine were
measured and compared to those that would be
expected to confer antifertility efficacy in fertile
women.
results obtained in die baboon efficacy studies.
Of the six women in each dose group, four
received the complete vaccine and two received
a "placebo" preparation consisting of the MDP
adjuvant and emulsion vehicle only. Immuniza
tion was effected by two injections into the
gluteal muscles at an interval of six weeks and
the subjects were followed up on an in-patient
and out-patient basis for a total of six months. A
large number of routine and trial-specific exami
nations and laboratory investigations were
carried out over this period.
F^.M aqnitud. and duration o< anU4KX3 a m ^ I K r a .
RESEARCH IN HUMAN REPRODUCTION
was formulated immediately prior to injection
by dissolving the peptide-carrier conjugate and
MDP in isotonic saline and subsequendy mixing
this aqueous component with the squalene oil,
using arlacel as the emulsifying agent. Vigorous
mixing of these components is required in order
to generate the high shear forces needed to
achieve satisfactory emulsification.
RESEARCH IN HUMAN REPRODUCTION
MD, USA, has recently iniated a programme of
research in this area under its Reproductive
Immunology Initiative. The projects supported
by this programme arc concerned primarily
with the identification and characterization of
gamete antigens which might represent suitable
candidates for FRV development
The National Institute of Immunology (Nil) in
New Delhi, India, has a large programme on
FRV development and evaluation, ranging from
the use of molecular genetics techniques to pro
duce bioengineered vaccines directed at a vari
ety of different reproductive targets, to the clini
cal evaluation of a number of different hCG vac
cine formulations all of which use the whole
B-subunit of hCG as the primary immunogen
(Taiwar et al, 1986,1987; Shaha et al, in press).
The Population Council in New York, NY.USA,
is also supporting studies on the immunobiology
of the gametes as well as a major programme of
anti-hCG vaccine development in which the
whole B-subunit of hCG is used as the primary
immunogen (Thau et al, 1985,1987).
The USAID supported Contraceptive Develop
ment Programme (CONRAD) in Norfolk, VA,
USA is primarily concerned with FRVs which
will exert an effect prior to fertilization and is
concentrating, therefore, on the identification
and characterization of sperm antigens and anti
gens of the zona pellucida (Gupta et al, in press;
Mahony et al, in press).
In addition to these major research programmes,
there is a large number of investigators work
ing independently in many countries in areas
relevant to FRV development. Many of these
activities have been stimulated by the recent
expansion of knowledge of immune processes
and developments in biotechnology and the
increasing interest being shown by both aca
demic and commercial institutions in the poten
tial these developments offer for novel vaccine
design and production.
The Task Force has defined research strategies
and drawn up research plans in six principal
areas. In addition to anti-sperm, anti-zona pellu
cida, anti-trophoblast and anti-hCG vaccines,
studies have been proposed to reassess the feas
ibility of producing an effective local (secretory)
immune response restricted to the lumen of the
male or female reproductive tracts, and to carry
out studies in the area of basic vaccinology rele
vant to the development of FRVs in general.
Because of funding constraints, the Task Force’s
activities over the past biennium have been
restricted to only two of these six areas of inter
est, namely the continuing development of antihCG vaccines and the initiation of prelimi
nary studies aimed at the development of anti
trophoblast vaccines (Ada et al, 1986). How
ever, some work has also been carried out,
largely as a collaborative exercise with other
agencies, on the establishment of a classification
system for sperm membrane antigens.
Development of the anti-hCG vaccine
Virtually all vaccines in use and under develop
ment at the present lime are directed against tar
gets, such as bacteria and viruses, which express
foreign antigens to which the vaccine recipient
is not immunologically tolerant. Although hCG
is a ‘foreign’ hormone, in the sense that it is pro
duced in significant quantities only by the early
embryo, the pregnant woman is tolerant to it and
does not mount an immune response against it,
either because hCG is very similar chemically
to the endogenous pituitary hormone hLH or
because of her prior exposure to hCG in utero.
The development of an anti-hCG vaccine, there
fore, is a totally new and experimental area of
immunotherapy in which there is little previous
information to guide investigators. To deter
mine the feasibility of developing this novel
approach to fertility regulation, two major ques
tions concerning the efficacy and safety of the
vaccine needed to be answered.
- Could an anti-hCG vaccine break maternal
tolerance to the hormone and elicit an immune
response of sufficient magnitude to neutralize
the hormone in the maternal circulation at the
peri-implantation stage of ‘gestation’?
- Could the anti-hCG response so pro
duced be restricted to the intended target so
that cross-reactions with other normal body
180
VACCINES FOR FERTILITY REGULATION
generation anti-hCG vaccine; development of
improved formulations of the current hCG vac
cine preparation and the development of an opti
mized anti-hCG vaccine with improved compo
nents and characteristics; and the continued
development of a baboon chorionic gonadotro
phin (bCG) vaccine to permit the evaluation
of the long-term safely and efficacy of this
approach to fertility regulation in a relevant
animal model system.
constituents, particularly hLH, would not occur,
and endocrine and metabolic disturbances and
the potential risk of immunopathology avoided?
The mandate of the Task Force, therefore, was
to develop a prototype anti-hCG vaccine to the
point of initial clinical testing in order to obtain
as much information as possible relevant to
these two questions. Subject to a satisfactory
outcome of the preclinical safety and efficacy
work and the clinical study, further development
would be justified to improve the vaccine to the
point where it was suitable for use in family
planning programmes. This final stage of devel
opment would be analagous to the structure/
activity studies that are carried out with any new
drug prototype in order to produce a preparation
with maximum effectiveness and minimum side
effects at the lowest possible dose.
Phase / clinical evaluation of the first
generation anti-hCG vaccine
The studies carried out under this section of
Task Force activities address three principal
objectives: the preliminary clinical evaluation of
the safety and antifertility activity of the first
The first generation anti-hCG vaccine developed
by the Task Force, consists of a synthetic pep
tide representing the B-hCG carboxyterminal
109-145 peptide (B-hCG-CTP) coupled to a
diphtheria toxoid (DT) carrier molecule,
mixed with a muramyl dipeptide (MDP) ad
juvant, and suspended in a squalene-arlacelsaline emulsion vehicle (Griffin, 1985, 1986;
Stevens, 1986a-c). This complex preparation
Table 1. Composition ol the vaccine and placebo preparations administered in the five dosage groups In
the Phase I clinical study of the anti-hCG vaccine
number
recipients
I
4
Placebo
recipients
Immunogen
(pg)
Adjuvant
(pg)
Vehicle
(PD
50
25
25
25
25
50
50
2
n
100
4
50
50
200
100
100
100
100
500
250
250
250
250
500
500
500
500
2
in
4
iv
4
V
4
2
2
1000
2
181
it will be commercially available for
which
use
among
has
also
the general populace.
often
the prototype vaccine
Incidentally,
-hCG-TT
received
an IND from the American FDA. Santiago,
Santa
Domingo
and
this
vaccine
shortly
Committee
for Contraception Research of the
using
Helsinki will commence trials
under
aegis
the
of
International
Population
Council, New York.
The present trend is to use different carriers to afford
protection
against
circumvent
the
response
diseases
other
problem
of
as
well
variability
in
as
and mild hypersensitivity reactions seen
cases. The genetic makeup of Individuals which
be
responsible
investigated.
developing
for
some
than
better
Efforts
polyvalent
people
others
are
do,
also
responding
is
being
may
the
to
also
being
focused
vaccines bearing more
a
1n
few
vaccine
to
immune
at
one
than
antigen of the reproductive tract. This will serve as
a
backup in case any one component of the vaccine did
not
succeed in blocking fertility by itself.
Problems
An
anti-fertility
vaccine
unlike
vaccines
against
infectious diseases, must be able to produce and sustain
immunity in more than 95% of the vaccinated
Human
proteins
population.
are very difficult to produce
in
bulk
amounts unlike most viral or bacterial antigens and^Wre
the
non-immunogenic.
foetus,
if
any,
Possible long-term
must
commencing mass immunization.
also
be
effects
studied
on
before
—SCIENTIFIC CORRESPONDENCE —
-NEWS-
Contraceptive vaccines
a-subunit of ovine luteinizing hormone
(oLH) with hCG to raise its antigenicity
and. second, by using two carriers, TT and
cholera toxin-B (CUB), to take care of
The vaccines prevent pregnancy by pro hyporesponders. The idea of using mixed
ducing antibodies against hCG, a hor carriers, according to Talwar, is that those
mone secreted by the pre-implantation who do not respond to one carrier will
embryo which is essential for establish respond to the other.
What Talwar has now is a cocktail of
ment and maintenance of pregnancy. Be
cause the hormone is a ‘self protein, the antigens and carriers. Two vaccines have
trick is to make the hormone antigenic by been standardized by the permutation and
tagging it to a suitable carrier. Taiwar's combination of these. One of the formula
early vaccine consisted of the purified and tions under trial is a mixture of oLHprocessed ^-subunit of hCG coupled to hCG-TT and oLH-hCG-CHB. The sec
tetanus toxoid (TT) carrier. The fl-hCG- ond formulation consists of a mixture of
TT vaccine was tested in 63 sterilized, oLH-TT-CHB and hCG-TT-CHB. Both
women in India, Finland, Sweden, Chile these formulations have been extensively
and Brazil under a programme supported tested on baboons.
by the international Committee for Con-Ij I Reporting the findings at a recent inter-1
traccptive Research in New York. It was I (national conference on contraception ini
*
found to be devoid of side effects, but 'New Delhi, Talwar said his new vaccines
further trials were abandoned because of produced twenty times more antibodies
poor antigenicity, wide variations in the than were obtained with his first vaccine.
amount of antibodies produced and low He said the animals responding poorly to
the single carrier responded extremely
response in one-quarter of test subjects.
Talwar says these limitations have now well to mixed carriers. In the absence of
been overcome, first by 'associating
*
the booster shots, the animals conceived and
delivered normal babies, showing that the
effect of the vaccine is reversible. With the
launching of trials in India, there is now a
race between Talwar and the USAustralian group that, last February, be
gan testing a similar vaccine in Australia
under the auspices of the World Health
Organisation (see Nature 317,288; 1985).
' That vaccine, developed by Vernon
I Stevens of Ohio State University, is based
! on the carboxy-terminal region of hCG
conjugated to diphtheria toxoid.
The results of the Australian trial will be
published first, but Talwar is sceptical of
its outcome as he believes that carboxyterminal /J-hCG is only a poor immuno
gen. The carboxy-terminal peptide.
however, is specific to hCG and, unlike
hCG, does not cross-react with LH.
According to Talwar. cross-reaction with
LH is beneficial and not harmful. In fact,
Talwar’s first vaccine has now been
cleared for human trials in the United Sta
tes by the Food and Drug Administration.
Although Talwar was the first to put
hCG vaccine into human trials in 1974, he
lost the race because of controversies that
cropped up after he jumped the gun. In a
hurry to beat his competitors, he yacdn-.
Trials in India launched
New Delhi
Clinical (rials of rwo locally developed
birth control vaccines have started in In
dia. Two hundted stenlized women volun(he vaccines in a phase one trial to deter
mine side effects, dose rales and relative
efficiencies. The effectiveness of the vac
cines in blocking pregnancy in unstenlized
trial, to begin by the end of the year.
The Indian Council of Medical Re
search. which has given top priority for
immunological research in contraception.
is supervising the trials of the vaccines.
var, director of the National Institute of
immunology in New Delhi. According to
Talwar. the vaccines are improved formu
lations of the subunit hCG (human chor
ionic gonadotrophin) vaccine he develo-
clinical trials in five countries in 1976-78.
vaccine in 1976 when its efficacy was still
in doubt. Two of the women became
pregnant. World Health Organisation
withdrew support and questions of ethics
raised by the Indian scientific community
forced him to go back to the laboratory
and animal trials.
Talwar says he now has more animal
data to show his vaccines are efficient and
safe. The babies bom to the two immu
nized women are perfectly normal, a point
stressed by Talwar to prove the vaccine's
safety.
K.S.Jayaraman
carboxy-terminal peptide as done by V.C.
A cautionary view of
Stevens and applied in the WHO super- *
antifertility vaccines
vised Australian trial'’. If this turns out to
Sir—K.J. Jayaraman’s news report' of be of poor antigenicity, as suggested by
trials of antifertility vaccines comprising Talwar. it would be necessary to investi
gonadotropin hormone subunits and their gate further the truly hCG-specific epi
derivatives calls for some comment. First, topes
*
and try to isolate them or to •
it is not quite correct to state that one construct appropriate mimotopcs'. AU
*
'cocktail
of antigens and carriers used by other nonspecific vaccines have to be
G.P. Talwar for vaccination consists of regarded with scepticism until their safety
oLH-hCG-TT (ovine luteinizing horm is clearly proven bearing in mind that they
one-human chorionic gonadotropin will eventually be applied to millions of
tetanus toxoid) and oLH-hCG coupled to people.
cholera toxoid chain B (CHB), and a
Institute for General and Experimental
c
Pathology,
either contain the a-subunit of oLH (a- University of Innsbruck Medical School, •
oLH) combined with the ^-subunit of Fritz-Pregl-Strasse 3,
hCG (P-hCG) coupled to the two car A-6020 Innsbruck. Austria
riers, or P-oLH-TT-CHB and pwas not mentioned, employs 0-hCG-TT
alone (for review see ref. 2).
More importantly, doubts arise con
cerning the hormone specificity, and
therefore the safety, of the antifertility
vaccines which either already are in phase
I clinical trials or are planned to be by the
i Population Council and the Indian Insti
tute of Immunology. Both groups claim
that their carrier-coupled antigens are safe j
on the basis that a-oLH, fi-hCG,
oLH and a-oLH/p-hCG are either
species-specific (because a-oLH and the
a-chain of human glycoprotein hormones
are considered immunologically distinct)
or, if antibodies against hLH are elicited
(because of similarities between 0-hLH
and 0-hCG) they would cause no side
effects. The first assumption is based on a
concept of Vaitukaitis’ which no longer
holds true; only three monoclonal anti
body-defined human a-chain epitopes
support the assumption
*,
whereas three
other epitopes — one of which is only
expressed by the non-assembled chain —
are not only shared by all a-subunits of
human glycoprotein hormones but are
also present on a-oLH.
Concerning the immunological specifi
city of 0-oLH and fi-hCG chains com
pared with P-hLH, the situation is even
worse. As Jayaraman states, there are
numerous repons of immunological cross
reactivities (for example ref. 3). Mono
clonal antibody based analyses reveal at
least three epitopes shared between the
two human 0-chams
*
J. two of which are
also common to oLH. Moreover, mono
clonal antibodies against all these shared
epitopes are able to inhibit the receptor
binding ability of hCG^as well as hLH.
Additional side effects on the target cell
from p-oLH/0-hCG vaccination might
also be caused by antibodies which still
have access to the receptor-bound
hormone.
One possible way of circumventing the
problem of shared epitopes would be to
use (or vaccination the hCG-specific
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of
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5
of
the policy and
162
TI: CEthical considerations in neonatal medicine!
AU: Hansen-TW; Finne-PH
AD: Neonatalseksjcnen Barnek1inikken Rikshospitalet, Oslo.
SO: Tidsskr-Nor-Laegeforen. 1995 May 30; 115(14): 1721-3
LA: NORWEGIAN; NON-ENGLISH
TI: Health care workers, patients, and HIV:
ethical debate.
AU: Shorn-AF
AD: Walter Reed Army Medical Center, USA.
SO: Pharos. 1995 Spring; 58(2): 7-13
LA: ENGLISH
an analysis of
6
TI: Decisions not to transplant: futility or rationing.
AU: Collins-EG; Pfiefer-PB; Mozdzierz-G
AD: Department of Veterans Affairs Edward Hines Jr. VA Hospital,
Illinois, USA.
SO: J-Cardiovasc-Nurs. 1995 Apr; 9(3): 23-9
LA: ENGLISH
Brooklyn,
162
of
162
Hines,
7
TI: The hospital-based attorney as patient advocate.
AU: Herb-A
AD: State University of New York Health Science Center,
SO: Hastings-Cent-Rep. 1995 Mar-Apr; 25(2): 13-9
LA: ENGLISH
of
USA.
8 of
162
TI: Healthcare Ethics Forum '94: organ transplantation and donation.
AU: Jacobbi-L; Franz-H; Coolican-MB
SO: AACN-C1in-Issues. 1994 Aug; 5(3): 324-8
LA: ENGLISH
9
TI: Abortion—some practical and ethical considerations [letter!
AU: Brooks-D; Nash-E; Abels-C; Abratt-R; Benatar-SR; Degenaar-J; Dent-D;
de-Villiers-M; du-Toit-A; Espley-K; et-al
SO: S-Afr-Med-J. 1995 Mar; 85(3): 183-4
LA: ENGLISH
of
162
10
of 162
TI: Why primary care physicians should not be restrictive gatekeepers.
AU: Manson-A
AD: Department of Medicine, Columbia-Presbyterian Medical Center, New York, New
York, USA.
SO: J-Gen-Intern-Med. 1995 Mar; 10(3): 145-6
LA: ENGLISH
11
of
162
12
of
162
13
of
TI: [Why do I act like this? Everyday health care ethics were shaped at the
Ethical Forum in Linkoping!
AU: Ludvigsson-J
AD: Barn- och ungdomsmedicinska kl.iniken, Halsouniversitetet, Linkoping.
SO: Lakartidningen. 1995 May 17; 92(20): 2113-5
LA: SWEDISH; NON-ENGLISH
162
14
of
162
15
of
162
TI: 'Doc Quixote' in hea1 th care reform [letter!
AU: Brown-JD-3rd
SO: Am-Fam—Physician. 1995 Jun; 51(8): 1830, 1832
LA: ENGLISH
TI: Cultural lag and the Hippocratic Oath.
AU: Robin-ED; McCauley-RF
AD: Tsural Indian Health Service Clinic, Trinidad,
SO: Lancet. 1995 Jun 3; 345(8962): 1422-4
LA: ENGLISH
TI:
AU:
SO:
LA:
Gatekeeping. Part 1: What and why?
Perkin-RL
Can-Fam-Physician. 1995 May; 41: 947,
ENGLISH; FRENCH
946,
CA 95570,
USA.
948
TI: [Health care services in hereditary cancer. Where are we now?!
AU: Moller-P
AD: Seksjon for medisinsk genetikk, Onkologisk avdeling, Det Norske
Radiumhospital, Oslo.
SO: Tidsskr-Nor-Laegeforen. 1995 Apr 20; 115(10): 1213-4
LA: NORWEGIAN; NON-ENGLISH
TI:
AU:
AD:
16
of 162
Multiculturalism, alternative health care, and responsibility for belief.
Fisk-W
Department of Medical Education, Mount Sinai Medical Center, New York, NY
10029. USA.
SO: Mt-Sinai-J-Med.
LA: ENGLISH
1995 Mar;
62(2):
148-51;
discussion
159-62
TI: An international perspective on artificial nutritional
community.
AU: Elia-M
AD: Dunn Clinical Nutrition Centre, Cambridge, UK.
SO: Lancet. 1995 May 27; 345(8961): 1345-9
LA: ENGLISH
support in
17
of
the
162
18
of 162
TI: HIV serosurveillance of newborns. A clinician's perspective on legislative
political, and ethical issues.
AU: Garrett-C
AD: Department of Psychiatry, North Shore University Hospital-Cornel 1
University Medical Center, Manhasset, NY 11030, USA.
SO: J-Subst-Abuse-Treat. 1995 Jan-Feb; 12(1): 29-33
LA: ENGLISH
19
of
TI : The ethics of global budgeting: some historically based observations
[editorial; commentJ
AU: Baker-R
SO: J-Clin-Ethics. 1994 Winter; 5(4): 343-6
LA: ENGLISH
20
162
of
162
21
of
TI: Clinical practice guidelines as tools of public policy: conflicts of
purpose, issues of autonomy, and justice.
AU: Redman-BK
AD: Johns Hopkins University School of Nursing, Baltimore, MD.
SO: J-Clin-Ethics. 1994 Winter; 5(4): 303-9
LA: ENGLISH
162
TI: Global budgeting in the real world [editorial;
AU: Gold—JA
SO: J-Clin-Ethics. 1994 Winter; 5(4): 342-3
LA: ENGLISH
comment!
22
of 162
TI: Healthcare rationing through global budgeting: the ethical choices [see
comments]
AU: Veatch-RM
AD: Kennedy Institute of Ethics, Georgetown University, Washington, DC.
SO: J-Clin-Ethics. 1994 Winter; 5(4): 291.-6
LA: ENGLISH
23
TI: Ethics: rational rationing?
AU: Devitt-P
SO: Nurs-Stand. 1995 Mar 29-Apr 4;
LA: ENGLISH
9(27):
TI: [Heal th care agreements are welcome!
services]
AU: Jarhult-B
of
162
43
Time to stop unethical
24
of 162
private care
SO:
LA:
Lakartidningen. 1995 May 3;
SWEDISH; NON-ENGLISH
92(18):
1884-6
Til Guarding the integrity o-f medical ethics.
[editorial; comment!
AU: Pellegrino-ED
SO: JAMA. 1995 May 24-31; 273(20): 1622-3
LA: ENGLISH
Some
25
of 162
lessens from Soviet Russia
26
of 162
TI: Health care, medical practice, and medical ethics in Russia today [see
comments!
AU: Cassileth-BR; Vlassov-W; Chapman-CC
AD: Department of Medicine, University of North Carolina at Chapel Hill, USA.
SO: JAMA. 1995 May 24-31; 273(20): 1569-73
LA: ENGLISH
27
of
162
28
of
162
29
of
162
30
of
the debate
162
31
of
162
of
162
responsibility in health reform.
TI:
AU:
Building bridges:
Strickland-jw"
AD:
SO:
LA:
Indiana Hand Center, Indianapolis, Indiana 46280-0434,
J-Bone-Joint-Surg-Am. 1995 May; 77(5): 655-60
ENGLISH
TI:
AU:
SO':
LA:
To do no harm.
Brykczynska-G
Paediatr-Nurs.
ENGLISH
1995 Apr;
7(3):
USA.
6-7
TI: Advance directives in COPD.
AU: Singer-P
AD: Centre for Bioethics, University of Toronto, Ontario,
SO: Monaldi—Arch-Chest-Dis. 1995 Jan; 50(1): 62-3
LA: ENGLISH
Canada.
TI: Alcohol-related end-stage liver disease and transplantation:
continues.
AU: KeIso-LA
SO: AACN-Clin-Issues—Cri.t-Care-Nurs. 1994 Nov; 5(4): 501-6
LA: ENGLISH
TI: Oppressive limits: Callahan's foundation myth.
AU: Dixon-KM
AD: Philosophy and Women's Studies, Bowling Green State University,
43403-0222, USA.
SO: J-Med-Philos. 1994 Dec; 19(6): 613-37
LA: ENGLISH
OH
32
TI:
AU:
SO:
LA:
EProblematic health expenditures for social
Boukhris-M
Tunis-Med. 1994 Apr; 72(3): 411-8
FRENCH; NON-ENGLISH
'
security!
33 of
162
TI: [Care of sick refugees—how shall we handle it?
ethical problem in health carel
AU: Palmgren-L
SO: Lakartidningen. 1995 Apr 26; 92(17): 1756-7
LA: SWEDISH; NON-ENGLISH
Illegal
immigrants as an
34
of
TI : Ethical values in health care in 1995: lessons -from the Nazi period.
AU: Franzblau-MJ
AD: Department of the History of Health Sciences, University of California
School of Medicine, San Francisco, USA.
SO: J-Med-Assoc-Ga. 1995 Apr; 84(4): 161-4
LA: ENGLISH
35
TI:
SO:
LA:
of
162
162
Cost benefit analysis Ceditorial!
Health-Visit. 1995 Apr; 68(4): 127
ENGLISH
TI: Long-acting contraceptives. Ethical guidance for policymakers and
care providers.
AU: Moskowitz-EH; Jennings-B; Callahan-D
SO: Hastings-Cent-Rep. 1995 Jan-Feb; 25(1): Sl-8
LA: ENGLISH
36
of 162
health
37
of 162
TI: Assessing the significance of treatment effects: comments from the
perspective of ethics.
AU: Lynn-J; Virnig-BA
AD: Department of Medicine, Dartmouth-Hitchcock Medical Center, Hanover, NH,
USA.
SO: Med-Care. 1995 Apr; 33(4 Suppl): AS292-8
LA: ENGLISH
38
of 162
TI: Ethical considerations with African-American elders.
AU: Mouton-CP; Johnson-MS; Cole-DR .
AD: Department of Family Medicine, University of Medicine and Dentistry-New
Jersey Medical School, Newark, USA.
SO: Clin-Geriatr-Med. 1995 Feb; 11(1): 113-29
LA: ENGLISH
39
of 162
TI: Gender comparisons of young physicians' perceptions of their medical
education, professional life, and practice: a follow-up study of Jefferson
Medical College graduates.
AU: Hojat-M; Gonnella-JS; Xu-G
AD: Center for Research in Medical Education and Health Care, Jefferson Medical
College, Philadelphia, PA 19107-5083, USA.
SO: Acad—Med. 1995 Apr; 70(4): 305-12
LA: ENGLISH
40
of 162
TI: CResponsibility for patient education in trials of new procedures in human:
from the physician's viewpoint!
AU: Schneider-V
AD: Institut fur Rechtsmedizin, Freie Universitat Berlin.
SO: Z-Arztl-Fortbild-Jena. 1994 Dec; 88(12): 1045-50; discussion 1050-4
LA: GERMAN; NON-ENGLISH
TI:
the
AU:
AD:
SO:
LA:
EConsent and education in trials of new procedures involving
legal viewpoint!
Deutsch-E
Universitat Gottingen.
Z-Arztl-FortbiId-Jena. 1994 Dec; 89(12): 1040-4
GERMAN; NON-ENGLISH
41
of 162
humans—from
42
of 162
TI: EPatient education regarding the suitability of medical practices,
hospitals and alternative treatment methods—from the physician's viewpoint!
AU: Fritz-HG
SO: Z-Arztl-Fortbild-Jena. 1994 Dec; 38(12): 1031-4; discussion 1035-9
LA: GERMAN; NON-ENGLISH
43
TI: EPatient education regarding the suitability of medical practices,
hospitals and alternative treatment methods—from the legal viewpoint!
AU: Jansen-C
SO: Z-Arztl-Fortbild-Jena. 1994 Dec; 88(12): 1027-31
LA: GERMAN; NON-ENGLISH
of
162
44
of 162
TI: A kidney donor's dilemma: the sibling who can donate—but doesn't.
AU: Bratton-LB; Griffin-LW
AD: School of Social Work, East Carolina University, Greenville, NC 27858-4353
USA.
SO: Soc-Work-Health-Care. 1994; 20(2): 75-96
LA: ENGLISH
45
of 162
TI: Physicians do not have a responsibility to provide futile or unreasonable
care if a patient or family insists Esee comments!
AU: Luce-JM
AD: Department of Medicine, University of California, San Francisco, USA.
SO: Crit-Care-Med. 1995 Apr; 23(4): 760-6
LA: ENGLISH
46
TI: Core and comprehensive heal th care services: 1. Introduction to the
Canadian Medical Association's decision-making framework.
AU: Wilson-R; Rowan-MS; Henderson-J
AD: Department of Family Medicine, Queen's University, Kingston, Ont.
SO: Can-Med-Assoc-J. 1995 Apr 1; 152(7): 1063-6
LA: ENGLISH
of
162
47
TI: Clinical and ethical perspectives on rationing of high-cost drugs.
AU: Poirier-TI; Giannetti-VJ
AD: School of Pharmacy, Duquesne University, Pittsburgh, PA 15282.
SO: Ann-Pharmacother. 1995 Jan; 29(1): 78-81
LA: ENGLISH
of
162
48
of
TI: Implications of managed care for medical ethics. South Carolina Medical
Association Medical Ethics Committee.
AU: Sade-RM; Marshal1-MF; Roberts-JM; MacDonald-D
AD: Department of Surgery, Medical University of South Carolina, Charleston
29425.
162
SO:
LA:
J-S-C-Med-Assoc.
ENGLISH
TI :
AU:
AD:
SO:
LA:
EEthics and cardiology!
Vacheron-A
Clinique cardiologique de 1'hopital Necker, Paris.
Arch-Mal-Coeur-Vaiss . 1994 Jun; 87(6): 783-9
FRENCH; NON-ENGLISH
1995 Feb;
91(2):
66-72
49 of
162
50 of
TI: Reflections in family practice. Family physicians as proceduralists:
striking a balance.
AU: Brody-H; Alexander-GP
AD: Division of Primary Care, Agency for Health Care Policy and Research,
Rockville, ND, USA.
SO: J-Am-Board-Fam-Pract. 1995 Jan-Feb; 8(1): 58-61
LA: ENGLISH
162
51
of 162
TI: Creating a dignified option: ethical considerations in the formulation of
prehospital DNR protocol.
AU: Fitzgerald-DJ; Milzman-DP; Sulmasy-DP
AD: Department of Medicine, Georgetown University Medical Center, Washington,
DC 20007.
SO: Am—J-Emerg—Med. 1995 Mar'; 13(2): 223-8
LA: ENGLISH
TI: Public psychiatry's destruction of therapeutic
general medicine.
AU: Lehrman-NS
AD: Kingsboro Psychiatric Center, Brooklyn, NY.
SO: J-Med-Assoc-Ga. 1995 Feb; 84(2): 65-9
LA: ENGLISH
trust.
A negative
TI: HIV-testing of health care workers: unethical request or moral
AU: Allerberger-F; Luthe-R
AD: Institute of Hygiene, University of Innsbruck.
SO: Wien-Klin-Wochenschr1995; 107(3): 91-4
LA: ENGLISH
52
of 162
lesson for
53
of 162
obligation?
54
of 162
TI: CPriority surveys: include the ethical principles in the health care law
(interview by Jan Lind)]
AU: Einhorn-J
SO: Lakartidningen . 1995 Mar 8; 92(10): 933-6
LA: SWEDISH; NON-ENGLISH
55
TI:
AU:
AD:
SO:
LA:
Issues of social policy and ethics in gene technology.
Sade-RM
Department of Surgery, Medical University of South Carolina,
Methcds-Find-Exp-Clin-Pharmacol. 1994 Sep; 16(7): 477-89
ENGLISH
TI:
AU:
Essential vs discretionary heal th care in system reform I letter]
Ashley-JT
of
162
Charleston.
56 of
162
918-9
SO:
LA:
JAMA. 1995 Mar 22-29;
ENGLISH
TI :
SO:
LA:
Core and comprehensive heal th care services.
Can-Med-Assoc-J. 1995 Mar 1; 152(5): 740A-740D
ENGLISH; FRENCH
TI:
AU:
SO:
LA:
EAn ethics for the future of the primary care team
Altisent-R
Aten-Primaria. 1995 Jan; 15(1): 1-2
SPANISH; NON-ENGLISH
TI:
AU:
AD:
SO:
LA:
EIndications!
Frohmuller-H; Theiss-M
Urologische Klinik und Poliklinik,
Urologe-A. 1995 Jan; 34(1): 62-8
GERMAN; NON-ENGLISH
273(12):
57 of
162
58 of
162
59 of
162
(editorial)!
Universitat Wurzburg.
60 of 162
TI: Futility and the common cold. How requests for antibiotics can illuminate
care at the end of life.
AU: Prendergast-TJ
AD: Division of Pulmonary and Critical Care Medicine, University of California,
San Francisco.
SO: Chest. 1995 Mar; 107(3): 836-44
LA: ENGLISH
61
TI: Qigong therapy—its effectiveness and regulation.
AU: Tang-KC
AD: Southern Sydney Health Promotion Unit, Kogarah, New South Wales,
SO: Am-J-Chin-Med. 1994; 22(3-4): 235-42
LA: ENGLISH
of
162
Australia.
62
of 162
TI: Long-term care, rehabilitation, and legal and ethical considerations in the
management of neuromuscular disease with respiratory dysfunction.
AU: Hotes-LS; Johnson-JA; Sicilian—L
AD: Department of Medicine, Tufts University School of Medicine, Boston,
Massachusetts.
SO: Clin-Chest-Med. 1994 Dec; 15(4): 783-95
LA: ENGLISH
63
TI:
Ethics of
rationing
AU: Cox-D
SO: BMJ. 1995 Jan 28;
LA: ENGLISH
health,care services
310(6974):
Eletter!
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intellectual property protection as dictated by the appropriate laws of your
country and/or by International Convention.
64
TI: CCost/benefit relations in heart transplantation!
AU: Scheld-HH; Deng-MC; Hammel-D; Roeder-N; Roetker-J
AD: Klinik und Poliklinik fur Thorax-, Herz- und Gefasschirurgie,
Wi1 helms-Universitat, Munster.
SO: Z-Kardiol. 1994: S3 Suppl 6: 139-49
LA: GERMAN; NON-ENGLISH
of
162
Westfalische
65
of 162
TI: Reforming the Israeli health care market.
AU: Chinitz-DP
AD: Department of Medical Ecology, Braun School of Public Health and Community
Medicine, Hebrew University-Hadassah, Jerusalem, Israel.
SO: Soc-Sci-Med. 1994 Nov; 39(10): 1447-57
LA: ENGLISH
TI:
AU:
SO:
LA:
66
of
162
67
of
162
Lifestyles and allocation of health care resources Cletter!
Goodman-NW
J-Med-Ethics. 1994 Dec; 20(4): 271
ENGLISH
TI: In defence of ageism Cletter!
AU: Rivlin-MM
SO: J-Med-Ethics. 1994 Dec; 20(4):
LA: ENGLISH
270-1
/
/TI : The Oxford Practice Skills Project: teaching ethics,
skills to clinical medical students.
AU: Hope-T; Fulford-KW
AD: Oxford Practice Skills Project.
SO: J-Med-Ethics. 1994 Dec; 20(4): 229-34
LA: ENGLISH
68 of 162
law and communication
f
69 of 162
'TI: Are withholding and withdrawing therapy always morally equivalent? [see
comments!
AU: Sulmasy-DP; Sugarman-J
AD: Division of General Internal Medicine, Georgetown University Medical
Center, Washington, DC.
SO: J-Med-Ethics. 1994 Dec; 20(4): 218-22; discussion 223-4
LA: ENGLISH
70 of 162
TI: Homophobia and the moral authority of medicine.
AU: Wilkerson-A
AD: Department of Philosophy, University of Illinois at Chicaqo 60607-7115.
SO: J-Homosex. 1994; 27(3-4): 329-47
LA: ENGLISH
71
TI :
AU:
SO:
LA:
Tight budgets and doctors' duties Cletterl
Nicholson-CH
Hastings-Cent-Rep .. 1994 Nov-Dec; 24(6): 40;
ENGLISH
TI:
AU:
SO:
LA:
Tight budgets and doctors' duties Cletterl
Glasson-J: DrentULcher-D
Hastings-Cent-Rep.. 1994 Nov-Dec; 24(6): 40;
ENGLISH
TI:
AU:
SO:
LA:
Tight budgets and doctors' duties Cletterl
Baily-MA
Hastings-Cent-Rep .. 1994 Nov-Dec; 24(6): 40;
ENGLISH
TI:
AU:
AD:
SO:
LA:
The ethics of excess.
Lamm-RD
Center for Public Policy & Contemporary
Hastings-Cent-Rep. 1994 Nov-Dec; 24(6):
ENGLISH
of
162
72 o-F
162
73 o-F
162
74 o-F
162
discussion 40-1
discussion 40-1
discussion 40-1
Issues,
14
University of Denver,
CO.
<
75 of 162
TI: Ethical and medico-legal problems concerning so-called hunger strikers.
AU: Neoral-L
AD: Department of Forensic Medicine and Medical Law, University Of Dlomouc,
Czech Republic.
SO: Forensic-Sci-Int. 1994 Dec 16; 69(3): 327-8
LA: ENGLISH
76 of 162
TI: The inhumanity of fairness: rationing resources for reconstructive breast
surgery.
AU: Wong-AM
SO: Can-Med-Assoc-J. 1995 Feb 15; 152(4): 577-9
LA: ENGLISH
.
TI:
AU:
SO:
LA:
77 of
162
Caring for unhealthy lifestyles Cletterl
Alibhai-SM
Can-Med-Assoc-J. 1995 Feb 15; 152(4): 469-70
ENGLISH
78
of
TI: Ethical issues in physical medicine and rehabilitation. Conclusion to a
series.
AU: Haas-JF
SO: Am—J-Phys-Med—Rehabil. 1995 Jan-Feb; 74(1 Suppl): S54-8
LA: ENGLISH
162
79
of 162
TI: Surgical issues in the management of carcinoma of the cervix in pregnancy.
AU: Lewandowski-GS; Vaccarello-L; Copeland-LJ
AD: Division of Gynecologic Oncology, Arthur G. James Cancer Hospital, Ohio
State University, Columbus.
SO: Surg-Clin-North-Am. 1995 Feb; 75(1): 89-100
LA: ENGLISH
TI: [Increase the quality of Swedish hernia surgery!
results is a challenge to occupational ethics!
AU: Nilsson-E
AD: Kirurgiska kliniken, Lasarettet, Motala.
SO: Lakartidningen. 1995 Feb 8; 92(6): 506-7
LA: SWEDISH; NON-ENGLISH
80
of 162
long-term
Improvement of
81
of 162
TI: Long-term effects of ethics education on the quality of care for patients
who have do—not-resuscitate orders [see comments!
AU: Sulmasy-DP; Terry-PB; Faden-RR; Levine-DM
AD: Division of General Internal Medicine, Georgetown University Medical
Center, Washington, DC 20007.
SO: J-Gen-Intern-Med. 1994 Nov; 9(11): 622-6
LA: ENGLISH
TI: Position of the American Dietetic Association:
feeding permanently unconscious patients.
SO: J-Am—Diet—Assoc. 1995 Feb; 95(2): 231-4
LA: ENGLISH
legal
82
of 162
issues in
and ethical
TI:
AU:
AD:
SO:
LA:
83
of 162
HIV and AIDS. Legal and ethical issues in the emergency department.
Derse-AR
Center for the Study of Bioethics, Medical College of Wisconsin, Milwaukee.
Emerg-Med-Clin-North-Am. 1995 Feb; 13(1): 213-23
ENGLISH
TI:
AU:
AD:
SO:
LA:
What do ethics have to do with lifestyle change?
Starzomski-R
School of Nursing, University of British Columbia,
Can-J-Cardiol. 1995 Jan; 11 Suppl A: 4A-7A
ENGLISH
TI:
AU:
AD:
SO:
LA:
Removal of life support in intensive care units.
Burrows-R
Intensive Care Unit, Addington Hospital, Durban,
Med-Law. 1994; 13(5-6): 489-500
ENGLISH
TI:
AU:
AD:
SO:
LA:
Ethical challenges to the palliative care volunteer.
Rothstein-JM
Volunteer Services, Victoria Hospice Society, British Columbia,
J-Palliat-Care. 1994 Autumn; 10(3): 79-82
ENGLISH
TI:
the
AU:
AD:
SO:
LA:
Ethics of palliative care in the context of limited resources:
need for attitudinal change.
Dossetor—J; MacDonald-N
Bioethics Centre, Edmonton, Alberta, Canada.
J-Palliat-Care. 1994 Autumn; 10(3): 39-42
ENGLISH
84
of
162
85
of
162
86
of
162
Vancouver.
South Africa.
Canada.
an
87
of 162
essay on
88
of 162
TI: Ethics of palliative care medicine: palliative care for the rich nations
only!
AU: Olweny-CL
AD: St. Boniface Unit, Manitoba Cancer Treatment and Research Foundation, St.
Boniface General Hospital, Winnipeg, Canada.
SO: J-Pal1iat-Care. 1994 Autumn; 10(3): 17-22
LA: ENGLISH
/
'TI: Perspectives in genetic screening. Principles and implications.
AU: Kaback-MM
AD: University of California, San Diego.
SO: Int—J-Technol—Assess-Health—Care. 1994 Fall; 10(4): 592—603
LA: ENGLISH
89 of
162
/
'TI:
AU:
AD:
SO:
LA:
90 of
162
91
of
162
92 of
1.62
93 of
162
Genetic technology in health care. A global view.
Galjaard-H
Erasmus University.
Int-J-Technol-Assess-Health-Care. 1994 Fall; 10(4):
ENGLISH
/TI: Changing the paradigm for informed consent
AU: Dagi-TF
SO: J-Clin-Ethics. 1994 Fall; 5(3): 246-50
LA: ENGLISH
/
'TI:
AU:
SO:
LA:
Informed consent: pondering a new piece of
Jacobson-JA
J-Clin-Ethics. 1994 Fall; 5(3): 244-6
ENGLISH
527-45
Ceditorial!
the puzzle
.
'TI: Patients' perceptions of consent Ceditorial;
AU: Shenk-I
SO: J-Clin-Ethics. 1994 Fall; 5(3): 243-4
LA: ENGLISH
Ceditoriall
comment!
/
94 of 162
'TI: Patients' perceptions of the quality of informed consent for common medical
procedures Esee comments!
AU: Sulmasy-DP; Lehmann-LS; Levine-DM; Raden-RR
AD: Division of General Internal Medicine, Georgetown University Medical
Center, Washington, DC.
SO: J-Clin-Ethics. 1994 Fall; 5(3): 189-94
LA: ENGLISH
TI:
AU:
SO:
LA:
CHigh technology medicine in the year 2000.(Editorial)!
Nel-CJ
S—Afr-Med—J. 1994 Sep; 84(9): 587-90
AFRIKAANS; NON-ENGLISH
TI:
AU:
AD:
HIV testing and informed consent—ethical considerations.
McLean-GR; Jenkins-T
Department of Philosophy, University of the Witwatersrand,
95
of
162
96
of
162
Johannesburg.
SO: S-Afr—Med-J.
LA: ENGLISH
1994 Oct;
84(10):
669-74
97
of
162
98
of
162
99
of
TI: AIDS and the emergency room physician and staff.
AU: Hirsh-HL
AD: Department of Health Care Administration, George Washington University,
Washington, D.C.
SO: Leg-Med. 1994: 201-28
LA: ENGLISH
162
100
of
162
101
of
162
TI:
AU:
SO:
LA:
The right to health care: an inevitable collision.
Flecker-CA Jr
Gen-Dent. 1994 May-Jun; 42(3): 256-7
ENGLISH
TI:
AU:
SO:
LA:
EEthics and health care reform!
Callahan-D
Cas-Lek-Cesk. 1994 Dec 22; 133(24):
CZECH; NON-ENGLISH
TI:
AU:
SO:
LA:
772-4
Some moral problems in medicine Eeditorial!
Warnock-M
Health-Econ. 1994 Sep-Oct; 3(5): 297-300
ENGLISH
TI: The role of ethics in quality and accountability initiatives.
AU: Veatch-RM
AD: Kennedy Institute of Ethics, Georgetown University, Washington,
SO: Med-Care. 1995 Jan; 33(1 Suppl): JS69-74; discussion JS74-6
LA: ENGLISH
DC 20057.
102
TI: Profiling and performance measures. What are the ethical issues?
AU: Povar—G
AD: Department of Health Care Sciences and Medicine, George Washington
University School of Medicine, Washington, DC.
SO: Med-Care. 1995 Jan; 33(1 Suppl): JS60-8
LA: ENGLISH
TI: Medicine's industrial revolution is here.
AU: Hadler-NM
SO: J-Occup-Med. 1994 Sep; 36(9): 1038-40
LA: ENGLISH
TI:
AU:
AD:
SO:
LA:
Marginal capacity: the dilemmas faced
Ho-V
University of Toronto.
Can-Med-Assoc-J. 1995 Jan 15; 152(2):
ENGLISH
TI:
AU:
Rationing heal th care:
Wachter-RM
in
Rally the Luddites
of
103
of 162
Eeditorial!
104
of
assessment and declaration.
162
259-63
105 of
preparing
162
for a new era.
162
AD: Division of General Internal. Medicine,
Medical Center, CA.
SO: South-Med-0. 1995 Jan; 88(1): 25-32
LA: ENGLISH
San Francisco General
Hospital
106
of 162
TI: Ethical issues in managed care. Council on Ethical and Judicial Affairs,
American Medical Association [see comments!
AD: Council on Ethical and Judicial Affairs, American Medical Association,
Chicago, IL 60610.
SO: JAMA. 1995 Jan 25; 273(4): 330-5
LA: ENGLISH
107
of
162
TI: [Hemosurveillance: ethical and medicoeconomic constraints!
AU: Duprez-A
AD: CHU Hopital Central, Nancy.
SO: Cah-Anesthesiol. 1994; 42(3): 411-4
LA: FRENCH; NQN-ENGLISH
TI: The yin and yang of heal th care system reform. Professional
strategies for setting limits.
AU: Daniels-N; Sabin-JE
AD: Department of Philosophy, Tufts University, Medford.
SO: Arch-Fam-Med. 1995 Jan; 4(1): 67-71
LA: ENGLISH
and
108
of 162
political
109
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TI: Living wills and resuscitation preferences in an elderly population.
AU: Walker-RM; Schonwetter-RS; Kramer—DR; Robinson-BE
AD: Division of Medical Ethics and Humanities, University of Sou-th Florida
College of Medicine, Tampa.
SO: Arch-Intern-Med. 1995 Jan 23; 155(2): 171-5
LA: ENGLISH
TI:
AU:
SO:
LA:
162
110
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111
of
162
112 of
162
113 of
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Doctors and society—the Biko Lecture [editorial!
Hoffenberg-R
S-Afr-Med-J. 1994 May; 84(5): 245-9
ENGLISH
TI: Experimental
AU: Lie-RK
SO: Soc-Sci-Med.
LA: ENGLISH
treatment,
1994 Oct;
values and rationing
39(8):
[editorial!
1011-4
TI:
AU:
SO:
LA:
Treating HIV infection: a question of ethics
Pegram-PS
N-C-Med-J.'1994 Nov; 55(11): 512
ENGLISH
[letter!
TI:
AU:
SO:
LA:
Treating HIV infection: a question of ethics
Levine-RH
N-C-Med-J. 1994 Nov; 55(11): 512
ENGLISH
[letter!
stinos-Cent-Rep.
LA: ENGLISH
1994 Sep-Oct;
24(5);
36-8
TI: The technological tether. An introduction to ethical
high-tech home care.
AU: Arras-JD
SO: Hastings-Cent-Rep. 1994 Sep-Oct; 24(5): Sl-2
LA: ENGLISH
and
social
126 of 162
issues in
127. of 162
TI: Randomized prospective trial of estrcgen-replacement therapy in women with
a history of breast cancer.
AU: Vassilopoulou-Sel1in-R; Theriault-RL
AD: Section of Endocrinology, University of Texas M.D. Anderson Cancer Center,
Houston 77030.
SO: Monogr-Natl-Cancer-Inst. 1994(16): 153-9
LA: ENGLISH
TI:
AU:
AD:
SO:
LA:
128 of
CPrioritization of fertilization in vitro—a systematic analysis!
Ruyter-KW; Forde-R; Norheim-OF
Senter for medisins'k etikk, Gaustadal leen 21, Oslo.
Tidsskr-Nor-Laegeforen. 1994 Sep 30; 114(23): 2735-8
NORWEGIAN; NON-ENGLISH
162
129 of 162
TI: United States and Canadian approaches to justice in heal th care: a
comparative analysis of health care systems and values.
AU: Jecker-NS; Meslin-EM
AD: Department of Medical History and Ethics, University of Washington, Seattle98195.
SO: Theor-Med. 1994 Jun; 15(2): 181-200
LA: ENGLISH
/
TI:
AU:
SO:
LA:
130 of
162
131
of
162
132
of
Ethical dilemmas for general practitioners under the UK new contract.
Smith-LF; Morrissy-JR
University of Western Ontario, Canada.
162
How much ethics is needed to be a good doctor? £ letter!
Chowdhury-AW
Lancet. 1994 Dec 24-31; 344(8939-8940): 1774
ENGLISH
TI: In defence of ageism.
AU: Shaw-AB
AD: Bradford Royal Infirmary, West Yorkshire.
SO: J—Med-Ethics. 1994 Sep; 20(3): 188-91, 194
LA: ENGLISH
TI:
AU:
AD:
SO:
LA:
J-Med-Ethics.
ENGLISH
TI:
AU:
AD:
SO:
LA:
133
Bioethics in developing countries: ethics of scarcity and sacrifice.
Olweny-C
University of Manitoba, Canada.
J-Med-Ethics. 1994 Sep; 20(3): 169-74
ENGLISH
1994 Sep;
20(3):
175-80
TI: Minimal breaches of confidentiality in health care research:
perspective.
AU: Emson-HE
AD: Royal University Hospital Saskatoon, Canada.
SO: J-Med-Ethics. 1994 Sep; 20(3): 165-8
LA: ENGLISH
TI: Equality, explicitness, severity, and rigidity:
from a Scandinavian perspective.
AU: Hansson-LF; Norheim-OF; Ruyter-KW
AD: Center for Medical Ethics, University of Oslo.
SO: J-Med—Philos. 1994 Aug;' 19(4): 343-66
LA:
of
162
134
of
a Canadian
162
135
of 162
the Oregon plan evaluated
ENGLISH
136
of
Institutes of
162
137
of
TI: It is time to emerge from the trench and survey the whole battlefield.
AU: Lamm-RD
AD: Center for Public Policy and Contemporary Issues, University of Denver.
SO: Camb-Q-Healthc-Ethics. 1994 Summer; 3(3): 403-4
LA: ENGLISH
162
138
of
TI: Outside the Garden of Eden: rural, values and healthcare reform.
AU: Brown-KH
AD: Center for Health Policy and Ethics, Creighton University, Omaha, NE.
SO: Camb-Q-Healthc-Ethics. 1994 Summer; 3(3): 329-37
LA: ENGLISH
162
139
of
Conclusion to a
162
TI: Joseph J. Jacobs on alternative medicine and the National
Health [interview by Thomasine Kushner and Charles MacKay!
AU: Jacobs-JJ
SO: Camb-Q-Healthc-Ethics . 1994 Summer; 3(3): 442-8
LA: ENGLISH
I: Ethical issues in physical medicine and rehabilitation.
series.
AU: Haas-JF
SO: Am-J-Phys-Med-Rehabi1. 1994 Nov-Dec; 73(6): 436-40
LA: ENGLISH
140 of
TI: The future of medicine [editorial; comment!
AU: Morrison-I; Smith-R
SO: BMJ. 1994 Oct 29; 309(6962): 1099-100
LA: ENGLISH
162
141
TI: Managed competition and managed care. What are the ethical issues?
AU: Jecker-NS
AD: Department of Medical History and Ethics, University of Washington,
Seattle.
SO: 01in-Geriatr-Med. 1994 Aug; 10(3): 527-40
LA: ENGLISH
of
162
142
of
162
of
162
TI: Tube-feeding decisions in the elderly.
AU: Hodges-MO; Tolle-SW
AD: Department of Medical Education, Providence Medical
Oregon.
SO: Clin-Geriatr-Med. 1994 Aug; 10(3): 475-88
LA: ENGLISH
Center,
Portland,
143
TI: Dialysis decisions and the elderly.
AU: Moss-AH
AD: Center for Health Ethics and Law, Robert 0.
West Virginia University, Morgantown.
SO: Clin-Geriatr-Med. 1994 Aug; 10(3): 463-73
LA: ENGLISH
Byrd Health Sciences Center of
144
TI: The life and death of Miss Mildred. An elderly black woman.
AU: Dula-A
AD: Center for the Study of Ethnicity and Race in America (CSERA),
of Colorado at Boulder.
SO: Clin-Geriatr-Med. 1994 Aug; 10(3): 419-30
LA: ENGLISH
145
Economic aspects of the care of patients in
Sailly-JC
Universite Catholique, Lille.
Acta-Neurol-Belg. 1994; 94(3): 155-65
ENGLISH
162
University
TI: Ethical issues and the breast cancer patient.
AU: Cummings-NB
AD: National Institute of Diabetes and Digestive and Kidney Disease,
Institutes of Health, Bethesda, Md 20892.
SO: Arch-Pathol-Lab-Med. 1994 Nov; 118(11): 1077-80
LA: ENGLISH
TI:
AU:
AD:
SO:
LA:
of
of
162
National
146
the vegetative state.
of
162
147
of 162
TI: Discontinuation of total parenteral nutrition in a patient with acquired
immunodeficiency syndrome: a Canadian perspective.
AU: Knowles-JB; Gilmore-N
AD: Nutrition Support Service, Deaconess Hospital, Evansville, IN.
SO: Nutr-Rev. 1994 Aug; 52(8 Pt 1): 271-4
LA: ENGLISH
148 of
:
AU:
AD:
SO:
Health care as a right: some practical implications.
Giesen-D
Institute for Private Law, Free University of Berlin,
Med-Law. 1994; 13(3-4): 285-96
Germany.
162
LA:
ENGLISH
149 of 162
TI: Medicolegal problems arising from AIDS and health care personnel with
special reference to Spanish law.
AU: Gal 1ego-Riestra-S; Martinez-Jarreta-B; Hinojal-Fonseca-R; Sahchez-Caro-J
AD: Catedra de Medicina Legal, Facultad de Medicina, Universidad de Oviedo,
Asturias, Spain.
SO: Med-Law. 1994; 13(3-4): 241-9
LA: ENGLISH
'
TI: Ethical issues in genetic therapy.
AU: Penticuff-J
AD: University of Texas at Austin 78701-1499.
SO: J-Obstet—Gynecol-Neonatal-Nurs. 1994 Jul-Aug;
LA: ENGLISH
23(6):
Ethics in managed care.
Fromer-LM
Hosp-Pract-Off-Ed. 1994 Nov
ENGLISH
TI:
AU:
AD:
SO:LA:
The democracy problem [comment]
Baily-MA
George Washington University, Washington, DC.
Hastings-Cent-Rep. 1994 Jul-Aug; 24(4): 39-42
ENGLISH
TI:
AU:
AD:
SO:
LA:
To whom? [comment]
Kamm-FM
New York University, New York.
Hastings-Cent-Rep. 1994 Jul-Aug;
ENGLISH
TI:
AU:
AD:
SO:
LA:
Four unsolved rationing problems. A challenge [see comments]
Daniels-N
Philosophy department at Tufts University, Medford, MA.
Hastings-Cent-Rep. 1994 Jul-Aug; 24(4): 27-9
ENGLISH
/
TI:
AU:
SO:
LA:
Responsibility and justice ... an ethical
Reynolds-C
Iowa-Med. 1994 Aug; 84(8): 344-6
ENGLISH
29(11):
24(4):
TI: Health care reform and professionalism.
AU: Wennberg-JE
AD: Center for Evaluative Clinical Sciences,
NH 03755-3863.
SO: Inquiry. 1994 Fall; 31(3): 296-302
LA:
162
151
of
162
152
of
162
153
of
162
154
of
162
498-501
TI:
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15;
150 of
51-2
29-32
balance
155 of
162
156 of
162
[comment]
Dartmouth Medical
School,
Hanover
ENGLISH
157 of
162
TIs Good clinical research practice in Canada.
AU: Chen-MJ; Scarth-BJ; Slack-CJ
AD: Research and Development Department, Ciba-Geigy Canada Ltd.,
Ont.
SO: Can-Med-Assoc-J. 1994 Nov 1; 151(9): 1255-7
LA: ENGLISH
Mississauga,
158 of
f
Anticipated changes in the doctor-patient relationship in the managed care
managed competition o-F the Health Security Act o-F 1993.
La-Puma-J
Department o-F Medicine, Lutheran General Hospital, Park Ridge, Ill.
Arch-Fam-Med. 1994 Aug; 3(8): 665-71
ENGLISH
TI:
AU:
AD:
SO:
LA:
159 o-F 162
Psychotherapy—a luxury the NHS cannot a-F-Ford? More expensive not to treat.
Holmes—J
Northern Devon Healthcare Trust, Barnstaple.
1994 Oct 22; 309(6961): 1070-1
ENGLISH
TI:
AU:
SO:
LA:
To treat or not to treat.
Strong-M
Trends-Health-Care-Law-Ethics.
ENGLISH
TI:
AU:
AD:
SO:
LA:
The Emperor's new scrubs: thoughts about heal th care reform.
Beiser-EN
Brown University School of Medicine, Providence, Rhode Island.
R-I-Med. 1994 Sep; 77(9): 304-6
ENGLISH
I
9
►
)
>
)
)
162
TI:
and
AU:
AD:
SO:
LA:
1994 Winter;
9(1):
160
o-F
162
161
o-F
162
41
162
of 162
TI: Ethics, so far.
AU: Alexander-E
AD: Department of Neurosurgery, Bowman Gray School of Medicine of Wake Forest
University Medical Center, Winston-Salem, N.C. 27157-1029.
SO: Pediatr-Neurosurg . 1994; 21(1): 2-5
LA: ENGLISH
■
....
•
V- ’ ’
, S
,V■
INTERVENTION IN HEALTH
J
(A People's Science Movement Programme)
"
''
'
25 Questions
" (
r
A DRAFT FOR DISCUSSION "
i Q-l, What is doe PSM planning in the health sector?
A_1 The PSMs are trying to evolve a programme that
a)
MBpEOves she health conditions of the poor.
the rtatus of health of the poor in India is amongst the worst in the world.
Almost all infant deaths and deaths at child birth are preventable. The
resurgence of communicable diseases can be checked. And the quality of
life can be increased considerably - now I
b)
uses health as an arena for mobilisation of the weaker section
The causes of ill-health lie in poverty and the poor working and living
conditions of the people. A better understanding of health leads to this
realization and therefore a health movement becomes part of a larger mass
movement against exploitation and oppression.
c)
uses inter cation in health as an opportunity to empower people.
People need more knowledge, skills and organisations to improve their
quality of life and increase their say in local and national decision making.
This is what we understand as empowerment. The nature of intervention
in health is (designed to promote such empowerment,
d)
uses interventions in health to facilitate structures especially panchayats that would
enhance people’s power and sustain the gains.
e -
,
Health care must necessarily be planned for and implemented in a
decentralized integrated, holistic fashion. Unless the panchayats are
transformed, as well as simultaneously the nature of planning for and
implementing health programmes changed a more effective public heahh
policy will not emerge. Our programme must be designed to promote
these objectives.
■a)
win tave an impact at a national or at least regional levels:
One may have to start small. But unless the movement is eventually big
enough it will fail to have an impact on policy making and it will be
difficult to sustain. So our programme design must necessarily be
replicable. It cannot be an understanding of NGOs delivering beahh by
themselves or even as a parallel structure.
Q-2-
What are the bread outcomes expected from the programme that one is (ksigmag the
programme for ?
A3. a)
b)
c)
d)
*)
f)
g)
■ better utilixation of exiting health facilities.
Better community awareness and participation in health programmes.
Better role for panchayats in ensuring accountability of health system.
Better mechanism for gathering health data and disease surveillance
Effective dcccntndizad planning for health (with |>anchayats and health personnel
in purtnersiup)
Greater public awareness and emphasis by health system on preventive and
promotive aspects of health care.
All the above must lead to measurable improvement in the health status of the
population as well as a more active role for people in a transformed paochayaL
W
Q-3- - What activities coeki lead to the above outcome^ ?
A3. The main activity areas identified are as follows
-
a) child health
b) women’s health
c) waterborne diseases
d) other coaunumcable and endemic diseases
e) disease surveys and disease surveillance
f) curative care.
in each of these these areas there can be three types of activities:
coordinated village level action - This will serve a mobilisational and educational
,
purpose and ensure community participation. Certain specific intervention’s can
only be done by such group activity.
- b)
Individual person to person contacts: For meaningful impact on people’s life and
for the community to take the programme seriously, this is essential.
2
£
I
.
<• c)
Q.4.
• Adnunistntive/Poiitical action: Some steps for example provision of adequate
drugs in the PHC, launching a food for work scheme in a particular area - can
only be dooe by the state itself. Here the role of the programme is to act as a
pressure group for this and ensure accountability of such functions.
Specifically what can be dooe in child health in tune with the approach that has been
outfened?
A.4. The suggestion is that every hamlet covered maintain a register that lists every child
below 5. The lift must be comprehensive taking special care not to miss out that 'last
5 per cent’, that is the poorest and most marginalised sections. Then the immunization
ttatm of each child is entered and so too is the weight of every child, along with what
level of malnutrition the weighing indicates. This process help us identify the
malnourished child/classified as Gr.l, 11 and 111. These people constitute the most
vulnerable sections. The rest of the programme then becomes primarily the task of
talking to the mother, assisting her to find ways and means to cope with child care given
her limited time and money resources. Only well-trained health activists, provided
excellent quality of support by the district or block team, can carry this out effectively.
The health activist must have the skills to analyze and understand the mother and child’s
problem and suggest the solutions most appropriate to that specific context. In this
process not only will they be able to ameliorate the malnutrition of the child but as part
of domg this they will attend to completing immunization, deworm the child, give
vitamin A supplements and appropriate timely management of diarrhoea and A.R.I.
Indeed malnutrition cannot be managed without all these measures. Thus focussing on
matamtnuoa becomes a focus on child health as a whole.
Q.6.
But this is a difficult task ! Why hot just focus on a single item - immumsatkxi or
diarrhoea control, etc - at least in the beginning.
Firstly all these problems of child health are closely inter-related and even if one wants
one cannot handle one without the other. Immunization alone can perhaps be done but
with a lot of effort and proportionately little impact on overall child mortality and
morbidity. Secondly how can one sustain these interventions if done singly ? And finally
if we are seriously talking to mothers it would neither be possible nor desirable to talk
to mothers about ARI and about diarrhoea and not about malnutrition, etc. Perhaps
immumzaiKxi is the only single point intervention that can be dooe without talking to
mothers about other aspects of child health and since it falls within the dominant
perception of health as something delivered through injections and drugs it can still get
accepted. For precisely this reason we would not take up immunization alone. Taking
up child health with a fricus on malnutrition has another advantage - it forces the
programme td identify the most deprived and to interact with such families. An
immunization campaign may be 90% successfull and still miss the most needy.
3
Q.7. Ba era our intervention make any impact on malnutrition ? After all this is mainly
» ' rrtord to poverty about which this approach can do little.
A.7. Poverty’s relationship to malnutrition is a bit more complex than simple cause and effect,
or a simple failure of not enough money to buy food. A number of wrong or sub-optimal
feeding practices, wrong perception of disease and health care and a wrong poonuzaoon
of time and resources contribute to malnutrition. A child from a more well off faintly
may still get enough food and care despite wrong priorities but^in a poor household
every rupee counts and any assistance to more efficiently utilise scant resources is
welcomed greatly by the mother. Still one cannot expect wonders.
In a good one or
two year programme we can hope to reduce grade 111 malnutrition significantly and to
some extent prevent under 5 deaths. We are less likely to have an impact on Gr.l and
11 malnutrition. In such parameters one many need a generation of work for the impact
Q-8.
Q.l
to become measurable !
But bow does one make this a campaign? The work described looks more like a person
to pereca to interaction done by health activists, rather than a mass campaign.
1b the total literacy campaign too, transaction of the primers was a person to person
■trrartion. Yet we found enough occasions to generate the environment by well chosen
campaigns. We must remember this relationship. Environment building and propaganda
campaign without an individual follow-up makes the whole programme lack depth and
seriousness (Imagine literacy jathas withou. any attempt to make people literate). On the
other hand without environment building individual level action meets too much resistance
and become impossible. In an area of child health too we can have balmelas or use
camps to weigh children and immunization camps as environment building activities. The
possfoilities are limitless. The general principles are the same.
Q.9. What about women’s health ? How do we propose to approach this area.
AA A wide variety of approaches are possible, depending both on the status of women and
* ■< fornt of dtacriminstion prevalent in that area as well as the efficacy of existing health
care delivery systems. In the worst states like in Bihar we are suggesting a major focus
on raising the age of marriage. This may even be taken up as a broad-based social
reform movement At the village level one may consider forming village level
coounitlees to oversee this.; Other women’s support activities like credit cooperatives
(thrift groups) may be integrated with this. Even where age of marriage is not the central
issue, the promotion of credit cooperatives, village libraries and counselling, support and
information centres catering especially (if not exclusively to women) may form the central
ooordmMed action.
tf such activities form the coordinated village level action, the individual level action will
largely relate to ensuring that all pregnant women received ante-natal care from trained
ANMs and have a trained dai to attend Io delivery. Of course in those areas where no
AN Ms are avadable or willing to undertake this work the health activists may have to
provide such care herself, (in which case she should he eventually absorbed as ANM).
The health activists will also need to be equipped to help women with primary health care
for simple reproductive tract ailments and provide counseling for planning her family
Q.10. What are our commitments to the family planning programme ?
A. 10. We do rxx plan to undertake any campaign for family planning as such We expect that
our work tn lowering infant mortality and in raising the age of marriage as well as
providing support to women will in themselves prove to be an excellent promotion of the
small family norm. Besides as part of provision of maternal care and reproductive health
care we hope to equip the health activists to lie in a jxisition to provide a high quality of
advice, especially for spacing. All this we expect to be reflected in better utilisauon of
MCH as well as family planning services in the sub centre and PHC level and may even.
over time be reflected in lower fertility rates. However (hough we can study lite impact
on our work on such parameters, we will not have or accept any target whatsoever lor
family planning.
Q. 11. The government of India and state governments have a major structure for just these
purposes (child and women health). How does our programme relate to it ? How do the
health activists of our programme relate to the health work of the government.
A. 11. The health activist is the village or hamlet level assistance tor the health worker who has
far too many houses spread over far too wide an area to cover effectively. There fore the
health worker harassed and overworked as she is should welcome such assistance And
we must plan to build as strong links as possible between them.
The health activist is also the means by which the community learns about the work ot
the health worker and monitors it and. builds up accountability of the health structure
To this extent the health activists (or for that matter this programme) may not be
welcomed by health workers or local health authorities. This is one reason why it is
necessary to keep health activists (or the earlier concept of village health guides etc 1
under an independent body or district level NGO and not place it under the health
authorities
But there are certain functions of the health activists, as conceived, which are distinct
from the health worker and have little overlap. The definition of the health activists as
coordinating village level action (for example holding a balmela or organizing a credit
cooperative) i.e., in mobilisation of people as well as in acting as the nucleus ol a kxal
pressure group ^or medical administrative or political action is one aspect that clearly
demarcates and differentiates them from the health workers.
Finally one must n<Xe that while the government programme claims to cover women and
child health, in practice it focus exclusively on family planning and immunization, with
some attention to ante natal care and training dais. In other areas like addressing child
malnutrition, and other causes of child mortality as well as in addressing issues like age
of marriage or reproductive health etc government programmes are often non-existent on
the ground.
Q 12. What are the expected achievements in terms of the status ol women’s health ?
what conditions can we hope to improve achievements ?
Under
A. 12. The bottom-line should be marked increase in the utilisation of all government presided
services available at the sub-centre and PHC. Today, even where extensive
infrastructure is created and there arc adequate personnel. utilisation of services i'
extremely low. If the administration plans its actions jointly with our programme and
implements needed steps on its side one can hope for a reduction increase in maternal
mortality and morbidity
The spin offs from this campaign towards women’s
empowerment will be considerable it care is taken about the processes employed Greater
partKipatHin of women, erosion of negative cultural stereotypes creation of women’s
credit cooperatives, a higher age of marriage and
*stronger
local women’s organisation and
movements can be expected outcomes from our intervention in women’s health
Q. 13. What are the possibilities for intervention in water-borne disease which accounts for the
greater part of ail preventable diseases.
A. 13. This is a question really of promoting sanitation at the personal, home and community
level as well as the provision of safe drinking water. Existing sanitation programms are
a dismal failure and even the provision of safe drinking waler is far from achieved. A
detailed understanding of these failures is essential but cannot be gone into here One
needs to construct an alternative approach. The basic principles of such an alternative
approach are
a)
The provision of safe drinking water must be a pan of a comprehensive watershed
management programme, using locally appropriate technology and involving the
community in planning and in maintenance of such water sources.
b)
Sanitation programmes must be comprehensive and planned for and implemented
by the panchayat bodies assisted with adequate technical and financial resources
and with the people’s involvement.
c)
Whereas community facilities (e.g., overhead tanks, common borewells.
standpost, community latrines, etc) are built for at the state’s expense, individual
level facilities like domestic latrines, must be paid lor by individuals. Subsidies
must be very limited and if any is provided must be targeted only for tbe poorest
and that too when the majority of the village have adopted the culture of using
6
toilets. On the other hand credit facilities, especially Linked to credit cooperatives
can be made available more liberally.
d)
The provision of safe drinking water and sanitation facilities - not only latrines but
all maMMion related products - soaps, tooth [xiwder. smokeless chultahs. etc must
become part of a huge employment generation programme and so structured that
the employment and income so generated goes to weaker sections. Since both the
generation of demand for these products and the considerable credit needed as
well as the costs of community level structures all come from the government. it
is important to ensure that the programme is so planned that the beneficiaries are
not a few rich contractors but preferably cooperatives and groups of rural woosn
acd youth.
Sense of these concepts have been tried out successfully in Midnapore district. They need
to be replicated elsewhere but so far it has not been possible to generate the intra
organcatjoaal will needed for this. This concept known as the ‘sanitary mart concept’
involves its own environment building,
*
production centre and a mechanism of sales of
such products. (Further details can be had on request).
Q. 14 What are the possibilities for control of other communicable disease (other than water
borne disease and immunisable diseases).
A. 14 This is specific to each disease. Ideally a district authority or better still each PHC must
draw up an estimate (based on surveys and analysis of outpatient data) of the numbers and
nature of various diseases in that area. Then based on which diseases are causing the
maximum loss o life of disability as well as a consideration of where there are
poMtbditiat of intervention, the diseases must be prioritised. Then working with the
panchayats and NGOs a programme for their control must be evolved out (Such an
approach is an contrast to the present vertical programmes where priorities and methods
are decided in the stale or national capital).
.
, To demonstrate the viability of such an approach it would be an excellent idea for our
programme to take up control of one or two communicable diseases, in each district.
Q,15. Could we have any examples of a successful campaign against any infectious disease.
A. 15. There are few. There is case of the programme against tuberculosis in Bangladesh.
There is (he Khcda malaria control programme and there are many examples of leprosy
control.
a u. Ixt us see the example of tuberculosis (as adapted for our needs).
x ■> A case detection camp for tuberculosis is held with adequate publicity and preparation.
The camp is advertised as a camp for all respiratory diseases so as to improve attendance.
\-rrer a doctor sad a few MPWs can conduct it. The suspected cases of tuberculosis are
subject to sputum examination then and there. Home to home visits and follow up ensure
that bo possible case is left out. The confirmed cases are all entered into a register. The
Becewfty of eirmring that all of them take treatment for 9 months without break is not
caty explained to them but they are also required to sign or state a pledge to that effect
before village elders. In some villages they were asked to give a money deposit also.
(This deposit would be paid back once they completed the course). Then the health
department (with some special mobilisation of resources) ensures ituh the local l‘HC has
adequate stock of drugs and the health activists ensure its distribution. Such simultaneous
identification and adequate treatment of all TB cases in an area is indeed the only sound
approach to TB control. BCG has little value and just identifying a given number of
cases per year and treating it will have no impact on stopping the spread of tuberculosis.
The control of leprosy uses a similar approach. Only the case detection camp for leprosy
is conducted as a skin diseases camp. A considerable amount of pyoderma and impetigo
aad scabies and ring worm would therefore in the process get identified and treated too.
The control of malaria on the other hand requires a much more Jmer-dtscipiinary
approach and much higher degree of organisation and community support and a much
higher degree of state commitment. Results will take longer and need a greater input to
sustain But it is essential to reiterate that not only is a campaign against malaria
possible, it would be ethically and practicady impossible to ignore this problem in many
places where malaria has a high endemicity.
Similar cpecific programmes against goiter, fluorosis or other health priorities can also
be thought of.
Q. \b. Why not take up a single disease like malaria for a national campaign. Would H not have
ir,.-. a More vwbte and concrete impact ?
A. 16. To fully understand why we do not recommend a campaign against a single disease one
■test felly understand our critique of the vertical health programmes and the causes
behind the resurgence of infectious disease like malaria. For more drtat Is eotuuct us
separately). Our intervention must be adequate to reinforce the health delivery system
- ' as a whole in a given area and mobilize people and initiate local level planning for health.
Necessarily therefore we must focus on local priorities and locally appropriate actioa
plans instead of carry through a programme as part of a single point oauonai plan.
Besides for a disease like malaria in most districts the incidence will be less than 5 per
1000. Thai is a very high incidence but it does not create enough affected in a village to
catch public attention readily. Only in those districts where the incidence is much higher
or there is an epidemic outbreak will it become a public issue. It is therefore much more
important in any participatory process, to identify the local priority, rather than declare
one disease as priority centrally and then seek local community participation for it in each
dxstnet, irrespective of how much that central priority is a local one.
8
Whar ©23 we do
'
dJcs^ca curveillanca and health intelligence ?
A. 17? These are essential inputs for health planning and at present these mechanisms are
virtually aoo-estiaesa or non-functionaJ. The government must more towards evolving
viable district and block level health and disease surveillance mechanisms, that will be
needed for local planning for health. We need to evolve and field test viable cost
effective models for such disease surveillance (and health planning).
-■ Owe viable example is the ‘NATH1 model’ run by a department in CMC hospital Vellore
with the Tamil Nadu government public health department. (This programme provides
disease surveillance of ten diseases in the districts of North Arcot and Th inivanna ma lai
Tins model has the advantage of involving a large number of private practitioners as
weH. It also provides regular inputs to health professionals oo disease profile in the
district and update them on therapeutic aspects of these disease. (For more details contact
* separately).
Of course any such disease surveillance necessarily must be as a joint programme with
fee
We hope to draw up a few such projects soon.
Wte this present programme however we need to maintain a much better surveillance
of ctnkS sesI maternal mortality. Unless this is done we cannot even ensure effectiveness
of our own programme. This surveillance therefore is planned as a record of all births,
deaths, pregnancies and marriages, maintained by the health activists with the assistance
of health committee members. Guidelines have been evolved on the exact techniques of
dcritg tfsta and these too if not already with you are available on request.
Q. 18. What about curative care ? Most people feel that unless we attend to curative care - thexr
Mtaswds <* no amount of emphasis on preventive care will be acceptable ?
A. 18. This is a difficult question. We know for example that a number of CHWs have set
themselves up as RMPs ( a local term in use to denote a 'quad.' medical practitioner).
Indeed it has been noted by some that when health workers function as curative
practitioners, they have much better acceptance from the community. Do we accept or
promote this tread in our health activists ? Some would say yes. Others would say no.
A general consensus is that at least for two years they must be mobi liters, educators and
preventive cure practitioners rather than provide curative care. They can be trained in
noo-drug remedies and management of some common ailments especially pertaining to
ctnid and women health but they do not become barefoot doctors. If their lack of ability
to give curative care is a handicap so be it. We will work actively for the coaummiry
Jo ice the health activist and thereby health as something more than curative care. The
comtnurnty learn to value and appreciate the visible impact made on child hcakh and
women’s health especially by the health activist’s interventions.
9
SKaukanecusiy we can act as a pressure group to ensure adequate curative care at PHC
acd tafek/Nock levels. This will mean finding out whether doctors are attending
regularfy, whether adequate essential drugs are available, whether bask diagnostk
faciJjces are functional and in preventing malpractice and irrational curative care. There
is considerable scope in letting people known of the list of essential drugs that should be
available and of the banned drugs and commonly used irrational drugs whkh waste their
money.
A few groups have initiated work in promoting the growing of coinmohly used mcdkmal
plants ta kitchen gardens and training health workers to use them for some common
ailments that are needed at the primary care level. Growing medicinal plants ax an
economically viable activity, processing them and selling them to local health care
practrtioaers who use them have also be conceptualized though no such programme is on
the ground anywhere to the best of our knowledge.
Q.19. What of the RMPs and ayurvedic and folk doctors and homeopathic doctors. Does the
programme concave involving them ?
A. 19. Fust one has to recognize the fact, that it is these categories that in most places today
provide the bulk of the primary -first level contact - curative care. The RMP is almost
invariably someone who has worked as a doctor’s assistant for a few months who has set
himself or herself up. It may also be noted that when a qualified pracuoner is available
many people prefer him er her as against an RM? but in most villages or even within 5
to 10 Km. no such doctor is available. Should we then involve the RMP ? Will they use
it to legitimize their case ? Car. we upgrade their skills ? These have to be worked out.
But certainly one can involve them l or surveillance of diseases as well as preventive care.
Much more thought and experience and study is needed on this question. However we
should be more ready to involve ‘well’ qualified ayurvedic and homeopathic doctors.
Q-20. What about the qualified MBBS doctors? What role can the play in this programme ?
“ " Findy we must be worried that the prevailing cultures and structure of the medical
profeaMoaal does not promote their involvement in such programmes. Most will be
apathetic and some may even be hostile. We should be ready for this. However property
' approached a number of them may support this programme and contribute in the
1 10
a)
’
b)
May attend public functions, inaugurate workshops and can see patients in case
detection health camps.
Many may participate in disease surveillance efforts as most patients of certain
types of disease wiU be seen by them.
to
c)
d)
May be of help in certain session of the training workshops- if given proper
training material and training evaluation forms well in time. Please note that most
doctors have no exposure to practical aspects of preventive health or even curative
care at the level the health activist will encounter these problems. So without
their using training material and being shown the evaluation forms it is not
advisable to involve them.
May lead their names for the district level health committee. This is an important
need.
' • it would be the invaluable if one or two doctors at least are PSM activists and in this
capacity get involved in the district team. This will lead to a much better programme
planning. The aim must be therefore to constantly educate friendly doctors on PSM
*
pcrrpectrve
and provide them with related information so that they develop their
capabilities and are able to consciously rebel against the dominant negative trends in the
medical profession trends which have played such a large role in creating an inadequate
heakfa care system and a retrogressive culture of health. At present many doctors who
are as PSMs have developed this consciousness, and much of this was initiated by their
being sensitized to these issues in rational drug prescription.
Even oow it is essential to work amongst doctors on such issues as rational drug
prescription, ethical issues in health care, medicial education methodologies so as to
craarientrae doctors to health policy concerns.
It may be pointed out that networks like AIDAN & NCCDP, and organisations like MFC
and drag action forums, journals like Radical Journal of Health and Health Action and
institutions Ike VHA1 and FRCH, JNU social medicine dejiartinent, to name a few have
played a major role in initiating and developing this critique of health policies in India.
What is being called a PSM understanding is not only the work of PSM organisations like
KSSP, and DSF and PSF in health, but also of such other forces as named above. Such
networks, organisations, institutions and journals continue to have relevance today and
must be drawn upon to constantly provide intellectual inputs to develop our programme.
Any one-upmanship in our approach to such groups will cost us dearly. What we need,is
to, in parallel with this programmes, continue work with groups and on our own to
devetopour theoretical understanding of the crisis in medicine and in health care delivery,
as weU as a theoretical understanding of the alternatives.
Q .21. But if not doctors who can lead the programme - both at district and block levels.
A_21. At present most persons emerging in this role are social activists, who are working on
health issues for developing an approach to social change. This commitment is crucial.
In terms of backgrounds wc would emphasize that at least half - if not more of the team
at district and bkkk level must be women. The main reason for this is that at the village
level this is largely (like in literacy) a women’s movement. In terms of qualification,
persons with paramedical training - health workers, nurses, health educators and
fltpervisors, anganwadi workers etc are the best. They will also make the Lest quality
of Cramers (of course after some unlearning and some learning). Where the programme
is being done as a project in collaboration with the government wfe should be able to
identify two or three persons from this section (i.e., paramedics) who are already
associated with people’s science movements and gel them on deputation for this role.
Two cautions however may be stressed. Firstly there must be no district or block level
organizers or coordinator who is not capable of or involved in the process of training and
providing support to health activists. Allowing a cadre of ‘pure’ organizers - persons
wkh no knowledge of the specific technical aspects - is a serious danger for this
programme.
Secondly whosever is providing such leadership must necessarily have some continuity
and (overt time and effort in developing capabilities - even if they are doctors - or health
workers. There is a lot of learning involved and persons not capable of this need not be
selected. (These warnings are made as sometimes some persons are selected on the basis
of loyalty, obedience and an abstract understanding of ‘being committed’ or ‘good
organizers' !*).
Q-22. Who are the health activists ? How is it planned to select and deploy them ? If voluntary
tor how tong and after that what ?
A.22. Every hamlet or habitation should have one or two women as health activists. In case
of large villages one would need about one per 200 households. More can be kept if
heads to train and support them are available. Ideally the health activist should be a
woman who is willing to spend part of her time on this work. If the person has enough
literacy to comfortably read a booklet or take notes and fill a register that would be
adequate. (This means about 5th class). Much more than this is not required. If a
■eoirterale committed to this programme is keen to play this role even this requiremcni
can be waived. (We should specifically try to not keep women who are interested or
likely to get jobs elsewhere).
At present there is no plan to pay any health activist. The work is fully voluntary. This
voluntarism u possible only when her work is a part of a health movement that is
people’s movement for health. There must also be a very good quality of support.
Without this mass movement approach and without regular support they can not continue
We expect the programme and health activists to continue for two years. After this what
will become of them in an important question that we must think about.
This will depend on the impact of the programme itself and on the quality of lhe
government structure. Where the government structure has been non-existent or weak
12
and unable to deliver, we can probably further Upgrade the skills of the health activist to
that of a health worker (ability to conduct delivery and basic curative care). Such a
health worker must be paid by panchayats. The panchayats in their turn must be
provided funds for these from the central and state health budget. But as this may take
time to get, one can even consider panchayat raising funds .for this. To prevent misuse
by panchayats in this situation, a district level support body to monitor and support the
. health activists must continue (probably by a district level NGO). If on the other hand
the government structure exists, its utilisation should improve and the health activists may
have less to do in future except provide some voluntary support to them. Even in a
situation where one has been unable to bring enough pressure to improve government
structure and their utilisation, the health activist must be able to continue as part of a
broad women’s movement (or a rural youth movement).
Q.23. How is the training planned ?
A_23. We are proposing that first the district team is trained. It may takerf 8 days initially with
two 3 or 4 day training after 6 month gaps. After the first eight days of training this
district team trains health activists for 5 to 15 gram panchayats (about 20 to 50 health
activists) and then conduct the programme in this 5 to 15 gram panchayats. The work
in these panchayats is seriously re-viewed and they learn from it. They also complete a
minimum reading in this area. This much can be done with little or no external funding.
Then the programme can be expanded to 3 or 4 blocks (about 100 to 150 gram
panchayats) and after this second year when enough resource person are available then
perhaps to the whole district.
The health activists themselves are probably better trained in 3 or 4 day camps conducted
ooce every 6 months, with a proper monthly review cum training meeting. Much of this
learning will be through inservice training Each spell of training will be on the
immediate focus of the campaign. However where it is decided to upgrade them into
health workers (preferably after 2 years) they should get a much longer at least 3 to 4
months training in a well equipped training centre where deliveries are conducted and
base curative care can be taught.
Q_24. What is the scale and duration of the programme ? What about funding ? In a given
programme does one expect to take up all objectives set out or only some of them.
A_24. This has to be decided upon both availability of funds and our preparedness.
There are broadly four types of situations where we may find ourselves. First is a
situation where there is no cooperation from either district or state authorities and no
project. Even in such a situation one can do a lot. Indeed interventions in health may
be one of the few intervention possibilities open to a PSM to keep their panchayat level
units active. Of course in such a situation one should invest in building up a good district
and block level team and then take up a few gram panchayats at a time and just one or
two themes, for example women’s health with child health or child health and malaria
13
and so on. Such activity can be critical in building up a capable health team and ia
str. agthensng our contacts .
'
A second situation is where there is no formal health project sanctioned, but one is able
to find or raise some money from various funding sources. For example a cotnmoo
situation is that post-literacy programme funds can be used for this purpose by the simple
expedient of choosing a suitable name like ‘health literacy project' or strengthening PL
through health literacy” or ‘functional literacy in health’ etc. Again organisations like
local charities, or some funds at a BDOs disposal or a body like Rotary etc can be tapped
for some one activity at a time e.g. a training workshop or an anci-TB campaign, etc.
About 6 districts in Tamil Nadu and 15 districts in the other states are today managing
like this
The third situation is when a formal proposal is submitted and approved. This is an
optimum situation for it provides a full time structure that is essential to provide the
health activists’ with support. Besides it allows a much larger area to be covered and
therefore a greater mass movement and impact. About 6 districts in the country today
have submitted such proposals to the Ministry of Health and Family Welfare. If in these
6 districts the health department is also ready to innovate a plan for health at the district
level an ideal situation becomes available for setting a new path in health care.
A fourth situation, which is true for most districts in the country is where the district
PSM team itself is not ready. Here througn a health education campaign, surveys and
perhaps some gram panchayats level work a district team should be built up. Even if the
government is willing to fund, we must not accept it. Invariably this would lead to
imptcmeacing a programme at conflict with our aims.
of the causes of ill health lie in the economic policies of the government - and
the rtructural adjustment advocated by the World Bank. Does not taking funds from the
government compromise the opposition to these policies. Indeed the World Bank wauls
the government to give attention to some aspects of health care (e.g., infant mortality)
as part of its safety net concept. The central role of the PSM must remain bringing
pressure to bear on the state for changing its policy and in the process exposing the true
nature of the state (and the roots of ill health). Providing services, even as a measure of
relief for the people cannot be done, without diverting away from our central task. This
is all the more true if one accepts government money. And to say that we will do it
voluntarily or build systems where people, especially the poor pay for their health is very
much the World Bank line.
Q.25. But most
A_25. The question raises a mix of very different issues but as this is the way in which many
articulate this let us try to sort it out.
Yer. The economic policies of the government, which are Work! Bank inspired have a
major role to play in creating ill-health. And yes mobilizing people against these policies
14
is a central task. No, we are not saying that people will pay for their own health nor are
we beikhng any parallel health systems. The proposed programme reinforces and places
a demand for strengthening existing health infrastructure and government expenditure.
And no, what the World Bank says or does not say is not an adequate factor to decide
our course of action. Precisely because health is a vital area where its policies become
exposed, the World Bank seeks both legitimacy and safety in organizing interventions in
health. This cannot make us ignore this area. Our aim should be to choose a process
most suited for mobilisation of people.
What can be the tactics of mobilisation against the present state's policies, especially as
pertaining to health ? Yes. Holding seminars and meetings and publishing books and
articles in the press can be ways of buikling pressure for policy changes. Such forms
of mobilisation will be very effective not only for winning support amongst the Liberal
intellectual and academicians but also in the larger politically important middle classes.
Today when van sections of this class are swayed by the aptxrvnt success of ecooomtc
refor ms (perceived in terms of both growth rales in press rqxirts and in the increased
availability of consumer goods and certain types of jobs) one needs to bring home the
human cost of the Structural Adjustment Programme by highlighting their impact oa
health.
But we hold that for mobilizing the vast sections of those who are most affected by these
reforms and policies, such a tactics of pressure or protest may be inadequate. If we must
use their ill health as the focus of mobilisation we cannot do it without organizing to
assist them in coping with ill health. This is in contrast to merely 'demanding' that the
state be held responsible. Ask any trade unionist. He knows that without helping the
worker defend their wage levels and without help on a number of shop-floor issues organizing worker; for political change is quite impossible. The fact that such interim
gain are in trade union struggle conceded by the owner or state and such interim gains
in a health movement are secured by prople’s voluntary contribution is of course there
and this does make a difference. But it is highlighted here to counter arguments that pose
winning interim gains or concessions for the people as inherently ‘reformist’ or
diversionary.
Another major reason for a ‘constructive campaign’ as opposed to a more oppositional
or protest campaign is that the impact of the economic reforms on health is not perceived
as such. Diseases are perceived largely as individual events affecting each indivkhial due
into natural factors. It is difficult to read politics into an epidemic of diarrhoea or even
as infant death.
Why, surprisingly a large numbers of mothers of malnourished children do Dot even
perceive these children as malnourished, (often doctors too can identify only grade III
malnutrition) Time and again we have talked to such mothers to find them insisung -
’No, its not fbpd my child needi. its tonic and medicines’. in such a culture of beaith,
and given the structure of the health delivery system the route of organizing the suffering
15
paar fix protest as usually understood, can even be counterproductive. For very often
demands that are not genuine needs, but wants created by the culture of health, get
v'caced. We must learn to recognize that modem day capitalism does not depend solely
oa state power to defend its pro-rich economic policies. It is able to alter the nature of
the production and distribution and knowledge as well as to generate a culture that
manufactures consent for its policies. This is clearly evident in health where social
problems are perceived as medical ones: and people perceive health as a matter of pillpopptng - of controlling diseases by consuming the doctors services, drugs and
dagoosucs. The stale as government, often dissociates itself from this culture and even
makes ineffectual protest against it, leaving it to its worthy allies in the medical
profession and the health industry to defend and promote this culture. To the profession
and io the industry the existence of this culture is an occasion for super profits, not a
cause for dismay.
Whereas the politics of protest focuses all its attention on the state if fails to grasp the
modern reality that power is not concentrated in the state but lies diffused through the
instHutioGS of civil society, and is effected as much by culture as by force.
if the terrain of conflict is culture and the nature of knowledge and the way people
perceive and value health, then it makes far more sense to choose a form of mobilisation
where such issues are focussed on. In such a perception of conflict, the health activist
tatting to the mother of a malnourished child or a village organizing a saniutxxt
campaign u no longer incidental to die cliangc process or |>urely tactical - it becomes
centre stage. Similarly if the terrain of conflict is seen as questioning the structure of
health care delivery and working to radically restructure it then an activity like drawing
up a district or pane hay at level health plan, or involving iwmchayats in health care.
becomes effective tools of mobilisation of the poor.
By reducing these issues to the issue of funding or no funding the emphasis gets shifted
off the real issues. One can see a number of non-funded programmes that reinforce the
dominant culture of health and reinforce its negative structural features. Indeed precisely
because they are easier to do without funding such activities get priority. Thus very often
we see groups running health camps or centre where free medical check up and drug
distribution is provided - often as their sole activity. Or we hear demands being raised
for more government expenditures in certain areas where the existing approach and the
structure of delivery used lead only to a larger leakage or serve as political patronage.
Demands for increased government expenditure arc usually in an absolute sense
justifiable but without restructuring delivery mechanisms they are counter productive.
But these same forces may never make the demands for restructuring the health care
delivery system a part of the demand for increased expenditure.
Paradoxically when finally government funding is conceeded within our organisation it
is done not with any understanding of the nature of conflict and therefore the nature of
mobdnatioo needed, but merely as an adhoc approach e.g., one needs it to sustain
16
organisation etc. The result of this is that the door becomes open to seek funding from
all sorts of government schemes most of which serve to reinforce existing health
structures and existing culture. It is obvious that funding will become available for a
target oriented family planning programme easier because it fits in with the existing
wisdom on family planning and the existing structure of health care delivery. (This is
much more true in developmental areas like watershed management (done without
concern for equity) or employment generation by encouragement of piece rate putting-out
*
system
- e.g., gem cutting, shampoo packing or IRDP type loans for cows, etc.
It is the way we do health, the processes we use (and refuse to use)
that arc critical
to determine whether real mobilisation and empowerment results and radical change is
being approached or not.
One cun uchteve success IhiIIi in terms ol orgamsatKmal
influence and even in a limited sense in terms of health statistics without any
empowerment by using existing cultural idioms and encouraging structures favourable to
the dominant paradigm. But the organisations so created may even become an
impediment to change. The emphasis must therefore be on designing and implementing
programmes to fulfil our objectives.
One other corollary of this discussion needs to be stressed. If the terrain of conflict is
the culture of health and the structures of health care delivery’ then the leadership of this
campaign needs to be equipped to lead in these areas. Organizers who are not so
equipped, are likely to take on uncritically the prevailing scientific and technological view
points as neutral knowledge and lead the programme astray.
This draft is prepared and circulated by jne on the basis of discussion and experiences so
fcr uhin the A1PSN/BGVS sub committee on health.
On many of these issues there may not be a clear consensus but unless we put down in
paper our views and identify how exactly we differ, no clear consensus will emerge.
This note is therefore circulated for initiating such a wider discussion. If all state and
where existenfsub committees on health as well as state PSM executive committee, could
respond to this notefin writing) by suggesting further questions or modifications in the
given answers,wfejeaiwou Id help us plan for a more meaningful discussion at the A1PSN
congress at Bhopal.
Dr. T. Sundararaman
for Sub committee coordination on health
17
Health
uc H 2> • 2-6
partner tracing
People with sexually transmitted diseases are
urged to divulge partners’ names, and the new medical
detectives track them down. LORI MILLER KASE reports
Z^athy Raevsky, an intelligent, compassionate thirty-three-year-old, walks up to a stranger’s door
step. silently rehearsing the devastating message she is
about to deliver. Paying visits like this is the. most diffi
cult part of her job.
The woman who. answers the door—a well-dressed
blond, about twenty-eight years'Old—fits the descrip
tion perfectly: “Can I speak to,you privately?-”.
Raevsky begins. .‘-‘I am from the state-health depart;
ment, and J have important information concerning
your health.” Not until the woman steps outside and
shuts the door does Raevsky continue.
“The reason I’m here is because you have been ex
posed to the vims that causes AIDS,” Raevsky says in
the calming tone she has perfected over the years.
..
.
“One of your sexual
The question is:. partncrs ha<tcstcd posi.
are people willing five for HIV.” The
.
. .
. .
woman,'who has had
to kiss and tell? only one scxual part.
ner—her husband—for the past eight years, is stunned.
RacvsRy, associate director of the Coloi'ad.O Depart
ment of Jffealth’s.-STD/AfDS scctiori,.has been notify
ing the sexual partners of HIV-positive patients for the
past three years—and STD-infected patients for more
than a decade. “It never gets easier,” she concedes.
‘ ‘ You just get better at dealing with people’s reactions.
You try to make them understand that exposure to HIV
isn’t necessarily a death sentence. It's hard because
you’re never the good guy, you're always delivering
bad news."
Raevsky’s message deals a crushing blow. Often the
person she contacts must confront the reality that her
partner (and perhaps she, too) carries a potentially fatal
disease. The underlying message can be just as devas
tating: the partner may have been unfaithful. And in
many cases, not with another woman, but with a man.
What happened to the young woman Raevsky visit
ed? No one knows. Once partners are urged to get test
ing and counseling, and encouraged to divulge the
names of sexual and IV-ncedle-sharing contacts, the
files are essentially closed.
The new medical detectives—people like Raevsky
who track down the unsuspecting partners of AIDS pa
tients—are messengers with a mission: they believe po
tentially infected people have the right to know they Tc
258
at risk. They hope to reach people before they become
infected, giving them thcchance to protect themselves.
The reality, though, is that many of the people they
contact already carry the deadly vims—arid must be
alerted before they spread the disease.
Raevsky, along with twcnty-tHree colleagues at the
Colorado Health Department; tracks;down an average
of ninehundfed pepplc/each month: some are the part
ners of people who have tested positi ve, for the human
immuno-deficicncy virus (HIV); others arc the partners .
of. people with other sexually transmitted diseases :
(STDs) like syphilis and gonorrhea. Though Colorado
is ranked nineteenth in the country in number of AIDS
cases and falls well below the nation's incidence of other
STDs, the State has one of the most active “contact-trac-.
ing” programs around.
Colorado’s medical sleuths come from-a variety of.
backgrounds, but all are specially trained in contacting .
and counseling potential AIDS/STD victims. As
Raevsky puts it: “You don’t just say ‘Hi, I'm from the
health department. Who are you sleeping with?" i”Field investigators must survive a rigpjpu? serceriinji;
process—only about 20 percent of applicarits do; then •
they spend about five months attending classes, role
playing, and tagging along with senior investigators.
For novice investigators, the first few months are emo
tional minefields. Says Raevsky: “You’re worried
you’re going to cause someone psychological harm."
How do people react to Raevsky’s visits? Reactions
vary, she says, from tears or angry outbursts to simple
surrender. “Who gave you my name?” is a question
commonly asked, but never answered.“If we blow
confidentiality,” says Regina Olson, a former health
department clerk-typist who has been investigating
AIDS/STD cases for the past two years, “we lose the
tmst of the people we talk to."
People who test positive for HIV arc given the option
of informing partners themselves. But according to Ol
son. though 97 percent of those interviewed at an STD
clinic said people should be informed when they come
into contact with someone with AIDS or another STD,
most admitted they would find it difficult to tell their
partners themselves if they were infected.
States have been notifying the partners of people
with STDs other than AIDS—especially syphilis and
gonorrhea—for decades. In the past few
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Motes
on talk delivered at CHAI-KA AGBM on
on 'Health as a Human Right".
~opic
-
1.
■■
16/09/96 as
panelist
Role of Voluntary Agencies
It is difficult to delienate the role of Voluntary Agencies
in
Health,
primarily
since we have started
our
work
as
organisations
or
individauls
with
a
set
of
Aims
and
Objectives unique to our perspective.
We are also caught up in our work towards this, focussing on
the
Annual reports. Evaluations and such other
imperatives
leading
to our Goals/Aims/Objectives.
it is only
at
such
meetings,
or seminars that we look at
wider/deeper/emerginq
issues and attempt to put it into our working framework.
- 2.
Our work revolves around the services we provide,
lobbying
and networking we- do, attempting as Holistic an approach
as
possible within our framework.
We do address the
Physical,
Mental, Social and Spiritual dimensions of Health within our
limitations.
This
is usually, the addressing
of
Disease
among the people we work with.
- 3.
Does this address the needs of Health as a Human Right?
I
will
be deliberately not addressing the issues
of
Poverty
and Gender discrimination already elaborated on by the other
panelists.
That
they are issues of
prime
importance
is
without doubt.
The great social reformer Swami
Vivekananda
had
said that it is criminal to talk of religion to
people
having empty stomachs.
It is the same with health too!
- 4.
The changing scenario in which Voluntary agencies
operate
needs an understanding.
We are in the midst of a number
of
revolutions occuring simultaneously, and adjusting our focus
to
Health as a human-right amidst all these
is
important.
T hey are
,
*
- al
The Communication revolution, making our planet a truly
global
village.
The world is aware of anything
going
on at even remote places.
How does this help Health
&
Human rights?
- b)
The Gender revolution - seen even in remote
villages,
where
women are becoming active participants
in
life
around, though may not be at the pace/in areas desired.
A change is definitely happening.
- c)
The Economic revolution, where we see that the rich are
becoming
richer, and the poor, poorer - despite
hopes
and proclamations to the contrary.
And.
-d<
5.
The
Spiritual
Revolution,
manifesting
as
religious
!undamenta1 ism
and
terrorism
at one
end.
and
small
spiritual-seeking
groups working for peace and
harmon ,■
at the other.
In this scenario, what we need to think aboi
- Are we working towards our own goals, or
the
people we are working with?
The needs
satisfaction is of the people - not ours.
We are caught in a paradox because of this - we need to have
the
EMPATHY
as
well
as maintain
an
OBJECTIVITY
to
be
successful in our work with the people.
This
type
of
work demands from
us,
multiple
roles
and
multiple
capabilities.
It can only be obtained with
team
work and networking.
Are we geared to do all this?
-6.
Another major requirement of the Voluntary agency role is the
ability to COUNSEL.
It is an onerous task indeed,
demanding
not
only
skills,
but also the
information
base
and 'the
ability
to demystify and transmit/communicate this
to
suit
the needs of the people.
To
summarise,
we
need
to
truly
understand,
that.
the
corollary
of
’Rights'
is
Responsibilities'.
As
voluntary
agencies, we have stepped forward to take these
responsibilities
and need to work towards our own level, till the time people take
this ’responsibility' onto themselves along with the rights.
that
we
go
beyond
identifying
It
means
rectifying
them,
to
a
positive
v i o 1 a t i on s
and
building up the concepts of human-rights in all work
You.
DR.
SHIRDI
PRASAD TEKUR.
human-rights
approach
of
that we do.
sterilization will remain a highly important contraceptive choice in spite of
developments of other effective spacing methods.
CONTRACEPTIVES OF TODAY AND TOMORROW
The need for evolving more acceptable and effective means of contraception
with nil or minimum side-effects is more acutely felt man ever before in view of
the frightening rate at which the population is growing. The world population
has already crossed the five billion mark out of which about 800 million live in
India at present Time is precious and this field is emerging as one of prime
importance in biomedical research and is attracting scientists and
investigators from a variety of disciplines - biology, medicine, chemistry.
biochemistry, immunology, biophysics and biomedical engineering, to
mention a few. This veritable fusion of d isciplines in a way reflects the range of
problems encountered in deciphering the laws of living systems. In the last two
decades, a great deal more effort and work has gone into surveillance of the
pill, IUDs, abortion techniques and sterilization, than was devoted to the initial
development of these forms of contraception. We now know more of the
dangers and benefits of the oral contraceptives which have been greatly
improved and made safer by lowered dosage levels. The second generation of
IUDs perform somewhat better than the first but no really fundamental
breakthrough has occurred. Sterilization cases have increased much more
than was envisaged in the 1960s and there have been important
simplifications in its application in women. Surgical abortion techniques have
proved far safer than anticipated when the medical termination of pregnancy
was liberalized in India. However, there is no male pill on the market and no
safe and simple menses inducer (postovulatory contraceptives).
The recently developed methods of contraception include hormonal
contraceptives and medicated IUDs. While the oral pill has undergone drastic
modifications in terms of the doses of the steroids used, other drug delivery
systems have been developed for delivery of these steroids at a low dose for
long-term protection. The medicated IUDs include the Copper T and
progestasert (Progesterone-containing IUD).
Long-acting Steroids
Long-acting progestogens were synthesized during the 1950s and
occasionally used in the treatment of gynaecological diseases. A variety of
progestogens and combination of progestogens and estrogens have now
been used as injectable preparations or as subdermal implants The Chinese
have developed a once-a-month pill. Before the year 2000, women around the
world may have a number of long-acting contraceptive methods to choose
from. All these methods are developed with long-acting steroids. They are
safe, effective, convenient to use and do not require the taking of a pill every
day. However, cycle control may be a problem.
36
0\
PotuK-E -
NII+F-Ia/
vOtt 3-2-^
Injectables
Two long-acting injectables are widely available-depot medroxyprogesterone
acetate (DMPA; trade name Depo-Provera: the Upjohn Company, USA) and
norethindrone enanthate (NET-EN; trade name Noristerat; Schering AG. West
Germany). Both are highly effective spacing (reversible) methods. DMPA is
approved for use in more than 90 countries; and NET-EN, in more than 40 (but
not in India).
DMPA was synthesized in 1954 and the depo preparation was first tested
as a contraceptive by Tyler and Coutinho and De Souza (1966). In the world as
a whole, about one and a half million women are using DMPA as a
contraceptive and over 10 million women have used it at some time or other. It
is normally given as a three-monthly intramuscular injection of 150 mg
although regimens extending to six months or more have been used. Within 24
hours of injection, serum levels reach 2.6 - 7.8 n mol/L and plateau at 2.6 - 3.9
n mol/L over the next two to three months (Ortiz et al. 1977). Once released
from the depo site, DMPA is cleared from the blood stream within about 24
hours. In a randomized trial of two DMPA doses, none of the women receiving
the standard 150 mg dose conceived, but the pregnancy rate among women
receiving 100 mg every three months was 0.44 per HWY (WHO, 1986). With
higher doses and a longer injection interval -250 to 450 mg every six months pregnancy rates have ranged from 0 to 3.6 per HWY (McDaniel and
Pardthaisong, 1974; Rail et al. 1977).
Other long-acting injectables include chlormadinone acetate, 17hydroxyprogesterone acetate, lynestranol phenyl propionate and
norethisterone enanathate (NET-EN). Only the latter has achieved
widespread use, but on a still more limited scale than DMPA. NET-EN is given
in both 2 months and 12 weeks regimens. With the 12 weeks regimen, the first
three 200 mg injections are given at 8-weeks intervals, and subsequent
injections are given at 12-weeks intervals. The 2-mon.th regimen is markedly
more effective. Two-year cumulative life-table pregnancy rates with the twomonth regimen range from 0.4 to 1.8 per 100 women (ICMR, 1984). In contrast,
with the 12 weeks regimen, 2-year rates are as high as 6.6 per 100 women
(WHO, 1983). However, maximum protection against pregnancy is observed
when the injectables are administered during the first week of the cycle. Any
delay may not prevent ovulation in that cycle and thereby the risk of pregnany
is increased.
The long-acting injectables abolish the cyclical release of LH and FSH,
probably by an action at the hypothalamic level as observed with combination
of oral pills. However, injectable contraceptives seem to have less effect on
overall bodily physiology, e. g. liver or thyroid function, than do the oral pills but
they have a more profound effect on the genital tract.
There are no serious adverse reactions encountered in those receiving
injectable contraceptives. The major side-effect is on patterns of menstruation
- irregularity to amenorrhoea. The overall blood loss is reduced but
occasionally there are episodes of heavy bleeding (Koetsawang, 1980). Many
women gain weight on DMPA or NET-EN, often as much as 0.5 - 2 kg. in the
first year.
CHARACTERISTICS AND STATUS OF LONG-ACTING INJECTABLES
Numerous studies have shown that the use of injectable steroids is
associated with a slow return of fertility. The median time to conception is
about 10 months after the last injection with fertility returning to 75 per ent of
women within 15 months and to 95 per cent in 24 months (Pardthaisong ef al.
1980).
cyclopenlyl carboxylate)
38
WHO HRP = World Health Organization, Human Reproduction Programme
Neither DMPA nor NET-EN has any adverse effect on the amount and
duration of lactation and infants of DMPA and NET-EN treated mothers gained
weight more rapidly than controls.
The greatest debate concerning the use of long-acting steroids has
revolved around possible carcinogenicity. In some studies, a higher
prevalence of-abnormal cervical smears has been recorded in DMPA users
(Litt, 1975) but not in others (Dabancens et al. 1974). The prevalence rate
declines with duration of use and there is no evidence of any change in the risk
of invasive cervical cancer. Another area -of concern is the possible
relationship between continuous low levels of progestogens and the incidence
of breast cancer. So far only two cases of breast cancer among DMPA users
have been reported (Zanartu et al. 1983) but this is not unlikely in the case of a
common disease. Liang et al. (1988) followed up 5000 women for 4-17 years
after their initial DMPA injection and found that relative risk of breast cancer
was 0.7 (95 per cent confidence limits 0.3 -1.4).
TABLE 6
RISKS OF VARIOUS CANCERS AND DMPA USE, WORLD HEALTH
ORGANIZATION - 3 COUNTRY CASE-CONTROL STUDY 1986
Site of
Cancer
No. of cases
No. of controls
Relative Risk for
who used DMP/\/ who used DMPA./ women who have
All cases (%)
All Controls (%) ever used DMPA'
Breast
39/427(9)
557/5951(9)
1.0
Cervix
129/920(14)
545/5833(9)
1.2
Ovary
7/105(7)
74/637(12)
0.7
Endometrium
1 /52(2)
30/316(9)
0.3
Liver
7/57(12)
34/290(12)
1.0
’Adjusted for centre and for factors known to affect cancer risk. None of
these relative risks is significantly different from 1.0. WHO (1986)
39
Since 1980, regulatory agencies in Sweden, the UK. France and West
Germany have approved DMPA for contraception. Several national and
international scientific groups have also endorsed DMPA. including WHO.
HRP and IPPF.
Monthly Injectables: Monthly injectables are widely used in Latin
America and China. The monthly injectables contain an oestrogen and a
progestin combined. These are highly effective. WHO is currently supporting
research on two new monthly injectables which appear to be effective and
safe and may be available by 1988.
Oestrogen-progestin combinations injected monthly produce regular
cyclicity. The approach seems to be better than long-acting progestins alone
since there is less spotting or no amenorrhoea. Remembering the date for
injection becomes easier. A visit to the clinic for injection every month ensures
a proper follow-up. However, there is the inconvenience of more frequent
injections and possible side-effects of the oestrogen component need to be
checked.
Two oestrogen-progestin formulations are currently in use: (i) a
combination of 75-150 mg dihydroxyprogesterone acetophenide and 5-10 mg
oestradiol enanathate, used primarily in Latin America; and (ii) a combination
of 250 mg 17-hydroxyprogesterone caproate and 5 mg oestradiol valerate.
used only in China.
In clinical trials with 150 mg dihydroxyprogesterone acetophenide and 10
mg oestradiol enanthate involving nearly 23,000 cycles in 2,400 women, no
pregnancies were reported. The drop-out was between 8-26 per cent due to
bleeding problems (Benagiano and Primiero, 1983). Return of ovulation may
be slightly delayed. Because of the concern about accumulation in the body of
the oestrogen over time, half.doses of oestrogen have been tried. These lower
doses prevent pregnancy effectively but severely disrupt menstrual patterns
(Recio et al. 1986).
In China, a formulation called injectable Number 1 accounts for less than
1 per cent of all contraceptive users. The major disadvantage of this method is
a very short cycle and prolonged bleeding.
WHO is conducting trials on two new monthly injectables along with
Family Health International in three countries: (i) Cycloprovera, a combination
of 25 mg DMPA and 5 mg oestradiol cypionate; and (ii) HRP 102, a
combination of 50 mg northindrone enanthate (NET-EN) and 5 mg oestradiol
valerate.
Preliminary results in a study of 2400 women in three countries show that
both formulations are highly effective, both preparations induced bleeding
patterns like normal menstrual cycles and side-effect have been minor (Hall
1987).
40
41
Microspheres and Microcapsules
Injectable microspheres and microcapsules consist of a biodegradable co
polymer and one or more hormones. These microspheres and microcapsules
may protect against pregnancy for one, three or six months depending on the
amount and daily release of hormones. The carrier of these injectables is poly
(dl-lactide-co-glycolide). Progestins can be dispersed in the polymeric
particle (Microsphere; Fig. 3) or contained in the core of the particle
(Microcapsule). With both systems, the hormone is released first by leaching
or by diffusion through the carrier and later by erosion of the carrier A 3-monlh
dose of injectable norethindrone (NET) microspheres usually contains
particles consisting of 50 per cent hormone and ranging in size from 0.06 to0.1
mm in diameter (Beck and Pope, 1984). For an injection, microspheres are
loaded into a syringe followed by a sterile suspension fluid and the total volume
of about 2.5 ml is injected into the buttocks with a 21 gauge needle. Various
preparations of the injectable microspheres are being tested for contraception
in women. The most promising hormones used in the microspheres are either
norethindrone or a new progrestin, norgestimate.
Norethindrone containing microspheres tested in about 200 women with
different formulations of 3-month injections have prevented pregnancy and
caused very few side-effects other than menstrual irregularities. The 3-month
injections containing 75 mg of norethindrone release on an average 0.48 mg
norethindrone per day, as compared'to 0.5 to 1 mg in combined oral
contraceptives.
Irregular menstrual bleeding is the only common side-effect and only a
few complained of mild headaches or nausea. No changes have been
observed in blood pressure, haemoglobin, serum lipoproteins, triglycerides.or
glucose metabolism (Bech and Pope, 1984). The reversibility is rapid and most
women-ovutete-withiirtwo-months-fRivera ef al. 1984).
A one month injection with 15 or 30 mg NET has been tested in 30 women
in Mexico. Animal studies in baboons with microspheres of NET and ethinyl
oestradiol indicate very little irregular bleeding and very slight endometrial
changes. Clinical trials with progesterone microcapsules containing 275 mg
progesterone on 10 women demonstrated good promise (Table 8).
In China, monthly injections of microcapsules containing 15 mg
megestrol acetate and 5 mg of oestradiol valerate in 434 women were found to
be effective with a pregnancy rate of 1.1 per HWY. Spotting occurred in only 3
per cent of menstrual cycles and only 9 per cent of cycles were either longer
than 36 days or shorter than 20 days (Han and Xiao, 1985).
Subdermal Implants
There are two kinds of implants made of poly dimethyl siloxane (Sialstic) or
other polymer-based rods or capsules that are placed under the skin by a
trocar. Depending on the amount and type of progestin, the number of implants
to be inserted vary as per desired duration of action of the drug. One kind of
implant is nonbiodegradable and the other is biodegradable. In the last two
decades a number of progestogens have been tested. The most promising are
ST-1435, norgestrienone and levonorgestrel (Roy ef a/. 1984). ST-1435 using
1 -5 capsules lasted only for six months and the pregnancy rate was 1 or less
per HWY (Coutinho et al. 1981). Norgestrienone (R-2010) implants last from
18 to 24 months with 6 capsules but the pregnancy rate was 3-5 per HWY.
Nonbiodegradable Implants: The nonbiodegradable implants
developed by the Population Council have undergone widespread clinical
trials involving more than 44,000 women in 31 countries (Population Council,
1986). The implant favoured by the Population Council, named Norplant,
contains levonorgestrel and proved to be highly effective, safe and liked by its
users. By 1987, a 6-capsule Norplant system had been approved for
marketing in seven countries - Finland, Sweden, Indonesia, Thailand, Ecuador,
Dominican Republic and Colombia.
^In clinical trials norethindrone microspheres prevent preg
nancy for three months. Microspheres are .06 to 0.1 mm in
diameter. The smaller microspheres release hormone faster.
(Stolle Research Corporation)
Norplant implants come in two forms (Fig. 4). The first, called simply
Norplant, consists of six hollow silastic capsules. Each capsule is 34 mm long,
witn a diameter of 2.4 mm and contains 36 mg levonorgestrel. The ends of the
capsules are sealed shut with silastic adhesive. This.is highly^effective in
preventing pregnancy for five years. The other form, called Norplant-2,
consists of two solid silastic rods, each 44 mm long and 70 mg levonorgestrel
is dispersed in the matrix of each rod. Norplant-2 is highly effective for at least
three years. This system was approved in Finland in 1987.
42
43
AND MICROCAPSULE CONTRACEPTIVES AS OF MARCH, 1987
44
Fig. 4. Norplant implants release levonorgestrel.
The progestin in the implants diffuses through the silastic membrane at a
steady and slow rate. Within 24 hours, the levels in blood plasma are,high
enough to prevent ovulation (Bardin and Sivin, 1985). The average daily
release ranges from 50 to 80pg in the first year and declines to 30 to 35pg over
the next five years (Diaz ef al. 1982).
Insertion and removal of Norplant implants require a minor surgical
procedure under local anaesthetic and a small incision. Removal is more
difficult than insertion. The best time for insertion is during menstruation to
ensure that the woman is not pregnant. The implants are inserted under the
skin. Infections and other complications after insertion are rare (3 per 1000;
Sivin ef al. 1983). With the exception of one trial in India (ICMR, 1985) capsules
and rods are rarely expelled. The removal of 6 implants takes about 15 to 20
minutes. Generally, the removal is comparatively easy if insertions are made
properly.
Capronor (long capsule at left) and contraceptive pellets are both
long-acting implants that dissolve in body tissue and do not need
to be removed. The special inserter can be used with either.
Norplant provides almost complete protection against pregnancy. In the
first five years of use of the Norplant 6-capsule system, the chances of
pregnancy are less than one per HWY. This rate is lower than for oral
contraceptives. IUDs or barrier methods. On-going international trials show
that Norplant-2 is as effective as the 6-capsule system for the first three years
of use (ICMR. 1986). After three years, a high number of pregnancies occurred.
in a larae 5-country trial.
Norplant suppresses ovulation in at least half of the menstrual cycles.
(Bardin and Sivin, 1985). Whenever ovulation occurs, the levonorgestrel is
effective due to its action on cervical mucus which becomes thick, scanty and
impermeable to spermatozoa. The cyclic development of the endometrium Is
also suppressed (Croxatto ef. al. 1984). About 60 per cent of women using
Norplant suffer from irregular menstrual bleeding during the first year (Sivin ef
al. 1983). Among 116 women using the 6-capsule system for five years, the
average number of days of bleeding and spotting per year dropped from 92 in
the first year to 70 in the fifth year (five per cycle). Amenorrhoea is less
common than prolonged bleeding or spotting. No serious reproductive side
effects have been reported so far. Transient ovarian cysts have been found in
10 per cent of users (Diaz ef al. 1982). The cysts however, regress
spontaneously within six weeks.
The contraceptive effect of Norplant is reversed rapidly after removal of
the implants and the infants are free from any after-effect of the progestin. Only
minor changes have been observed tn liver function, carbohydrate
metabolism, blood coagulation, blood pressure, immunoglobulins, serum
cortisol, urea nitrogen, uric acid, minerals and body weight but all remained
within the normal range.
Biodegradable Implants: The problems associated with the removal of
Norplant implants led to the development of biodegradable implants. These
implants degrade in situ while releasing the impregnated progestins and in the
process obviate the requirement of removals. However, once the carrier
begins to dissolve, it cannot be removed.
The biodegradable implants undergoing clinical trial at present include
Capronor and Norethindrone pellets. Capronor consists of a biodegradable
capsule made of the polymer only (E-caproIactone) containing the progestin
levonorgestrel. Norethindrone pellets are made of 15 per cent pure cholesterol
and 85 per cent norethindrone (NET).
Capronor: Current trials with this biodegradable capsules (Fig. 5) involve
implants that are less than 0.24 cm in diameter and either 2.5 cm or 4 cm long.
The shorter capsule contains 16 mg and the longer 26 mg levonorgestrel In
both capsules the progestin is suspended in ethyl oleate. Studies in rabbits and
monkeys suggest that the contraceptive protection would last for about 18
months and longer. The polymer carrier remains largely intact for 18 to 24 .
47
46
months and can be removed easily during this period, if necessary. However, it
is not completely absorbed for several years. The phase 11 clinical trials
comparing the 2.5 and 4 cm capsules began in early 1987 and are being
conducted by US National Institute of Child Health and Human Development
(NICHHD). the World Health Organization (WHO) and the Indian Council o’
Medical Research (ICMR).
In the preliminary study on eight women in the US, none reported bleeding
between menstrual periods, average length of the cycle was four days shorter
and there was no change in blood pressure or blood biochemistry, including
lipids. The capsules did not cause inflammation at the insertion site (Ory et al.
1983)
Norethiadrone Pellets: Each of these pellets contains 35 mg NET which
is released as tne pellets gradually biodegrade. The size of each pellet is little
larger than a grain of rice (Gupta st al. 1984; Singh et al. 1985). Preliminary
trials have been conducted with two, three and four pellets in over 100 women
in four countries. The release of the progestin was fairly constant (Singh et al.
1985).
TABLE 10
HORMONE RELEASE RATES AND NUMBER OF PREGNANCIES
WITH TWO, THREE AND FOUR NET PELLETS
No. of
Pellets
48
Mean Daily
Release (ug)
No. of Women
No. of
Pregnancies
2
11± 2
50
3 at 6 months
3
150i 7
51
2 at 12 months
4
213+ 9
30
0 at 12 months
49
The 4-pellet regimen appears to provide a high level of protection against
pregnancy.
One of the main drawbacks of these pellets is menstrual irregularity.
Lengthy menstrual period, spotting as well as amenorrhoea were encountered
in women who had these pellets inserted.
Vaginal Rings (Fig. 6)
Steroids can be absorbed through the vaginal mucosa which pass directly to
the veins draining into the inferior vena cava and, as with injectables and
implants, bypass the liver on their first pass. A number of progestogens have
been made into sustained release systems that can be left in place in the
vagina for three weeks and removed for one, during which menstruation
occurs (Fraser and Weisberg, 1981; Sivin et al. 1981). A poly siloxane ring is
impregnated with levonorgestrel, progesterone or a combinatioin of progestin
and estrogen.
With the vaginal ring, the cycle control is usually good. The ring
sometimes gives rise to a discharge and the acceptability of inserting such a
ring, leaving it in place for three weeks and then removing it, cleaning it and
storing for one week has not been extensively investigated.
Research is most advanced on a ring developed by WHO that releases 20
jug levonorgestrel per day. This ring is designed to stay in the vagina for three
months. The inner core of the ring contains 6 mg of levonorgestrel mixed with
silastic and an outer shell of silastic alone.
The overall diameter of the ring is 55.6 mm and cross-sectional diameter
is 9 5 mm The ring prevents ovulation in at least half of the cycles and thickens
the cervical mucus. However, this ring was found to be less effective than
implants or injectables. In a multicentric trial involving about 1000, women
there were 25 pregnancies in one year, the rate being 3.5 per HWY (WHO
Annual Report, 1985). About 8 per cent of women stopped using the ring
because of vaginal discharge, irritation or infection and about 4 per cent,
because of expulsion.
Another ring contains the natural hormone progesterone designed
especially for breastfeeding women to prevent exposure to synthetic
hormones which mayalter the composition or quality of breast milk. Currently,
WHO and Population Council are testing rings releasing 5 or 10 mg
progesterone daily.
The Population Council is working on several rings that deliver both
progestins and oestrogens. Preliminary studies with a ring releasing 400£ig
norethindrone acetateand 40 gg ethinyl estradiol daily stopped ovulation in all
of the ten women recruited for the study and caused very little irregular
bleeding. The Population Council also plans to test vaginal rings with two other
progestins, ST-1435 and levonorgestrel acetate, either alone or in
combination with ethinyl estradiol.
The rings appear to have several disadvantages for large scale use
among the population.
Medicated IUDs
The success of IUDs depended on their surface area and the larger was the
device, the better it protected a woman against pregnancy. However, the
larger the device, the more were the complaints and the higher the expulsion
and removal rates due to bleeding or pain. It was in response to this problem
that medicated devices were designed. These devices work on the principle
that the plastic is used as a carrier for chemicals which work to prevent
pregnancy. The first medicated device was developed by Zipper eta/. 1969; in
which 200 sq. mm of copper surface was exposed by wrapping copper wire
around a T device. A low concentration of copper ions is released into the
uterine cavity and there is a direct relation between the area of copper
exposed and the contraceptive efficacy. Copper ions have no inhibitory effect
on ovulation or fertilization but may be spermicidal and certainly stimulate
migration of white blood cells into the uterine cavity. This particular device
known as TCu 200 is being used in the National Programme in India. With this
device, pregnancies were effectively prevented for2-3years.Thecopperwas
found to be released at the rate of 45jjg daily and the amount of qopper in the
device could be exhausted by six years. However, fragmentation of copper
and deposition of calcium were responsible for decline in effectiveness
beyond three years. To prevent the fragmentation and loss of effectiveness,
various surface areas of copper with or without other metals like silver were
». g.
Two vaginal rings (shown actual size) release hormone for 3 months.
The upper ring contains norgestrel; the lower, progesterone.
51
wri 3-3>o
'u irent
abstracts
April 1990
37% had used a Hulka clip, and 21% had used a tubal ring. Four pregnancies were confirmed, all
occurring between two and seven years following VSC: three ectopic pregnancies in the
electrocoagulation group and one uterine pregnancy in the Hulka clip group (no pregnancies
occurred in the tubal ring group). Because pregnancies occurred as late as seven years following
VSC, the authors concluded that short-term failure rates for female VSC probably do not represent
actual failure rates. Other conditions often thought to be sequelae of VSC, including adnexal
masses, pelvic infection, and various conditions requiring hysterectomy, could not be linked to VSC
or to the use of a specific occlusion technique.
Long-acting Progestins
Klavon, S.L. and G.S. Grubb. Insertion site complications during the first year of NORPLANT®
use. Contraception, Vol. 41, No. 1, January 1990, pp. 27-37.
First-year clinical trial data on insertion site complications among 2,674 NORPLANT® acceptors in
seven countries showed that infection and expulsion rates were low, but that a substantial
proportion of insertion-related complications occurred after the first two months of use.
Complication rates varied widely among countries and between clinics within a country. At one
year, complication rates were: insertion site infection, 0.8%; expulsion, 0.4%; local reaction, 4.7%.
While most complications occurred within 60 days of insertion, some 35% of insertion site infections
and 64% of expulsions occurred after 60 days; about two-thirds of these infections and expulsions
were among women without insertion site complications during the first 60 days. Possible causes of
later infection were (1) trauma to the insertion site causing it to open or (2) change in the
immunologic environment of the implants. The authors recommended that implants be removed
when infection occurs: of 16 women with infections who did not have the implants removed
immediately, half eventually had them removed.
Paul, C. et al. Depot medroxyprogesterone (Depo-Provera) and risk of breast cancer. British
Medical Journal, Vol. 299, September 23,1989, pp. 759-762.
This New Zealand population-based case-control study found no overall increase in risk of breast
cancer with use of the three-month injectable contraceptive Depo-Provera (DMPA), but found
increased risks in users who: (1) were diagnosed with breast cancer before age 35, (2) had used
DMPA for at least two years before age 25, and (3) had used it recently. Cases consisted of 891
women age 25-54 with recently diagnosed breast cancer selected from the National Cancer Registry;
controls consisted of 1,864 women randomly selected from electoral rolls and matched to cases by
age. DMPA had been used by 12.3% of cases and 13.5% of controls. The relative risk of breast
cancer (adjusted for confounding variables) with any duration of use was 1.0. In women age 25-34,
the relative risk was 2.0. For women who first used DMPA before age 25, the relative risk was 1.5.
In both groups, risk was higher in those who used DMPA for six years or longer. The relative risk
for women who last used DMPA within five years was 1.6; the highest relative risk in these women
was associated with the shortest duration of use. For all categories of duration of use, risk declined
with increasing time since last use. The authors determined that a possible explanation for this
finding is that DMPA increases the risk of breast cancer only during the first few years after
exposure, suggesting that it may act as a promoter during late stages of carcinogenesis. The authors
commented that these results could be interpreted to-mean that DMPA has an initial harmful effect,
followed by a protective effect, and noted the need for additional research to clarify the findings.
2
'urrent
abstracts
July 1990
while 19 women said a WPC-333 was less convenient and 6 said it was less comfortable than a male
condom, some 80% said they would advise other sex workers to try it. The women were counseled
concerning their risk for AIDS and how to use the new device, then given unlubricated WPC-333s,
lubricant, and male condoms and allowed to decide which device to use, if any. All women tried
the WPC-333. After two weeks and 247 episodes of vaginal intercourse, they reported their use of
the devices: no device, 34%; male condom, 35%; WPC-333,32%. The women's principal objections
to the WPC-333 were that it was too big (17 cm) and, since it needed to be lubricated, was messy and
inconvenient. Partner reaction to the WPC-333 varied: half of the women said all of their partners
objected to it, 40% said partner reaction was mixed, and 10% said all of their partners approved of it.
No rips or tears in the WPC-333 were reported. Researchers plan to repeat the study at the same site
using 15 cm prelubricated WPC-333s.
Long-Acting Progestins
Zimmerman, M. et al. Assessing the acceptability of NORPLANT® implants in four countries:
findings from focus group research. Studies in Family Planning. Vol. 21, No. 2, March/April
1990, pp. 92-103.
This qualitative research project conducted in four countries where NORPLANT® contraceptive
implants had been available for at least five years produced new data and confirmed previously
reported findings on attitudes, perceptions, and experiences related to NORPLANT®. Focus group
discussions and in-depth interviews were held in the Dominican Republic, Egypt, Indonesia, and
Thailand with potential acceptors, current NORPLANT® users, discontinuers, husbands of women
in these three groups, and service providers. Perceived advantages of NORPLANT® use were
similar in all countries and included ease of use; high, long-lasting effectiveness; reversibility; and
few side effects compared with other methods. Potential acceptors in all countries were concerned
about pain during insertion and removal. In all countries there was evidence that some women did
not have access to removal services for a variety of reasons; for example, some providers were
reluctant to remove an expensive method after short-term use, women migrated to areas that lacked
trained personnel, etc. Among the major findings were (1) service providers need additional
technical training in insertion, counseling, and removal and (2) additional and better information on
NORPLANT® is required for various audiences, including friends and family of potential users.
Pregnancy Termination
Grimes, D.A. et al. Predictors of failed attempted abortion with the antiprogestin mifepristone
(RU 486). American Journal of Obstetrics and Gynecology, Vol. 162, No. 4, April 1990, pp. 910917.
This U.S. study found three factors significantly associated with likelihood of failed abortion with
RU 486 use: drug regimen used, patient body mass, and Inhuman chorionic gonadotropin (B-hCG)
level before treatment. The analysis included data for 271 women who received various regimens of
RU 486 for early pregnancy termination (less than 50 days amenorrhea) in research trials from 19841989. Thirteen different regimens were used, grouped into three categories for analysis. The
regimen used was the most powerful predictor of failed abortion: women who received 600 mg of
RU 486 (single or multiple doses with or without prostaglandin) (118 women) were significantly less
likely to experience failure compared with women who received various doses over 7 days
'urrent
Lbstracts
October 1990
Long-acting Progestins
Singh, K. et al. A three-year clinical evaluation of NORPLANT-2® rods in Singapore. Advances in
Contraception, Vol. 6, No. 2, June 1990, pp. 63-69.
Three-year data for 100 NORPLANT-2® users in Singapore showed that, among these women,
NORPLANT-2® was highly effective, safe, and well-accepted. Women in the study were age 18-40,
had demonstrated fertility (at least one birth), and were at risk of pregnancy. All 100 women were
followed for the full three years of the study. There were no accidental pregnancies. Twenty-six
women requested removal: 14 because a pregnancy was desired, 8 for bleeding disturbances, and 4
for other medical reasons. Prolonged bleeding was the most common side effect. All types of
bleeding disturbances diminished over time; incidence of disturbances after three years was:
prolonged or frequent bleeding, 0%; infrequent bleeding, 4.1%; and amenorrhea, 3.5%. Of the 14
women who stopped using NORPLANT-2® to become pregnant, 7 conceived within 3 months of
removal, 4 decided not to become pregnant and adopted another contraceptive method, and 3 failed
to become pregnant during the study period.
Intrauterine Devices
Chi, I. etal. Is the Copper T 380A device associated with an increased risk of removal due to
bleeding and/or pain? An analysis. Contraception, Vol. 42, No. 2, August 1990, pp. 159-169.
Analysis of 12-month data from four randomized comparative clinical trials showed that the
Copper T (TCu) 380A was at least as effective as the comparative device (TCu 200, TCu 220C,
Multiload 250, or Lippes Loop D) and was no more likely to be removed for bleeding and/or pain.
Data were collected at four sites (two in Latin America and two in Asia) between 1984 and 1987 and
involved 1,181 insertions performed at least 42 days after the last pregnancy. At all sites, the 12month accidental pregnancy rate was consistently lower for TCu 380A users than for users of the
comparative device. The difference in pregnancy rates was statistically significant only when the
TCu 380A and TCu 200 were compared. There was no statistically significant difference in any of
the trials between the TCu 380A and the comparative devices in removal rates for bleeding and/or
pain: the rates were (1) TCu 380A, 6.6% and TCu 200,3.2%; (2) TCu 380A, 0.9% and TCu 220,1.5%;
(3) TCu 380A, 1.5% and Multiload 250,2.0%; and (4) TCu 380A, 3.1% and Lippes Loop, 4.9%. None
of the findings changed substantially when data for 31 nulligravid women were excluded from the
analysis.
Sinei, S.K.A. et al. Preventing lUCD-related pelvic infection: the efficacy of prophylactic
doxycycline at insertion. British Journal of Obstetrics and Gynaecology, Vol. 97, No. 5, May 1990,
pp. 412-419.
A study of 1,655 Kenyan women followed for one month after IUD insertion found that a single
dose of the antibiotic doxycycline (200 mg) given orally at least one hour before the insertion was
associated with a reduced rate of unplanned clinic visits for IUD-related problems. Women in the
study had requested IUD insertion at a Nairobi hospital clinic between December 1984 and January
1986. Those who did not have pelvic inflammatory disease (PID), had not used antibiotics within
the last two weeks, and otherwise met the study's inclusion criteria were randomly assigned to
receive doxycycline (827 women) or a placebo (828 women). The rate of unplanned clinic visits
within one month of insertion for IUD-related problems was significantly lower in the doxycyclinetreated group (8.9%) than in the placebo-treated group (13.0%). The rate of PID one month after
3
Pgmislatfon
HIGHLIGHTS
How Norplant works.................. 3
How Norplant compares with
other methods......fe:>............. 4
Easy to use, safe, and reversible.5
Changes in bleeding patterns
most common side effect....... 5
Next generation of implants
tested........................................ 7
Norplant use in Indonesia,
Thailand, and Colombia ......10
Users like and recommend
Norplant ................................12
Questions women ask—
and answers............ .............. 14
Positioning Norplant helps
clients, programs.................... 16
High-quality services essential .19
Avoid unnecessary barriers...... 21
Norplant counseling crucial ....23
Resources available for
program managers................27
CONTENTS
What Is Norplant?....................... 3
Norplant Comes of Age............. 9
Deciding on Norplant.............. 13
Planning To Introduce Norplant 22
Bibliography.............................. 29
Published with this issue:
"Norplant at a Glance" fact sheet
for policy-makers; "Guide to Nor
plant Counseling" for providers
Printed, Published & Edited by
Dr. J.K. Jain for Dr. Jain Clinic Pvt. Ltd.
A-39, NDSE-n, New Delhi-110 049.
Printed at Surya Art Press, C-4 Sector II,
N0IDA, Ghaziabad (UP.)
Volume I, Number 2
Series K, Number 4
fsnoos for
fPorpfamt Programs
Norplant is new. After decades of care
ful development and testing, Norplant
implants are taking their place as the
newest choice among family planning
methods. Family planning programs
now face important decisions about
whether to offer Norplant and how to
offer it in ways that meet clients' needs.
Norplant is already becoming popular. To date the implants
are widely available or their use is expanding rapidly in 14
countries, including Indonesia, Thailand, and the US. An esti
mated 1.8 million women have used the method. Regulatory
agencies in 23 countries have approved the product.
What Is New About Norplant?
The unique feature of Norplant is how it is used. Six flexible
capsules, each about the size of a paper match, are placed
just under the skin of a woman's upper arm. For five years
the capsules steadily and slowly release a hormone that pre
vents pregnancy. Only one woman in every 500 becomes
pregnant in the first year of Norplant use—a first-year rate as
low as for any temporary family planning method. Over five
years, one in every 25 women becomes pregnant. When the
capsules are removed, a woman's normal fertility returns
quickly. In the meantime, the method is easy to use: the user
needs to do nothing more to avoid pregnancy.
Norplant implants are likely to suit some women especially
well. Norplant may particularly suit women of all ages who
do not want to become pregnant for several years, women
Implants for Injectables
May 1993
who want no more children but do not want or cannot ob
tain sterilization, women who want the effectiveness of a hor
monal method without the side effects of estrogen, women
who do not want to worry about remembering a daily pill,
and women far from dependable supplies of contraceptives.
This issue of Population Reports was
prepared by Ann P. McCauley, Ph.D.,
and Judith S. Geller. Ward Rinehart,
Editor. Stephen M. Goldstein, Manag
ing Editor. Design by Linda D. Sadler.
Production by Merridy Gottlieb.
Like every other family planning method, Norplant implants
also have drawbacks. Like voluntary sterilization and intrau
terine devices (IUDs), implants depend on specially trained
personnel, who must insert and remove.them. Like progestinonly injectables and minipills, they change menstrual pat
terns in most women. Also, they cost donor organizations
and developing-country family planning programs US$23
per set, not including training, salaries, and other service
costs for counseling, insertion, and removal. In the US, a set
of Norplant capsules costs $350.
The assistance of the following review
ers is appreciated: Marcia Angle, Clay
ton Ajello, Lynn Bakamjian, Sandor A.
Balogh, Karen J. Beattie, Jane Bertrand,
John Bratt, Cynthia Calla, Susan Coch
rane, Elizabeth Crane, Philip Darney,
Andrew Davidson, Juan Diaz, Laneta
Dorflinger, George Huggins, Roy Jacobstein, Barbara Janowitz, Neeraj
Kak, Laurie Krieger, Liisa Lindstrom,
James McCarthy, Maria McDonald,
Noel McIntosh, W. Henry Mosley,
Phyllis Tilson Piotrow, Malcolm Potts,
Jose G. Rimon II, Judith Rooks, Pramilla^r>
Senanayake, James Shelton, Irving"
Sivin, J. Joseph Speidel, Sandra Wald
man, Edward Wallach, Celia Woodfill,
and Margot Zimmerman. Some review
ers read portions of the manuscript;
others, all.
Deciding on Norplant
Because Norplant use depends on providers, a program that
decides to offer Norplant makes a special commitment to
meeting users' needs. These needs include a free and in
formed choice among methods, including Norplant; mass
media information and face-to-face counseling that help
clients understand Norplant and decide whether it will suit
them; services that do not create unneeded barriers to using
Norplant by requiring unnecessary tests, procedures, or eligi
bility criteria and yet give adequate attention to clients who
want more attention; help on hand when users need advice;
and convenient services when they want the capsules re
moved. Programs must decide whether they can afford the
necessary high quality of care, keeping in mind that in the
long run poor care is more costly and more wasteful than
good care.
Introducing Norplant
For programs that choose to offer Norplant, a clear consen
sus on its role is important. Managers in each program need
to assess what are the most important characteristics of the
new method, who might find Norplant most appealing, and
what implants offer compared with other available meth
ods—a planning process known as positioning. The role of
Norplant in a program may depend greatly on what other
methods, such as voluntary sterilization, IUDs, and oral con
traceptives, are available and popular.
Program managers may want to position Norplant for
women who want long-term, reversible contraception. At the
same time, providers should not withhold Norplant or any
other method from any client who can use it. Nor should
they pressure any client into choosing it or continuing to use
it against her wishes. In the long run programs are seeking
successful users of family planning, and the most successful
users are satisfied clients.
Suggested citation: McCauley, A.P., and Gel
ler, J.S. Decisions for Norplant Programs.
Population Reports, Series K, No. 4. Baltimore,
Johns Hopkins University, Population Informa
tion Program, September 1992.
Population Reports (USPS 063-150) is publish
ed five times a year (March, May, September,
November, December) at 527 St. Paul Place,
Baltimore, Maryland 21202, USA, by the Pop
ulation Information Program of The Johns
Hopkins University and is supported by the
United States Agency for International Devel
opment. Second-class postage paid at Balti
more, Maryland. Postmaster to send address
changes to Population Reports, Population In
formation Program, The Johns Hopkins Uni-^.'
versity, 527 St. Paul Place, Baltimore, Maryland")
21202, USA.
Population Reports is designed to provide an
accurate and authoritative overview of impor
tant developments in the population field. It
does not represent official statements of policy
by The Johns Hopkins University or the United
States Agency for International Development.
Population Information Program
Center for Communication Programs
The Johns Hopkins School of Hygiene
and Public Health
Phyllis Tilson Piotrow, Ph.D., Director, Center
for Communication Programs and Population
Information Program
Ward Rinehart, Deputy Director, Population
Information Program, and Editor, Population
Reports
Anne W. Compton, Associate Director for
POPLINE computerized bibliographic services
Jos6 G. Rimon II, Deputy Director, Center for
Communication Programs, and Project Direc
tor, Population Communication Services, de
veloping family planning communication
strategies, projects, training, and materials
POPULATION REPORTS
/$ Norplant?
*
Norplant
implants are a new contraceptive method. Nor
plant consists of six flexible capsules, each about the size of
a paper pocket match (see photograph, this page). The
capsules are inserted under the skin usually on the inside of
a woman's upper arm. The implanted capsules prevent
pregnancy by releasing the hormone levonorgestrel into the
blood stream at a slow, steady rate.
during insertion, removal, and the management of side
effects, (2) thorough, high-quality counseling, and (3) pub
licity that appeals particularly to women who might want
Norplant and that informs them of available services (see pp.
16-17). Program managers must plan all of these activities
before they introduce Norplant.
Cost is an issue in deciding how, or whether, to introduce
Norplant. Both the costs of introducing the method and of
providing the implants are higher than those of most other
methods (see p. 15). Introductory costs include training
health care providers to insert and remove capsules and to
Norplant has many advantages. It is:
counsel women. Continuing costs
• Very effective at preventing
include the salaries and infrastruc
pregnancy;
ture for the providers and the cost
• Approved for five years of use;
of the implants themselves, as well
• Reversible at any time by having
as continuing training. Each set of
the capsules removed;
implants costs US$23 to nonprofit
• Free from estrogen side effects;
groups and public organizations
• Easy to use, with nothing to re
in developing countries and to do
member each day or at the time
nor agencies. This commodity cost
of intercourse;
is much higher than the cost of an
• Convenient because there is no
initial supply of other temporary
need to obtain supplies peri
methods. Because Norplant can
odically.
be used for as long as five years,
The chief disadvantagesofthe meth
however, its cost per year may not
od to the user are that she must
be much more than that of some
depend on a health care provider
other methods (see Table 1). The
to insert and remove the capsules
cost per year for an individual
and that the hormone, a progestin,
woman depends on how long she
changes menstrual bleeding pat
uses Norplant. Some women will
terns.
decide to have their implants re
moved before five years of use,
More than 1.8 million women in
51 countries have used Norplant. Norplant implants consist of six small caspules. and these decisions must be hon
Several thousand women have Inserted under the skin of a woman's upper arm, ored. Program managers must be
used Norplant in clinical and pre the capsules prevent pregnancy for up to five years. sure that they can afford to intro
duce and provide Norplant in a
introduction trials conducted by, or
way that does not compromise their clients' right to make
in association with, the Population Council, developer of
their own health care decisions.
Norplant (151, 171). Implants are now widely available or
their use is rapidly expanding in 14 countries including
Indonesia, Thailand, and the United States, where hundreds
The Implant Method
of thousands of women use Norplant. In nine other countries
regulatory agencies have approved Norplant, but it is not yet
Norplant implants combine materials used in other medical
widely available, and three countries without drug approval
products into a new contraceptive delivery system. Norplant
processes offer Norplant in family planning programs. In
consists of a set of six capsules filled with the progestin
these and other countries family planning officials are assess
levonorgestrel, which has been used in oral contraceptives
ing Norplant and considering how to introduce it.
for more than 20 years. The capsules are made of medical
grade Silastic tubing, a material like that used in medical
Norplant expands the range of family planning choices
drainage tubes and prosthetic devices since the 1950s. Each
available to women. As with any method, its unique combi
capsule is 34 mm long and 2.4 mm in diameter (151).
nation of features will serve some women particularly well.
Through a small incision, the capsules are inserted one by
Women who want a long-term, reversible method may
one in a fan-shaped pattern just under the skin.
especially like Norplant. Women who have had, or are likely
to have, difficulties with the intrauterine device (IUD) or the
Each capsule contains 36 mg of levonorgestrel in crystalline
estrogen in combined estrogen-progestin oral contraceptives
form (151, 184).’The six capsules together initially release
may want to try Norplant. Also, women who do not want to
approximately 85 pg per day, decreasing to 50 pg per day
have a pelvic procedure can choose Norplant as an alterna
by 9 months of use, to 35pg per day at 18 months, and then
tive to an IUD. As with other hormonal methods, Norplant
to 30 pg per day during the third, fourth, and fifth years of
can be used by women of any age and by women who have
use (151, 219).
never been pregnant.
How Norplant works. The levonorgestrel in Norplant pre
A new family planning method offers an opportunity to serve
vents pregnancy in several ways. It makes cervical mucus
more people who want to control their fertility. Taking ad
thicker and reduces the amount produced. Sperm have
vantage of this opportunity requires: (1) good medical care
difficulty moving through such thick and meager mucus, and
therefore few sperm pass through the cervical canal to reach
the uterus (32, 44, 151, 219). Also, the progestin suppresses
•NORPLANT is the registered trademark of The Population Council for levonor
ovulation in at least half of menstrual cycles (31). Recent
gestrel subdermal implants.
□
POPULATION REPORTS
3
■■■■■■■
Method
v
.
■
Lowest Expected/
Typical First-Year
Pregnancy Kate
(per 100 Women)
Table 1. Norplant Implants Compared with Other Methods
Continuation Ra e
1 Year/S Years
Resupply
Frequency
Reversibility
Dependence on
Specially Trained
Service Provider
POPULATION REPORTS
Norplant
implants
0.2/D.2c
82-95%/
25-78%d
Immediately
after removal
Every 5 years
High
Tubal ligation
0.2/0.4f
—
None
High
Vasectomy
0.1/0.15f
None
High
Intrauterine
device (IUD)
0.8f/2.0-3.48
Surgery
required;
success not
guaranteed
Surgery
required;
success not
guaranteed
Immediately
after removal
Every 8 years
High
Depo-Provera
injectable/
Noristerat
injectable
Combined oral
contraceptives
O.3/0.3f "1
Usually several
months after last
injection
Depo-Provera: Every
3 months
Noristerat: Every 2
months or 12 weeks
One month per
packet; multiple
packets available
Each act of inter
course; can be
obtained in multiples
Each act of inter
course; can be
obtained in packages
of 6-20
Spermicide at each
act of intercourse;
available in tubes of
various sizes
None
0.4/0.41 J
75-95%/
33-41%"
70%f/NA
o.f/s.g8
73%f/NA
Condoms
2/12f
64%f/NA
1-3 months
after discontinu
ation
Immediate
Spermicide
tablets
3/21f
43%f/NA '
Immediate
Diaphragm +
spermicidal
cream
6/18f
57%k/NA
Immediate
Natural Family
Planning
*
1-9/20
67%'/NA
Immediate .
NA - Not available
aAverage duration of Norplant use in clinal trials
bPrice to United States Agency for International Development (US AID) and United Nations
Population Fund (UNFPA): commodity cost only. Price from International Planned Parenthood
Federation (IPPF) to affiliates: includes commodity, shipping, and shipping insurance.
cSource: Population Council (174)
dSource: Sivin (219)
eTrocar not included
Moderate
Most Common
Side Effect
Approximate
Commodity Cost
for 3.5 Yean?
(US$)b
Changes in
menstrual
bleeding
Postoperative
complications
US AID:$23e
IPPF: $29e
UNFPA: $23c
Some pain &
swelling;
postoperative
complications
Increased
bleeding and
uterine pain
Changes in
menstrual
bleeding
—
—
USAID:$1‘
IPPF: $.80'
UNFPA: $.70'
IPPF:$14/$27
UNFPA: $8/$ 14
Low
Nausea
Low
None
Low
Local allergic
reaction
US AID: $6—$11
IPPF: $8-$24
UNFPA: $6-$7
US AID: $17'
IPPF: $11-$28
*
UNFPA: $9'
IPPF: $30-$43’
UNFPA: $33-$43'
Low
Urinary tract
infection
IPPF: diaphragm $6.50,
spermicide $32—$66'
None
None
Moderate
'Source: Trussell et al. (240). Except for injectables, rates are largely from English-speaking
developed countries; developing-country rates not available.
8Source: Moreno & Goldman (135)
hSource: Sivin et al. (228)
‘For TCu-380A IUD
‘Assumes 150 units = 1 couple-year of protection
kSource: Edelman (61)
research suggests that, even when ovulation occurs, endo
crine dysfunction would usually prevent fertilization of the
egg if sperm were to reach it (72). The constant low levels of
levonorgestrel also may suppress the growth of the en
dometrial lining of the uterus, thus preventing implantation
(46, 200, 201). A recent study of one menstrual cycle per
woman found no sign of fertilization among 32 Norplant
users, but 9 of the 20 women in a control group who wanted
to become pregnant produced the glycoprotein human chor
ionic gonadotropin (hCG), which indicates the presence of
a fertilized egg within nine days after conception. Six of these
women in fact were pregnant (193).
■
Features That Women Most Appreciate
Women who have used Norplant like the fact that the
implants are easy to use, effective, and reversible.
Easy to use. Once the implants are put into a woman's arm,
she needs to take no further steps to prevent pregnancy for
up to five years. Thus Norplant is particularly appropriate for
"\vomen who do not want to worry about remembering to
*take a pill every day or to use condoms, spermicide, or a
diaphragm at the ti,me of sexual intercourse.
Effective. Norplant is one of the most effective contraceptive
methods. The Population Council has compiled annual preg
nancy rates and the cumulative 5-year pregnancy rate for
.2,670 woman in 13 countries (174, 224):
Annual Pregnancy Rates and 5-Year
Cumulative Pregnancy Rate Among Norplant Users
No. of Women
Completing
Year
Year
1,954.
Year 1.........
Year 2..........
1,379
1,067
Year 3..........
743
Year 4..........
476
Year 5..........
5-year cumulative................
Rafe per
100
Women
0.2
or 1 in 500
0.5
or 1 in 200
1.2
or about 1 in 80
or about 1 in 60
1.6
0.4
or 1 in 250
3.9
or 1 in 25
\The first-year pregnancy rate of 0.2 per 100 women for
^Norplant is lower than the first-year rates for injectables, oral
contraceptives, and most other contraceptive methods (129,
151, 240) (see Table 1). In the first year Norplanfis about as
effective as the first year of progestin-only injectables, vasec
tomy, or tubal ligation (154).
Pregnancy rates among Norplant users have been higher
among heavier women than among lighter women. In pooled
data from Population Council studies, women weighing 70
kg or more had a cumulative pregnancy rate of 76 per 100
over five years of use compared with 0.2 per 100 for women
who weighed 50 kg or less (151, 219). During the first two
years of Norplant use, pregnancy rates were similar for
women of different weights, but the pregnancy rate increased
for heavier women after the second year as the daily release
of levonorgestrel diminished (219). It is not known whether
the differences in pregnancy rates are due to dosage require
ments, genetic factors, metabolic characteristics due to dif
ferent diets, or other causes (10).
Preliminary data suggest that pregnancy rates may be lower
in all women and may differ less by weight with new tubing
that has been introduced by the manufacturer, Leiras Oy
(219, 224). By the end of 1992 the Finnish company will
produce Norplant implants only with the new tubing.
POPULATION REPORTS
If a woman wants to continue using Norplant longer than
five years, she can have the original capsules removed and
a new set inserted. After five years of use the capsules
continue to release levonorgestrel but in gradually decreas
ing amounts; thus the risk of pregnancy increases. All women
should have the Capsules removed after five years in any case
because little is known about the effects of implants left in
place longer.
Reversible. The implants may be removed at any time.
Within 96 hours there is little progestin left in the blood (45).
Thus a woman's previous level of fertility returns quickly. In
a study of 17 Nigerian women who discontinued Norplant,
14 ovulated within four weeks, and all ovulated within seven
weeks. Also, cervical mucus gradually increased, and by the
seventh week 80% of the women had mucus levels sufficient
to facilitate pregnancy (110).
Several small studies show that more than 75% of women
who want to become pregnant do so within one year after
the implants are removed, a rate similar to those for most
other methods (57, 140, 151, 191, 209, 219, 232). In studies
of 260 women of similar age and parity in Indonesia and
Chile, pregnancy rates at four months were similar to those
of women who had stopped using the IUD and higher than
those of women who had stopped using injectable contra
ceptives, which are known to delay the average return of
fertility somewhat beyond when the next injection would
have been given (8, 57). The length of time that a woman
has used Norplant does not affect how soon she conceives
after the capsules are removed (57, 232). In the Nigerian
study, however, those with regular cycles while using Nor
plant had more cervical mucus; they also ovulated and
became pregnant more quickly after discontinuation (110).
•.
Continuation Rates
Continuation rates for Norplant in clinical trials have matched
or exceeded rates in clinical trials of,the IUD, the other
multi-year reversible contraceptive method (3, 126). The
average user in clinical trials has relied on Norplant for about
3.5 years (224). Rates have varied, however. In five studies
around the world, 76% to 90% of users completed one year
of use, and 33% to 78% completed five years (219,224). Most
women who discontinue Norplant for method-related rea
sons cite the changes in menstrual bleeding patterns that are
common with this method. Others have the-capsules re
moved because of headaches, weight gain or loss, hyperten
sion, expulsion of a capsule, acne, h,air loss, or hair growth.
Norplant users in clinical trials had the capsules removed for
other reasons as well. Some wanted to become pregnant, or
their husbands objected to implant use. Others were moving,
or they were widowed or divorced (7,14,107,187, 190,219,
230).
■
Side Effects
The side effects of Norplant resemble those of progestin-only
pills (minipills) and progestin-only injectables. Change in
bleeding patterns is by far the most common side effect.
Bleeding patterns. In various clinical trials 60% to 100% of
women experienced menstrual changes (190, 219,225). The
changes that women experience vary greatly. They include
bleeding on more days per cycle, heavier bleeding, spotting
between periods, infrequent or scanty bleeding, and amen
orrhea (no.bleeding at all).
5
patterns (201). Women in the US study were heavier
than those in other clinical trials, and heavier women
are more likely to ovulate (47). The women in the study
were not using implants made with the new tubing,
which is expected to lower pregnancy rates.
Although a woman may experience bleeding at shorter
intervals or bleeding on more days, she is likely to lose
less blood than if she had a normal menstrual period
(219). In some studies the hemoglobin levels of Nor
plant users are higher than those of control groups—a
beneficial effect for anemic women (64, 73, 151, 201,
219). Not surprisingly, women whose bleeding de
creased while using Norplant were most likely to have
higher hemoglobin levels (73).
Other physical effects. Clinical trials comparing Nor
plant and IUD users find that certain conditions are
statistically associated with Norplant (see Table 2).
These conditions include headache, nervousness, nau
sea, dizziness, dermatitis (skin rash), acne, change of
appetite, hairloss, increase in facial or body hair, breast
tenderness, nausea, and enlarged ovarian follicles (14, Q
A thin woman may see the outline of the capsules when she extends her 51,107,151,174,190,219). Although women who used
arm. Most women can feel the capsules with their fingers, but they cannot Norplant reported these conditions more often than did
see them. Some women are pleased when others notice their implants. women who used IUDs, it is not clear how implants
might cause them. Acne, hair growth, and hair loss may
be due to the androgenic activity of the hormone and
Women who weigh less may be more likely to experience
are seen in women using oral contraceptives that contain
amenorrhea. For example, in a study of women in the US
levonorgestrel (26, 51). Ovarian follicles sometimes become
who weighed an average of 65 kg, 7% were amenorrheic
large enough to feel like cysts to a physician doing a pelvic
(201). In contrast, 20% to -30% of women were amenorrheic
examination. These follicles usually disappear without treat
in a study in Sri Lanka and the Philippines, where women
ment. Surgery is necessary only on the rare occasions that
are generally lighter (21). In a study of 1,000 Norplant users,
the follicles twist and rupture, causing pain (174).
lighter women in Chile, Sri Lanka, and Thailand had less
Insertion-site complications. If aseptic technique is used
irregular bleeding and less intermenstrual bleeding than
during insertion, the implant site seldom becomes infected.
heavier women, but the pattern was reversed among Chinese
Other insertion-site complications also are uncommon. A
women, suggesting that dietary, genetic, or other factors may
pooled analysis involving 2,674 first-year users in seven
influence bleeding patterns (10). It is impossible to predict
countries found that 0.8% experienced infection, 0.4% ex
accurately, however, just what pattern an individual woman
perienced expulsion of a capsule, and 4.7% had temporarily
will experience.
irritated skin at the insertion site (104).
A Norplant user who has regular menstrual periods may be
Insertion-site complications did not always occur immedi
ovulating regularly and therefore face greater risk of preg
ately after implantation. Some 35% of infections and 64% of Qi
nancy (54, 58, 201). In a US study of Norplant use, the
expulsions took place after the first two months of use.
cumulative 5-year pregnancy rate was 1.4 per 100 women
Similarly, 36% of skin irritations occurred after 4.5 months
overall but 17.4 per 100 for women with regular bleeding
or more of use (104).
Some clinics have lower rates of
..'t
'
infection at the insertion site than
% Developing Condition in First Year of Use
others. The differences suggest
Table 2
Study 1
Study 2
that some providers are more
■ Norplant Side
Norplant
IUD
Norplant
IUD
careful than others about main
7.0
18.5
10.2
Headache....................... .. 16.7
■ Effects
taining aseptic conditions during
2.0
3.1
2.6
Conditions Other Ovarian enlargement.... .. 11-6
insertion (24, 78, 104, 105).
4.0
5.6
8.1
5.9
Dizziness........................ ..
than Changes in
Duration of side effects. Side ef
1.7
6.2
6.8
4.7
Breast tenderness.......... ..
Bleeding that
fects,
including disruption of
6.8
2.0
6.2
2.4
Nervousness...................
Occurred
bleeding patterns, appear to be
1.7
7.7
5.1
Nausea........................... ..
4.0
Significantly More Acne...............................
most common and most severe
4.5
1.0
7.2
* 2.6 .
Often with
during the first year of use, when
3.8
0.7
8.2
Dermatitis...................... .
1.9
Norplant than
progestin levels in the blood are
3.5
2.7
5.1
Breast discharge.............,.
1.9
highest (186). In one study 72%
with IUDs in Two Change in appetite........ .
0.7
3.5
6.2
1.9
of participants had irregular
1.0
3.3
Multinational
6.2
Weight gain.................... .
0.9
bleeding
patterns during the first
.
1.8
0.5
Hair
growth
or
loss
.......
2.6
0.5
*
Studies
year, but by the fifth year only
'Condition occurred more frequently with Norplant in at least one study or in
38% had irregular bleeding pat
combined results.
terns (201) (see Figure 1).
Source: Population Council (159)
Women who abandon Norplant
■■■■■MHU
6
POPULATION REPORTS
Next Generation of Implants Tested
The progress of Norplant implants has set the stage for the
development of other implants. Several different hormonal
implants now under development may follow Norplant. All
involve fewer capsules than Noiplant, and some are biode
gradable—that is, they dissolve harmlessly in the body and
do not require removal.
Norplant II
The first implant to follow Norplant is likely to be Norplant
II. The Population Council is developing this implant, which
consists of two rods slightly longer than Norplant capsules.
While each Norplant capsule contains levonorgestrel in a
cavity, the Norplant II rods contain levonorgestrel embedded
homogeneously within a Silastic rod, which is covered by a
thin sheath of plain Silastic (155, 175). Side effects are simi
lar in type and frequency to those of Norplant (142,204,
207), but Norplant II should be easier to implant and to re
move because there are fewer rods. Clinical tests on an early
version indicate that it is effective for al least three years (38,
106, 151, 162, 180,206,219,232). The new formulation of
Norplant II now being tested, however, may prove to be ef
fective for up to five years (183). Clinical studies now in pro
gress will be used to support applications for regulatory
approvals, which may be filed by the mid-1990s (249).
Implanon
Implanon, developed by Organon International, is a single
30 mm Silastic rod that releases the progestin 3-keto desogestrel at the rate of 30 pg per day. Like Norplant, Implanon
can be placed under the skin with a trocar. Implanon appears
to be effective for two to three years. Removal is quick and
relatively simple since there is only one rod to locate. Bleed
ing patterns are similar to those seen with Norplant, but 3keto desogestrel may inhibit ovulation more often than does
levonorgestrel at the levels released (112, 141). Clinical tri
als of Implanon are underway in the US, several European
countries, and countries in East Asia including Indonesia.
Depending on the results, Organon will decide whether to ap
ply for regulatory approval in the US and elsewhere. Or
ganon also is attempting to develop a biodegradable version
of Implanon but has not yet begun trials (112).
ST-1435 Single-Rod Implant
The Population Council is now testing a single modified Si
lastic implant using the new progestin ST-1435, which has a
contraceptive effect and side effects similar to those of
levonorgestrel. The implant, effective for two years, contains
ST-1435 crystals encased in a rate-limiting cellulose mem
brane in the Silastic capsule, which releases the progestin at
the rate of 100 pg per day. Like other effective progestins,
ST-1435 both inhibits ovulation and thickens cervical mucus
to prevent pregnancy. Unlike most other progestins, how
ever, ST-1435 appears to have no effect on blood cholesterol
levels. Also, it is inactive when swallowed and so would
have no possible effect on a nursing infant. The Population
Council has completed early clinical trials on 120 women in
Chile, the Dominican Republic, and Finland; has plans for
POPULATION REPORTS
multicenter trials; and expects this implant to be on the mar
ket by the year 2000 (84, 183,237).
Capronor
The Research Triangle Institute currently is developing two
new versions of its biodegradable implant Capronor—
Capronor 2 and Capronor 3. Capronor 2 is a 4 cm capsule of
the polymer caprolactone filled with 18 mg of levonorges
trel. Recent research shows that two capsules may be re
quired with this formulation. Capronor 3 is a single 4 cm
co-polymer capsule (a caprolactone and trimethylenecarbon
ate blend) filled with 32 mg of levonorgestrel. Thus far, no
human trials have been conducted with these new formula
tions, but nonhuman primate studies are encouraging and in
dicate very steady release rates in both versions. The
co-polymer blend releases the drug more readily, allowing a
thicker capsule that produces a more steady release of the
hormone. The co-polymer also biodegrades more quickly
than the single polymer (30).
In earlier formulations of Capronor—which consisted of
levonorgestrel suspended in an oily solution of ethyl oleate
within caprolactone tubing—clinical studies on women
showed promising results for a biodegradable implant. It was
effective for only 8 to 10 months, however, in part because
of an unsteady release rate caused by the ethyl oleate vehi
cle, now eliminated.
The Capronor tubing appears to be easier to insert and re
move than Norplant’s Silastic tubes in part because the
caprolactone polymer has a slipperier surface and offers less
resistance in body tissues (52, 128). The capsule remains in
tact through the 12-month period of levonorgestrel release.
Thus it may be removed during this interval if desired. Later,
however, over several years the capsule biodegrades gradu
ally to E-hydroxycaproic acid, then to carbon dioxide and
water, which are absorbed by the body (50). Capronor may
be available by the end of the 1990s.
Norethindrone Pellets
Small pellets made of 90% norethindrone (NET) and 10%
pure cholesterol are another biodegradable implant, now un
der study by Family Health International. The very small
amount of cholesterol in each pellet—less than 2% of the
cholesterol in a single chicken egg—helps the pellets main
tain integrity and is considered harmless. Current clinical
studies in the US are testing regimens of four and five pel
lets. Each pellet is 8 mm long and contains about 35 mg
NET. The hormone is released as the pellets gradually biode
grade over a 12-month period and then disappear completely
within 24 months. During the first 12 months—the period of
contraceptive effectiveness—the pellets can be removed if
desired. The pellets are inexpensive to make. It may be many
years before the pellets become available; researchers are
still testing different fonmulations in an attempt to improve
efficacy (77, 119, 128,211).
Figure 1. Bleeding Patterns
Based on the Dominant Pattern of Bleeding Reported for Each Year of
Implant Use During Five Years of Use, 198 Women, United States
the pregnancies that do occur are ectopic, how
ever. In five years of clinical trials, 8 of the 46
pregnancies that occurred, or 17%, were ec
topic (219, 224).
Ectopic pregnancy rates among Norplant users
may be higher among heavier women and may
increase with longer use of Norplant (151,174).
Health care providers should consider ectopic
pregnancy when examining a Norplant user
who becomes pregnant or has lower abdominal
pain. The possibility of increased ectopic preg
nancies with longer use reinforces the need to
remove the implants after five years, at least
until longer use is studied further.
■
Physiological Effects
because of bleeding problems account for part of this de
crease, but some women who continue to use Norplant
experience decreases in bleeding over time. In a study of 116
women who kept menstrual diaries for five years, the number
of bleeding and spotting days decreased each year from a
mean of 92 in the first year to 70 in the’fifth year (151, 219).
In some women a bleeding pattern becomes established by
six to nine months, but that pattern may not be a monthly
cycle. The pattern may change little thereafter (24, 122, 219,
247).
One small study suggests that normal menstrual patterns
resume after Norplant use. Of 12 Singapore women who
discontinued use because of changed menstrual patterns, all
reported normal periods one year after removal (209). The
World Health Organization (WHO), Family Health Interna
tional (FHI), and the Population Council are now conducting
a postmarketing study on reversal of side effects after discon
tinuation as well as other aspects of Norplant use.
Ectopic pregnancy. As with other hormonal contraceptive
methods, ectopic pregnancies among Norplant users are a
concern in the rare event that conception takes place. Pro
gestin may reduce the motility of the fallopian tubes, slowing
the progress of a fertilized egg and increasing the chances of
implantation in the tube rather than the uterus (201). Ectopic
pregnancies can rupture tubes and cause internal bleeding
and death.
Studies of physiological effects indicate that
Norplant is safe. Studies have found no signifi
cant changes in liver, kidney, adrenal, or thy
roid function in Norplant users (151). Studies of
cholesterol levels have yielded ambiguous re
sults (87, 151). Although levels of total choles
terol consistently decreased, half of the studies
found that the level of high-density lipoproteins
(HDD significantly increased—a beneficial effect—and the
other half found that HDL decreased (87,151,195,202,203,
208). The results of studies on clotting factors also vary,
suggesting that other influences, such as diet, may be in
volved (151,195, 205). Until more is known, the Population
Council suggests assuming that clotting factors change as
they do in women who use combined estrogen-progestin
oral contraceptives. They do not recommend Norplant for
women with blood clots in the legs or eyes, which may be
evidence of active cardiovascular disease (151). Such
women are at greater risk for complications in pregnancy,
however. If they cannot or will not use a reliable nonhormonal method, progestin-only methods such as Norplant are
preferable to combined oral contraceptives.
Norplant probably does not heighten the risk of strokes and
heart attacks, as has been alleged with oral contraceptives
and blamed largely on the estrogen component. Norplant
contains no estrogen. Still, lacking long-term epidemiologic
studies on circulatory system disease and Norplant use,
which are feasible only after a method is widely used, the
United States Food and Drug Administration j^JS FDA) and
the Population Council have chosen a conservative ap
proach and suggest that women who have hypertension, an
important risk factor for stroke, should use a nonhormonal
method unless their blood pressure can be regularly moni
tored (174). A study of 600 Norplant users in Indonesia found
no change in blood pressure during the first year of use,
however (123). A recent Nigerian study of 117 low-dose pill
users and 76 Norplant users found that increases and de
creases in blood pressure occurred with about equal fre
quency and in both groups. The change in either {direction
was moderate, but the range with Norplant was narrower
than with oral contraceptives (65).
Among Norplant users the rate of ectopic pregnancy is lower
than among women who use no contraceptive method. In
the US the estimated ectopic pregnancy rate among women
who do not use contraception is 6.5 per 1,000 woman-years.
The rate may differ substantially in other countries (121,214).
Among Norplant users in clinical trials, the rate of ectopic
pregnancies was 1.3 per 1,000 woman-years (15J). By com
parison, the estimated ectopic pregnancy rate for unmedi
Recent studies report that glucose and insulin levels rise
cated IUDs is about 1.2 per 1,000 woman-years of use, and
slightly when women start Norplant but remain within the
the estimated rate for combined oral contraceptives, which
normal range. These studies suggest that Norplant may affect
prevent ovulation, is 0.4 per 1,000 woman-years (214). The . carbohydrate metabolism (108, 109, 203, 205, 210, 241). A
rate of ectopic pregnancies is lbw for Norplant users because
woman with diabetes can use Norplant, however, if she or a
there are so few pregnancies at all. A higher percentage of
health care provider can monitor her condition.
POPULATION REPORTS
Norplant
Comes of Age
The Population Council began work on an im
plantable contraceptive in 1966. In the 1990s
that work is reaching its objective as Norplant,
the first implantable contraceptive, wins govern
ment approvals around the world and attracts
more users. Over the years of development,
research focused first on effectiveness and safety
and then on Norplant users' opinions, the man
agement of side effects, and program managers'
needs. The Population Council has planned the
introduction of Norplant to ensure that programs
offer the implants with good medical care and
counseling that helps women make a free and
informed choice among methods.
cosmetic purposes (246), Silastic is a solid and
does not leach into body tissue or circulation.)
In 1965 Sheldon Segal, then head of the Popu
lation Council's biomedical research staff, hap
pened to discuss the properties of Silastic over
lunch with a representative of its manufacturer.
The conversation concerned an experiment in
which a dye from Silastic tubing used in canine
pacemakers dispersed and harmlessly disap
peared into the animals' systems (93). This dis
cussion suggested to Segal that a similar slow
diffusion of progestin might provide long-term
contraception—a conclusion soon confirmed
by research (192).
Horacio Croxatto, a Chilean physician then a
Fellow at the Population Council, developed
the delivery system by creating the capsule
(93). Over time his research team tested various
Several organizations have cooperated in the
synthetic steroids and various capsules in ani
development of Norplant. The Population Coun
mals to ascertain their different release rates.
cil has developed the implant concept, has con
ducted and overseen research and development, Clinical trials. Multinational blind comparative
and is guiding the process of introduction. studies took place in 1974. Researchers tested
Wyeth-Ayerst Pharmaceutical Company carried implants containing eight different progestins
out the toxicology studies on its drug, levonor in 36 different doses with 1,100 volunteers (93).
gestrel, and Leiras Oy designed the equipment These studies gathered information on efficacy,
used to manufacture the capsules. The United duration of effect, and side effects.
States Agency for International Development
(US AID), the International Planned Parenthood Clinical trials of the three most promising cap
Federation (IPPF), the United Nations Population sule and progestin combinations began in Bra
Fund (UNFPA), and governments and private zil, Chile, Denmark, the Dominican Republic,
organizations in several countries supported Finland, and Jamaica in 1975 (93). In these
trials 1,500 women volunteered to use the im
clinical and pre-introduction trials.
As of mid-1992 Norplant has been used in 51 plant formulations, which were randomly as
countries and is widely available or rapidly be signed. The volunteers were asked to keep
coming available in 14 (see table on back of records of their menstrual patterns and to return
"Norplant at a Glance,-" published with this is for follow-up visits for one year (93, 151). In
sue). Norplant is playing different roles in the 1977 levonorgestrel was chosen as the pro
family planning programs of different coun gestin for the new implants because of. its long
tries—roles influenced primarily by the range of period of effectiveness and high level of effec
other methods available and differing abilities to tiveness, and because extensive toxicity test
results were already available (93, 151). More
pay for supplies and services.
clinical trials began between 1980 and 1982 in
Chile, the Dominican Republic, Finland, Swe
den, and the US (151).
Chronology of
Norplant Development
..
Research on implants
begins
First tolerance trial
First clinical trial, in
Chile
. .
Clinical trials in 6
countries; pharmaco
logical studies in US
1977 Levenorgesterel
formulation chosen
. 4979 NORPLANT registered
as trademark for
implants
■ -1980-82 Pre-introduction
trials in 5 coun
tries; clinical trials
in 5 more countries
• -1983 Leiras Oy is licensed
to produce Norplant;
Finland is first to give
regulatory approval
• -1984 Pre-introduction trials
begin in 11 more
countries
■ -1985 WH0 andIPPF review
Norplant favorably;
Sweden approves
Norplant
■ -1986 IPPF makes Norplant
available; Dominican
Republic, Ecuador,
Indonesia, and Thai
land approve Nor
plant
1987 China, Colombia, Peru,
and Venezuela ap
prove Norplant; Pre
introduction trials in
12 more countries
History of Development
The development of oral hormonal contracep
tion—the pill—in the 1950s paved the way for
implantable methods. First with the combined
estrogen-progestin pills and then with the progestin-only pills, researchers learned the dos
ages of these synthetic steroids required to
prevent conception (191). Of all the progestins,
or progesterone-like compounds, tested,
levonorgestrel eventually became one of the
most widely used in oral contraceptives as well
as the progestin chosen for Norplant (93).
The method of delivery, not the active agent,
makes Norplant unique among contraceptives.
Silastic, a polymerized silicone rubber material,
is used in surgical tubing, pacemakers, and pros
thetic devices because it is well tolerated by the
body. (Unlike the silicone gel in the now-contro
versial breast implants used for prosthetic and
POPULATION REPORTS
Pre-introduction trials. Norplant pre-introduc
tion trials began in 1980 and have taken place
in 43 countries in all regions (see table on back
of "Norplant at a Glance"). Pre-introduction
trials typically involve more women and more
service sites than clinical trials. About 40,000
women have participated, although published
results are not available for most of these stud
ies. These trials help to design appropriate
training and informational materials for provid
ers and users, to acquaint local medical person
nel with the method, and to gather
country-specific information for local regula
tory approval. In addition, this experience with
a small program assists managers later with
logistics, training, and service delivery on a
larger scale (19, 233). The Population Council
has collaborated with FHI, the Program for
Appropriate Technology in Health (PATH), and
■ 1988 Application made to
US FDA; Chile and
Sri Lanka approve
Norplant
■1990 l S FDA approves
Norplant
1991
.6 million women
in 51 countries have
used Norplant; 23
countries have given
regulatory approval
1992 Leiras Oy switches
to soft tubing, semi
automatic production
Orange type = Early implant research before
current Norplantformulation was determined
Sources: Adaptedfrom Population Council
(151. 171). IDRC/Population Council (93)
9
the Association for Voluntary Surgical Contraception
(AVSC) in pre-introduction and information efforts.
WHO, FHI, and the Population Council now are collaborat
ing on a postmarketing study of 8,000 Norplant users and
8,000 sterilization or IUD users in Barbados, Chile, China,
Colombia, Indonesia, Sri Lanka, and Thailand. Focused on
safety, the study will follow up all of the women as they use
their contraceptive method for five years. All women who
discontinue any time after six months of use also will be
followed up. The findings should be able to identify healthrelated events associated with implant use that occur with a
frequency of one per 2,000 women or greater (158, 224).
■
Regulatory Approvals
By August 1992 Norplant had been approved for marketing
in 23 countries and adopted by family planning programs in
3 more countries that have no regulatory approval process.
The first country to approve Norplant was Finland, in 1983.
This approval permitted Leiras Oy to export the capsules. As
manufacturer of Norplant, Leiras Oy prepares the documents
for submission to national drug regulatory agencies in all
countries except the US. The Population Council, which
applied to the US FDA, received regulatory approval for
Norplant on December 10, 1990. Most countries require
regulatory approval before a drug can be marketed, but
manufacturers do not always immediately market the ap
proved product. Thus Norplant is not widely available in all
countries where it has been approved.
Leiras Oy and Wyeth-Ayerst Pharmaceutical Company have
agreed on Norplant production and distribution. Wyeth-Ay
erst produces levonorgestrel and sells it to Leiras Oy. Leiras
Oy manufactures all of the implants and sells them to WyethAyerst, donor agencies, government family planning pro
grams, and pharmaceutical distributors in countries other
than the US and Canada. Wyeth-Ayerst markets Norplant in
the US and, when approved, in Canada.
As noted (see p. 5), Leiras Oy has changed the Silastic used
in making the capsules. This shift required changing the
manufacturing equipment used in semi-automated produc
tion. Some regulatory bodies including the US FDA had
earlier approved the capsules made manually with the new
tubing. Leiras Oy must submit a supplement to the approved
US FDA application to cover implants produced by the
semi-automated process. Most other countries have already
certified the implants with the new tubing made by the
semi-automated manufacturing process. Supply of Norplant
has not been affected by these changes (86, 257).
□
Norplant in the United States and Europe
Early clinical trials in the US, supported by US AID, involved
400 women and took place in the 1980s in Los Angeles, San
Francisco, and New Brunswick, New Jersey (224). WyethAyerst began preparing for nationwide introduction in 1988,
when the company decided to market Norplant in the US
(175). In the first two years that Norplant was available in the
US, about 500,000 women obtained implants. Almost threequarters were under age 30. About half were married (264).
While the price for implants is US$23 per set for donor
agencies and developing-country, not-for-profit family plan
ning programs (see p. 15), in the US the price for a set of
Norplant implants is US$350 to both public clinics and
private physicians (117, 252). All contraceptives are more
10
expensive in the US than in developing countries. The US
price covers Wyeth's expenses for its training program, pro
motion and sales of the method, and individual packaging
of each implant with all the material required for insertion.
Clients pay additional fees for counseling, insertion, re
moval, and follow-up visits. For example, in Baltimore clin
ics of the Planned Parenthood Federation charge a total of
about $600—$350 for the implants plus $25 for a counseling
session, $45 fora physical examination, and $175 for inser
tion and two follow-up visits (23, 146). Removal at Planned
Parenthood clinics in Baltimore costs the client about $100.
Others' fees vary, but total cost can be as high as $1,000 (70).
Despite the costs, some providers in the US have a waiting
list for implants because demand exceeds supply (15, 82).
Many US women have health insurance that will pay for
Norplant. As of August 1992, 46 of the 58 major health
maintenance organizations in the US had decided to reim
burse women for at least part of the cost of Norplant insertion
(257). Health maintenance organizations provide all health
care to members who pay a periodic fee. Private insurance
organizations, such as Blue Cross, also will reimburse in
some cases (15, 260). Medicaid, the government-funded
health insurance program for the poor, pays for the implants
and a portion of the cost of associated medical services.
Some public clinics that provide free or reduced-price serv
ices doubt that they will offer Norplant, however. They can
serve more clients when they buy less expensive methods
(251, 252). Physicians and nurse-practitioners at clinics can
apply for free implants to the new Norplant Foundation
established by Wyeth-Ayerst to help low-income women.
The foundation has an initial US$2.8 million to provide
implants to about 10,000 US women who cannot afford the
method and do not qualify for Medicaid (11, 69, 117, 250).
The foundation does not pay service costs. It has recently
changed its requirements so that providers no longer must
fill out a form for each woman who wants Norplant (68).
In Europe the first countries to approve Norplant were Fin
land in 1983 and Sweden in 1985. In both countries many
contraceptive methods are available. In Finland about 3% of
women who use contraceptives currently use Norplant
(248). About 70% of the 20,000 Finnish women who use .. A
Norplant received their implants in private clinics, and the
rest received their implants in government family planning
centers. On average, Norplant insertion costs US$200 to
$250. The government has subsidized 60% of these costs in
public clinics, but the amount of the subsidy is decreasing (248).
Elsewhere in Europe, Leiras Oy has guided clinical trials in
Belgium, Bulgaria, Denmark, France, and Germany. Nor
plant has been approved in Czechoslovakia and the former
USSR, but it is not widely distributed in these areas (118, 248).
■
Norplant in Three Countries
Indonesia, Thailand, and Colombia are among the first coun
tries where Norplant is widely available. Patterns of use in
these countries vary, reflecting differing circumstances.
□
Indonesia: Widespread Norplant Use
Over one million women in Indonesia have received Nor
plant through the extensive government family planning
program. Indonesia aims to reach zero population growth by
2035-2050 (92). Achieving this goal requires substantial
increases in the number of contraceptive users (127). At
present, 49% of married women use a modern method of
POPULATION REPORTS
,
v
contraception. The government family planning pro
gram hopes that introducing new methods such as Nor
plant will attract new clients to family planning (91, 92).
Norplant is a valuable new method in the Indonesian
program, particularly because sterilization is not available
through the government family planning program. After
clinical trials in 1981, the national family planning coor
dinating board, Badan Koordinasi Keluarga Berentjana
Nasional (BKKBN), planned to offer Norplant primarily
to women in remote areas where resupply of pills, con
doms, or other contraceptives was difficult (123). That
same year, however, the Board of Islamic Religious Lead
ers issued a statement opposing all forms of sterilization
(5). As a result, government facilities stopped offering
voluntary sterilization as part of the official family plan
ning program (18, 127). By that time BKKBN had begun
a campaign to encourage couples to use more effective,
long-term methods in place of oral contraceptives and
condoms. Therefore they urged women who wanted to
delay or end childbearing to use Norplant or IUDs (127).
Islamic leaders have recently stated that sterilization may
be used judiciously, but it is not widely available (40).
A provider in Indonesia shows a couple where Norplant implants are
placed. More than one million Indonesian women have used Norplant.
In 1984 BKKBN, with support from UNFPA, bought 30,000
implant sets and made Norplant available at 87 hospitals and
large health centers (97, 247). UNFPA supplied another
25,000 sets in 1987 and 109,000 sets in 1988 (243). The
Indonesian government also has purchased implant sets with
its own funds and with loans from the Asian Development
Bank and, since 1990, the World Bank (175, 234).
Since regulatory approval in 1986, the number of new
Norplant users has grown each year (92). Norplant now
accounts for 3% of Indonesian contraceptive use (91). Most
Norplant users live in the densely populated areas of rural
Java, where providers were first trained. BKKBN has intro
duced the method in other areas with less dense populations,
and 6% to 7% of contraceptive users in some of these areas
use Norplant (91).
A variety of Indonesian women like Norplant. In rural Java,
where the method was first widely used, most women are
^Muslim and do not accept sterilization or the pelvic proce
dure necessary for an IUD (5). But women in other areas also
like implants. In a national survey of 3,000 users conducted
by BKKBN, 72% of the women interviewed said that they
would recommend implants to others. About 65% of users
did not want more children, but 30% definitely desired a
future pregnancy (90).
By 1991 Norplant was used in all Indonesian provinces,
especially in rural areas (91). Government programs served
95% of Norplant users—50% at health clinics, 21 % at tem
porary service sites called "safari," 16% through health posts
or field workers, and 7% at hospitals. Private practitioners
served 4% (91). Two-thirds of married women knew about
implants, and 60% knew where to obtain them (91).
BKKBN has set a national goal of 300,000 new Norplant
users per year (92). As with goals set for other methods,
provincial program managers must decide what portion of
the national goal they can meet. Each year they assess past
use of Norplant and other methods, estimate the anticipated
number of new users, and then request supplies and service
support accordingly (100). Hospitals, clinics, and other cen
ters receive their supplies and their funding according to their
expected number of clients. At current international prices,
it would cost more than US$8 million each year to supply
POPULATION REPORTS
Norplant capsules for the intended 300,000 new users, most
of whom will use public clinics. Indonesia is considering
local manufacture in hopes of reducing costs (92, 98).
Indonesian officials are now reassessing their past emphasis
on numbers of new users. Health officials have concluded
that, although initial acceptance of family planning has been
high, continuation rates need to be higher. Therefore family
planning services in Indonesia are now emphasizing highquality service, including better counseling and screening,
as well as numbers of new users. Temporary service sites—
"safari"—are no longer used to provide implants because
program managers found it difficult to screen and counsel
women adequately at such sites (92). Also, offering Norplant
only in fixed facilities should hold rates of infection at the
insertion site to a minimum and improve record-keeping.
Some 27 regional centers now train physicians to provide
Norplant, including insertion and removal. Midwives also
are trained to insert Norplant under the supervision of a
trained physician, but they may not remove Norplant (34).
In addition, the general family planning curricula in medical
and nursing schools cover the implant method. Recently,
Indonesia has begun training more physicians in removal
techniques because need for removals is growing.
Currently, women who receive Norplant in a public clinic
pay nothing, while those who obtain Norplant through a
private provider pay Rp. 70,000 (US$36) (41). Indonesia's
Blue Circle campaign, which provides participating private
physicians and trained midwives with supplies at low cost,
will soon offer Norplant.
Because Indonesia has the first large implant program, it is
the site of several studies exploring long-term side effects,
women's attitudes towards implants, and the planning re
quirements for a high-quality program. Indonesia is one of
the locations in the multinational postmarketing study. BKKBN
also is conducting its own internal evaluations of Norplant
program needs (92). Operations research studies are cur
rently underway to review use dynamics, follow-up, and
provision of removal services for women who- have used
their implants for five years (175). The program also is
participating in preliminary field trials of other contraceptive
implants such as Implanon (see box, p. 7) (92).
11
What Women Say About Norplant
Most users like Norplant, and a majority would recommend
it, according to survey and focus-group responses. Research
on users' attitudes was part of some pre-introduction trials.
Most Users Recommend Norplant
More than 75% of Norplant users would recommend im
plants to their friends, according to research in Brazil. Egypt,
Indonesia, Nigeria, the Philippines. Sri Lanka, and the US
(16. 21,22,51, 62, 63. 79, 90). As one Norplant user com
mented. "For me this method is the best....To me, the abso
lute certainty that you are not going to become pregnant is
something that you cannot buy with anything” (178).
Best-Liked Features
Most Norplant users found that they liked its effectiveness.
long duration of effectiveness, and reversibility (24, 51.62,
102, 190, 230, 262). They also liked the convenience of few
clinic visits: no resupply, as with condoms or pills, and noth
ing to remember at the time of intercourse (79).
Concerns About Bleeding Changes
Some women in Bangladesh, Egypt, the Dominican Repub
lic, Indonesia, and Thailand reported that health workers
were reluctant to remove the implants (101, 126, 253, 262).
Some other women did not know that implants had to be re
moved after five years or that they could be removed earlier.
Still others thought that the removal procedure involved ma
jor surgery or was done without anesthesia (262). Providers
must be thoroughly trained and supervised to ensure that
they give full and accurate information and do not refuse re
quests for removal.
The Influence of Husbands
Husbands influenced women’s decisions about Norplant. Al
most all of the women in the Dominican Republic, Egypt, In
donesia, and Thailand discussed their decisions with their
husbands before choosing implants (29, 262). In Bangla
desh. Haiti, Nepal, and Nigeria, one-third of women who de
cided not to use Norplant mentioned their husbands’
disapproval as a reason (102).
Most women experienced changes in menstrual patterns, but
they reacted differently (24. 51, 79). In one US clinical trial
79% of participants reported menstrual changes, but only
18% were bothered by them (136). In contrast, frequent
bleeding bothered some Muslim women, whose religion for
bids them to pray or to have sexual intercourse while men
struating (262). Some other women also said that frequent
bleeding interfered with sexual relations.
Some users’ husbands became uneasy about side effects.
Some were alarmed by their wives’ frequent bleeding, and
some women mentioned this as a reason for removal (190,
262). Some husbands in the Dominican Republic, Egypt, and
Nepal were concerned that amenorrhea was not healthy
(102,262). In Thailand 5% of women questioned said that
their husbands disliked the menstrual irregularities or dis
trusted a method that they considered experimental (190).
Some women were bothered by amenorrhea and did not un
derstand that missing menstrual periods while using Nor
plant is not harmful. Several women in the Dominican
Republic, for example, felt that the “bad blood" was not
draining from their bodies (179). One woman’s remark
points out the value of thorough counseling about menstrual
changes: “Older people in my family tell me it’s absolutely
necessary to have your period. If not, one can have prob
lems. But the doctor says there’s no problem” (178).
The support of family and friends was often crucial to Nor
plant users’ ability to adjust to the method. A participant in a
Norplant study said, “Both my husband and mother know
that I am using Norplant. In fact, it is my mother who keeps
track of my clinic appointments” (178).
Feelings About Other Side Effects
Women’s attitudes about other side effects also varied. Head
ache. depression, and hair loss—conditions that some
women attributed to Norplant—troubled most who experi
enced them. Weight gain, however, was a positive effect in
the Dominican Republic, Egypt, and Indonesia but a nega
tive one in the US (51, 262). Weight loss was unacceptable
in the Dominican Republic, Egypt, Indonesia, and Thailand.
Implants usually cannot be seen under the skin, but in any
case most women were not concerned about other people see
ing their implants (102, 190). Indeed, some women in the
US and the Dominican Republic were proud when people no
ticed their implants (136, 261).
Attitudes Toward Insertion and Removal
Most women in Egypt, the Dominican Republic, Indonesia,
Thailand, and the US said that they felt no pain at the time of
insertion (51.62, 190, 262). Removals were not painful for
most women, either, although removal generally took longer
and was less comfortable than insertion.
12
Women’s Suggestions for Better Services
In focus-group discussions women made detailed comments
about the health services they had received, and they sug
gested improvements. Women in the Dominican Republic
and Indonesia wanted more counseling before insertion and
during the first six months of use (90, 262). Women in
Egypt did not want follow-up examinations, particularly if
the health clinic did not have a female physician. In contrast.
women in the Dominican Republic approved of the frequent
medical check-ups that they received as part of pre-introduc
tion trials (262). Some women suggested informational vid
eos in waiting rooms as well as written material. Others were
frightened by photographs, intended to train physicians, that
were hung in the waiting room (262). Some women have
suggested that providers show women the capsules during
counseling.
Women wanted to learn not just for themselves but also to
tell others. A Dominican woman objected when the provider
told her to look away during her insertion procedure. She
said, I think the doctor should let one see the process if one
wants to. People always ask how that is done, and how the
implants are put in your arm. If you’re not allowed to see,
how can you explain to people who ask?” (178).
POPULATION REPORTS
Thailand: Limited Use of Norplant
Thai family planning managers expect Norplant to attract
new users to their program. The Thai government established
the National Family Planning Program (NFPP) in 1970, and
the contraceptive prevalence rate grew from 15% in 1969-70
to about 71% in 1987—a level like those in developed
countries {27, 114, 138). When the rate of increase in preva
lence slowed in the 1980s, however, NFPP looked to Nor
plant and injectable contraceptives to attract women who
were not using modern contraceptives.
Apre-introduction trial of Norplant began in 1980 with 1,000
volunteers (190). In 1985 NFPP took the first steps to intro
duce the method nationally. NFPP held an orientation meet
ing for the chief medical officers of all 73 provinces, won
regulatory approval for Norplant in 1986, prepared informa
tional materials for trainers and general-practice physicians,
trained trainers and other physicians in insertion and re
moval, and obtained implants and trocars (114, 151).
i v^'n
7^0 physicians were trained, one from every district
I-’hospital (27). They were to serve an expected 10,000 users
nationwide (114). When import duties increased the cost of
the implants from the 1986 price of US$13 to $36, however,
NFPP bought one-third the number of implants originally
planned (139). Supplies vyere not adequate to meet demand
throughout Thailand (2'7). Thus implants were offered only
to women in the remote northern hill areas and to Muslim
women in the south, as an alternative to sterilization (139).
Training of physicians has expanded steadily (97). Nurses in
some hospitals also have learned insertion, removal, and
counseling (95). Norplant is discussed in medical and nurs
ing school curricula, and some doctors and nurses are learn
ing insertion and removal. For the most part, practicing
health care providers learn the procedures and counseling
skills informally by observing experienced practitioners.
In 1991 the Thai government bought 40,000 implant sets and
made Norplant part of the contraceptive services available
at all district hospitals. By mid-1992, 150,000 Thai women
had used Norplant (249). Because physicians have limited
TJJtime available to do insertions, hospitals with nurses trained
■" in insertion provide more Norplant than hospitals without
specially trained nurses (95).
Women pay for the implants according to a sliding scale.
Poor women and those in remote areas receive Norplant free
of charge; other women pay something, and a few pay as
much as US$8 for the implant and insertion (95, 97, 139).
Occasionally, NFPP runs campaigns to promote long-term
family planning methods. To attract new users, they offer
Norplant, IUDs, and voluntary sterilization without charge
for a limited time (76). NFPP expects Norplant to appeal to
about 5% of women who seek contraceptives (139).
Thai couples have many contraceptive options, and NFPP
considers Norplant appropriate only for women who want
long-term birth spacing or who live in remote areas. The
program discourages short-term use of Norplant because of
the cost (27). Women over age 30 with several children are
encouraged to choose either IUDs or voluntary sterilization
rather than the more expensive implants.
Colombia: Norplant in the Private Sector
In Colombia the private sector has played the largest role in
offering Norplant. The family planning association AsociaPOPULATION REPORTS
cion Pro-Bienestar de la Familia Colombiana (PROFAMILIA),
an affiliate of the International Planned Parenthood Federa
tion (IPPF), provides most contraceptive services, including
Norplant. Some private physicians offer implants, too.
Use of Norplant has grown gradually since government
approval in 1986. The Corporacion Centro Regional de
Poblacion (CCRP), a private research institute, began the first
pre-introduction Norplant trials at two hospitals of the Min
istry of Health (18, 239, 254). In 1988 and 1989 more trials,
involving nearly 3,000 women, began in PROFAMILIA clin
ics (97). An additional 1,000 women received implants from
PROFAMILIA in 1990 through the postmarketing study. In
1991 about 15,000 women were using Norplant in Colom
bia, and about 15,000 more are expected to receive implants
in 1992 (239).
The first Colombian physicians to offer Norplant, from the
Ministry of Health and PROFAMILIA, trained in the Domini
can Republic. These physicians informally trained others at
PROFAMILIA until 1991. Then 2-day seminars began to train
personnel in all 40 PROFAMILIA clinics,(239).
In 1987 the Sociedad Medico Farmaceutica (SOMEFA), a
society of physicians in private practice, became the distribu
tor of Norplant implants in Colombia (18). In cooperation
with the CCRP and the Fundacion Sante Fe (a private hospital
in Bogota), SOMEFA organized training courses in insertion
and removal. Since 1990 more than 50 physicians in private
practice have attended these courses, and more than 500
health professionals have attended informational seminars
in five locations (18). SOMEFA has distributed over 1,000
implant sets to trained private physicians and expects that
each will insert five implants per month (18, 97).
PROFAMILIA currently charges US$30 for Norplant if the
client is not involved in a research study. This charge covers
the implants, insertion, follow-up, and removal. While the
charge is below PROFAMILIA's costs, it is still expensive for
many Colombian women (239). Although PROFAMILIA
charges less than cost for all methods, it charges more for
implants than for any other method including vasectomy and
tubal ligation. Currently, PROFAMILIA is undertaking two
studies on the cost of Norplant. One will study the demand
for Norplant at different prices; the other will compare the
cost components of Norplant and of other methods in part
to determine whether Norplant is more expensive to provide
than voluntary sterilization (18, 175).
[Redding on Norplant
In deciding whether to introduce Norplant, providers must
assess the benefits and costs of the method. Managers of
family planning programs first need to determine how this
new method might meet clients' needs. They also must
consider the requirements for starting and maintaining the
program and how they will pay the costs. Private providers,
too, must determine whether their clients will be interested
in this new contraceptive method and willing to pay for it.
To make such assessments, providers may want to consider:
• How will Norplant help meet women's needs?
• Will implants further program goals?
• How much will Norplant services cost?
• Can the program provide high-quality Norplant services?
• Who can help support Norplant services?
13
How Will Norplant Help Meet
Women's Family Planning Needs?
Family planning clients are best served when they can
choose from a variety of methods (35). Different clients have
different needs and preferences, and any client's needs may
change over the years that she uses family planning. When
a variety of methods is available, clients are more likely to
find a method that they like and will continue using.
In clinical trials Norplant's unique combination of features
appealed to several different groups of women. Many wom
en were attracted to Norplant because it was effective for five
years but also reversible. Others liked the convenience of a
method that did not require frequent clinic visits. Still others
were interested in trying a new method. In clinical trial sites
in Thailand and the US, 50% of new Norplant users had been
using oral contraceptives before trying implants. In Thailand
another 20% switched from injectables, and 12%, from IUDs
Questions Women Ask—And Answers
The following are questions that wom
en have asked about Norplant and the
answers that providers might give (51,
97, 150). Providers also may want to
give more detailed information based
on other sections of this report.
Q: When should I have Norplant in
serted?
A: Norplant should be inserted during
or soon after a menstrual period to en
sure that you are not already pregnant.
Q: Can I use Norplant if I am breast
feeding?
A: You do not need to use a family
planning method if you are breastfeed
ing without giving your child other food.
If you wish to use a method, hormonal
methods are not the first choice for
breastfeeding women, especially for the
first six weeks after birth. You may
want to use another method for at least
six weeks. You can use Norplant after
the first six weeks of breastfeeding.
Q: Will the capsules move around in
my body?
A: The capsules remain where they are
placed. You should be able to feel them
with your fingers.
Q: Can men use Norplant as a contra
ceptive?
A: Norplant is effective only for wom
en, not for men.
Q: If the medicine is put in my arm,
how can it work in my sex organs?
A: The capsules slowly release a hor
mone that enters the blood stream and
circulates through the body. The hor
mone works only on the reproductive
organs.
Q: If I want three years of protection,
can I use three capsules instead of six?
A: Six capsules are always necessary to
prevent pregnancy. Fewer capsules of
this kind would not be enough no mat
14
ter how long you wanted to use Nor
plant.
Q: Will insertion hurt?
A: Insertion is not painful. A local anes
thetic is used to prevent pain in the area
of the implants, and the procedure takes
8
to 10 minutes.
Q: Will my arm hurt after the inser
tion?
A: There may be some soreness and
bruising around the implant site for a
few days.
Q: Will removal hurt?
A: Removal is also done using local an
esthetic, and so it is not painful. Re
moval does take longer than insertion.
Q: Why do I need to have the im
plants removed after five years?
A: The implants must be removed after
five years of use until research demon
strates that they are safe longer.
Q: Can I use Norplant for more than
five years?
A: Yes. After your first set of capsules
is removed, you can have another set in
serted, usually in the other arm.
Q: Will Norplant make me or my hus
band too weak to work?
A: Norplant will not weaken you or
your husband. Even women who bleed
more frequently do not lose more blood
than they did with their normal menstru
al periods. The changes in menstrual
bleeding patterns do not weaken women.
Q: If my monthly bleeding stops or
decreases, will bad blood build up in
my body?
A: No. Many Norplant users have little
or no menstrual bleeding because their
bodies produce less blood. No blood
builds up in the body.
Q: Will the capsules break if they are
bumped?
A: The capsules are made of a soft, flex
ible material. They wiU not break if they
are pressed, bumped; or touched. If you
are worried that they have broken, a health
care provider can check your implants.
[If possible, the provider should show
the client a capsule and let her handle it.]
Q: Will the implants be visible?
A: When Norplant is first inserted,
there may be a bruise around the inser
tion site, but the bruise disappears. A
small scar may form at the insertion
site. Many thin women say that the im
plants appear as raised lines under their
skin when they extend their arms. Other
women cannot see them at all, but they
can feel them with their fingers.
Q: Will implants protect me from AIDS?
A: No, implants will not protect you
from AIDS or any other sexually trans
mitted diseases such as syphilis or gon
orrhea. If there is any chance that your
sexual partner is infected with any sexu
ally transmitted disease, or if you or
your sexual partner has other sexual
partners, he must use condoms.
Q: How long does it take for Nor
plant to become effective?
A: Norplant is effective within 24 hours
after the capsules are inserted.
Q: How soon can I become pregnant
after the implants are removed?
A: You can become pregnant within the
next month. Over 30% of the women
who want to become pregnant do so
within three months, and 75% become
pregnant within one year after the im
plants are removed.
Q: Can a young woman who has
never been pregnant use Norplant?
A: Women who have never been preg
nant, including adolescents, can use
Norplant, just as they can use other hor
monal contraceptives such as pills.
POPULATION REPORTS
(107). In the US, another 14% had been using condoms, and
14% had been using diaphragms (48).
Couples dissatisfied with other methods also may choose
Norplant. Women who do not want to take a daily pilkmay
prefer the ease of implant use. So may couples who dislike
using condoms, diaphragms, or spermicides at the time of
intercourse. Implants also may appeal to women bothered
by estrogen-related side effects of combined oral contracep
tives, such as nausea and headaches, and to women who
have had difficulties with IUDs.
The range of methods available will influence the appeal of
Norplant. When the Indonesian family planning program
decided to encourage women to use long-term methods,
they offered implants, injectables, and IUDs but not volun
tary sterilization (see p. 11). Because IUDs and implants do
not need frequent resupply, Indonesian clinics emphasized
these two methods (123). Thus in Indonesia Norplant is often
a method for women who want no more children (7). Simi
larly, many of the women who chose Norplant in clinical
trials in Egypt, the Philippines, and Sri Lanka said that they
did not want more children (21, 24, 71). By comparison, in
Thailand, where sterilization is widely available, women
who do not want more children are encouraged to choose
sterilization rather than Norplant (179, 262).
In Sri Lanka many younger women who used modern con
traceptives were interested in using Norplant. As part of the
Rural Family Planning Survey in 1985, interviewers told
more than 2,000 women about implants and asked whether
they would be interested in using them. More than one-third
were interested. These women tended to be younger women
who wanted to delay pregnancy for several years and who
already used some form of modern contraceptive method,
either alone or along with a traditional method (236).
Norplant may appeal especially to certain groups of women
for geographical or cultural reasons. In Indonesia, Kenya,
and Thailand, family planning program managers initially
addressed Norplant services to women in remote areas
where it is difficult for them to obtain oral contraceptives,
condoms, and other family planning supplies (123, 153).
These policies have been modified in Indonesia and Thai
land, however, until it becomes possible to ensure good
follow-up services for these women. Also, implants may
appeal particularly to some Muslim women who may not
approve of sterilization—or whose husbands or religious
leaders may not approve—or who want to avoid the pelvic
procedure necessary for an IUD (247, 262). These women,
however, may particularly object to the irregular menstrual
bleeding that can be a side effect of Norplant because they
cannot pray or have sexual intercourse while bleeding.
Once Norplant is more widely used, researchers will be able
to develop profiles of women who are likely to be most
satisfied with implants. Then providers can use this informa
tion to advise women about contraceptive choices, and
programs can use it to help design promotional and informa
tional messages and materials (see pp. 16-17). These profiles
will differ from one country to another because of religious,
cultural, geographic, and programmatic factors. A study
found that potential Norplant users in Bangladesh, Haiti,
Nepal, and Nigeria differed in average age, education, desire
for future pregnancy, and number of children. For example,
in Bangladesh and Nepal the women with the least educa
tion were most interested in Norplant, but in Haiti the most
educated women were most interested (102). Providers should
POPULATION REPORTS
remember, however, that some women who do not fit the
profile may want to use Norplant and may be very satisfied
with it. For example, young women who have no children,
including unmarried women, may want to use Norplant as
much as older women who have all the children they want.
■
Will Implants Further Program Goals?
Most family planning programs are established to improve
the health of women and children and/or to contribute to
socioeconomic development by slowing population growth.
Thus most programs seek to increase the number of couples
using family planning, increase the effectiveness of use, and
lengthen the use of effective family planning methods. In the
long run this is best done by making readily available the
services that people want. By meeting clients' needs, Nor
plant can help accomplish all three goals. As a new method,
Norplant can attract women who have never used an effec
tive method and can serve women who have discontinued
other methods. As a highly effective method, Norplant can
improve the effectiveness of the overall method mix. As a
long-acting, low-maintenance method, Norplant can extend '
overall continuation rates.
To what extent will Norplant attract women to contraception
for the first time? At this point, evidence is slight because
Norplant has not yet been widely offered in many countries.
The pre-introduction trials did not promote the method to
the public but instead found volunteers among women who
came into family planning clinics for contraception.
There is some evidence, however, that implants may attract
new contraceptive users. In Egypt, word of the new method
spread, and women lined up to join the pre-introduction
study (261). In Indonesia a study of 8,681 Norplant clients in
1984 found that 36% had not used any method previously
(81). In Thailand 13% to 20% of women who chose Norplant
in clinical trials had never used any contraceptive method
before (107, 190). In a study of 550 women at 11 Thai hos
pitals, 12% of women who chose Norplant had never used
a modern contraceptive method before. Most of the women
in this last study were young, however, and just beginning
to need contraceptives. Nearly all would have chosen an
other method if Norplant had not been available (96).
Most women who switch to Norplant from other methods
will be switching to more effective contraception. For the first
year of use Norplant is more effective than oral contracep
tives, condoms, spermicides, and Natural Family Planning,
and over five years Norplant is as effective as the most
effective IUD (154).
In clinical trials Norplant continuation rates have been about
the same as or better than the clinical trial rates for the IUD
and better than the rates for other temporary methods (see
Table 1). As with all other methods, the best way to improve
continuation rates is to satisfy clients. In an Indonesian study
75% of those who were given the method that they preferred
continued use for at least one year. In contrast, after one year
only 15% of those who did not get the method they wanted
were still using the method that they had received (144).
■
How Much Will Norplant Cost?
Cost is a major consideration with Norplant. The cost of the
implant itself and the cost of introducing the method make
implants more expensive than other methods. The implants
cost nonprofit and government programs in developing
15
PRESENTING
A NEW METHOD:
perception of a product or service—
what marketers call an image—in the
minds of both public and providers. In
commercial marketing, positioning is
intended to differentiate products and
thus to reduce competition and encour
age consumers’ loyalty to a specific
brand. In family planning, program
managers want to position different
contraceptives to help clients deter
mine which method they want to use.
Why Positioning?
Positioning helps family planning pro
grams assist their clients in several
ways. It helps the public understand the
differences among the available meth
ods and, through the mass media, sug
gests reasons for choosing among
methods even before people come
face-to-face with providers. Thus it
helps clients to make informed choices.
Informed choices lead to more satisfied
users and thus more effective, longer
use of methods.
Positioning also helps providers, even
if no special public promotion or pub
licity is planned initially. The position
ing process anticipates how a new
method will fit into a family planning
program both at first and in the long
run. This facilitates planning for sup
plies and services and informing health
care providers about the method. Thus
a well-planned process of positioning
is important for the program and its
staff. Since the positioning process in
volves comparison with other methods,
positioning a new method such as Nor
plant is a good occasion to assess the
positioning of other methods as well.
I
j
Positioning Norplant
When introducing a new family planning method, program managers can position it to
attract a specific clientele—people who are most likely to find that the method satisfies
their needs. “Positioning” is a marketing term that means presenting a product or service
in a way that helps to distinguish it from other, similar products or services, usually by
emphasizing one or a few important characteristics (1). Positioning helps to create a
Positioning does not mean that only
certain women will receive Norplant or
that women will be denied a choice of
methods. The process attempts to con
nect the women who are looking for
certain features with the methods that
have those features. All women should
be able to choose the method that they
prefer so long as it is medically appro
priate for them and the program can
provide it.
To position a product or service, mar
keters analyze the features of the prod
uct and the needs of the clients who
might most want the product. Research
POPULATION REPORTS
such as the pre-introduction trials of
Norplant provides the basic information
for this analysis. So can focus-group re
search and consultations with women’s
groups and consumer groups who speak
on behalf of potential clients. The analy
sis may lead to a positioning statement—
a slogan highlighting the product
characteristics that are most responsive
to the needs of intended clients. The po
sitioning statement then becomes the
starting point for message design.
Positioning Norplant:
Three Examples
Characteristics of Norplant that help to
position it relative to other methods in
clude:
• Easy to use and convenient,
• Very effective,
• ‘ Reversible,
• Long-lasting,
• New method of delivery,
• Does not interrupt sexual relations,
and
• Placed in the arm; a pelvic examina
tion is desirable but not necessary
(255).
After studying these characteristics, par
ticipants in a 1991 workshop convened
by the Johns Hopkins University Center
for Communication Programs decided to
emphasize newness, convenience, and
long-lasting effectiveness. Participants
settled on the positioning statement:
i “Norplant: The new contraceptive op
tion for women, effective up to five
years” (255).'
In Zimbabwe the National Family Plan
ning Council is starting a campaign to
promote Norplant along with other long
term family planning methods. Norplant
pre-introduction trials are in their second
year in 1992, and providers are just be
ginning to become familiar with the
method. Physicians in government hos
pitals and in private practice will be the
first to offer Norplant. Their clients are
expected to be urban, educated people
who can afford hospital or private serv
ices because their health care is paid for
by employer-provided insurance. Within
the past two years insurance policies
have begun to cover part of the cost of
family planning services. The Zimbabwe
National Family Planning Council has
POPULATION REPORTS
decided to use the slogan “Norplant: The
five-year contraceptive plan.” One pro
motional poster is headlined “We have
taken a five-year insurance plan.” The
poster is designed to attract clients who
understand insurance and can afford this
new method (263) (see photo, p. 16).
Similarly, in Indonesia advertisers have
designed a private-sector campaign to
appeal to urban professional women.
These career-oriented women want to
delay pregnancy for at least several
years; they can afford private family
planning providers; and they are at
tracted to new technologies. Therefore
advertisements picture a career woman
near her computer. The slogan used in
print and on radio is “Implants from Nor
plant. The exclusive way of family plan
ning” (see photo, below). Clients remem
ber this kind of short slogan, especially
when reinforced by a logo or symbol,
better than a lengthy explanation. The
slogan and logo cannot convey a great
deal of information, but they can help to
create a positive image for Norplant.
Why Care About Image?
Why deliberately try to create an image
of a new product? Because any new pro
duct will soon develop an image with
consumers in any case. Experience with
other contraceptive methods suggests
that rumors and negative news can easily
overwhelm a balanced view of risks and
benefits (see Population Reports, After
Contraception: Dispelling Rumors
About Later Childbearing, J-28, Sep
tember-October 1984). If
no organized effort is
made to shape the image
of the new contraceptive,
happenstance or rumor
will determine it. Worse
yet, negative images
spread by groups who op
pose family planning and
those who distrust new
medical technologies
may shape the public’s
perceptions.
(39). Thus their image of Norplant was
that of a major surgical procedure.
In contrast, in Indonesia and Zaire coin
cidence has linked the image of Norplant
to traditional medicine, which some
times involves placing small bits of gold
or other material under the skin (7, 124).
In fact, in Indonesia Norplant is often
called by the name of the traditional im
plant, susuk (81, 173). Indonesian
women may choose Norplant more read
ily because they are already familiar with
traditional implants. This image, how
ever, is not always positive. While some
Indonesians associate susuk with en
hanced beauty, others link it to black
magic and prostitution (179).
Creating a positive image at the start
saves money (145,182). Creating a good
first impression is easier and less costly
than trying to overcome a bad impres
sion once it has become established in
the public mind.
Developing a positive image for Nor
plant or any other method is more diffi
cult if family planning services in
general have a negative image. The im
age of Norplant will be tied to the image
of the people and organizations that pro
vide it. No communication campaign can
create a positive image if those who pro
vide family planning are abusive, conde
scending, or cavalier to clients or try to
pressure them into using a particular
method. To succeed, services and prod
ucts must live up to the positive image
created for them.
In India rumor contrib
uted to an inaccurate im
age of Norplant. Women
initially heard that Nor
plant required surgery
17
US FDA Approves Depo-Provera
The United States Food and Drug Administration (US FDA)
approved the injectable contraceptive Depo-Provera on October
29. 1992. The regulatory agency’s decision makes the highly
effective progestin-only contraceptive available to US women.
Depo-Provera has been widely approved and used around the
world for more than two decades (see Population Reports.
Hormonal Contraception: New Long-Acting Methods, K-3,
March-April 1987). but it had not been approved in the US. US
FDA approval means that the United States Agency for Interna
tional Development (US AID) will be able to provide Depo-Pro
vera to family planning programs in developing countries. US
AID now is making plans to purchase the injectable.
Depo-Provera consists of the progestin depomedroxyprogesterone
acetate. The contraceptive dose is 150 mg, administered every
three months by injection in the arm. Depo-Provera is as effective
as Norplant and the most effective IUD. the TCu-380A.
countries USS23 per set. In addition, medical professionals
must be specially trained to insert and remove the implants.
As with other new methods, there are also start-up costs for
training other personnel and for communication.
Much of the program cost for supplies, training, and service
delivery is up-front cost—that is, cost incurred before a
woman begins using implants. Voluntary sterilization, too,
has high up-front costs. Therefore the cost per couple-year
of contraception provided by both methods decreases as
length of use increases.
Thus length of use—and client satisfaction, which deter
mines length of use—are crucial to cost-effectiveness. To
compare the costs of implants and other methods, planners
should average the costs for supplies and services over the
years of use. In clinical trials the average length of use for
implants was 3.5 years (224), and the implants can be used
for as long as five years. In terms of the cost of the commodity
alone, Norplant costs somewhat more than a 3.5- to 5-year
supply of oral contraceptives, condoms, or injectables and
costs far more than an IUD over the period (see Table 1).
A study in the Dominican Republic found that the full service
cost per couple-year of protection was greater for Norplant
than for the IUD or female sterilization. Researchers at the
Asociacion Pro-Bienestar de la Familia (PROFAMILIA), the
family planning association, considered the costs of person
nel and materials for each office visit, the average number of
client visits for each method, and the duration of visits. They
assumed that Norplant users would continue with the meth
od for an average of 3.5 years, as did IUD users, and that
sterilized women receive on average 16 years of contracep
tive protection. They calculated that in 1993 the PROFAM
ILIA clinic would incur costs of US$15 for an IUD, $16 for
female sterilization, and $30 for Norplant for each coupleyear of protection (12).
Norplant may increase the costs of a family planning organi
zation if women switch from less expensive methods or if
they switch from private medical facilities to publicly funded
ones in order to obtain Norplant. The study of 550 new
Norplant users in 11 Thai hospitals found that 97% of the
women would have used another method if implants had not
been available. Also, 19% of the women had been buying
contraceptives from pharmacies or private clinics but came
to a government-funded hospital for Norplant (96). In Thai
18
land the great majority of women who want to control their
fertility are using family planning. Where more of the de
mand for family planning goes unmet, Norplant might attract
more new users to family planning and fewer from private
sources of contraceptives.
Norplant price. How is the price of Norplant implants deter
mined? The Population Council and Leiras Oy concluded a
licensing agreement in 1983. The agreement establishes a
formula for setting the price of implants for developing-coun
try nonprofit organizations. Leiras Oy periodically recalcu
lates its price based on its manufacturing and distribution
costs, which include labor, materials, factory overhead and
depreciation, insurance, and dissemination of information
(165). According to the formula, the price for nonprofit
organizations cannot be greater than a fixed margin over
these costs. This price is available to donor agencies and
various organizations in developing countries—govern
ments, government agencies, private nonprofit agencies of
fering family planning, and other groups offering family
planning services at or below cost or without charge. Over
the years the price of the implants has risen as Leiras Oy has f )
begun charging purchasers for the full costs of production
(118). The price was US$13 in 1986, $18 from 1987 to 1989,
and has been $23 since 1990 (243). Prices in the commercial
sector in developed and developing countries are not con
trolled (168). In the US, a set of capsules costs $350.
The current price of US$23 for nonprofit organizations in
developing countries covers only the implant set. There are
additional costs for shipping, and a trocar that can be reshar
pened and used for about 50 insertions costs US$6. Includ
ing freight and insurance against damage in transit, the
International Planned Parenthood Federation (IPPF) charges
US$28.58 to its affiliated family planning associations for an
implant set not including the trocar (194).
By the end of 1992 Leiras Oy expects to replace the manual
process of making implants with a semi-automated process
that will increase production. Eventually, increased sales
may help to reduce the price, but Leiras Oy first must recover
US$23 million spent on developing the manufacturing proc
ess and on applications for regulatory approval (168).
Indonesia and China plan to manufacture their own implants
in hopes of reducing costs. Indonesia is negotiating with
Leiras Oy for a local manufacturing agreement, and China is
developing its own implant (75). Local production of other
contraceptive supplies has lowered their prices to family
planning programs and users (241).
Projecting total commodity cost. Experience is too limited
to offer much help in predicting demand for Norplant. In
Finland, where a wide variety of methods is available, 3% of
contraceptive users have chosen Norplant. Laneta Dorflinger
has used this rate to project commodity costs for various
countries. She has estimated the number of insertions each
year needed to supply 3% of the projected number of users
of modern contraceptives in 1995. Her analysis assumes a
rate of population growth, number of women of reproductive
age, and estimated prevalence of modern contraceptives
based on data from the US Bureau of the Census. This
analysis also assumes a discontinuation rate of 15% per year
for Norplant. In Kenya, for example, there are projected to
be 4.3 million women of reproductive age in 1995, with 28%
using modern contraceptives. If 3% of these women used
implants, 9,935 implants would have to be inserted each
year, at a commodity cost of about US$228,500 per year for
POPULATION REPORTS
the implants only. In Mexico 63,990 annual insertions would
be needed to supply implants for 3% of the women who use
contraception. The commodity cost would be about US$1.5
million (60). Of course, analysts must adjust such cost pro
jections to local conditions, making their own estimates of
the expected level of Norplant use.
Can the Program Provide
High-Quality Norplant Services?
Program managers may see Norplant as a new method that will
benefit clients, but they also must assess their ability to provide
high-quality services (116). Judith Bruce has identified six ele
ments that are fundamental to the quality of all family planning
care (35). These six elements apply to Norplant services:
C’
Choice of methods. Clients have different contraceptive
preferences and needs. High-quality family planning serv
ices offer a choice of contraceptives and provide a reliable
supply of all of the methods that they offer. When Norplant
is introduced as an additional choice, women should still be
told about other methods and encouraged to choose the
method that they prefer.
™
Information given to clients. Providers should give clients
accurate information about all available methods and more
detailed information about the method that they choose—all
in ways that clients understand and find relevant to their
needs.. When Norplant is introduced, providers should al
ready know and be able to explain how the method works,
how it is used, its advantages and disadvantages, the possible
side effects, and the insertion and removal procedures (see
p. 23). Providers also should be able to help women decide
whether Norplant suits their needs and how to take a relevant
medical history. Clients must also know where to come for
care, the signs that indicate that they should return to the
clinic, the schedule of follow-up visits, the date for implant
removal, and where to go for removal (see p. 24).
Technical competence. Providers should be competent in
performing all necessary medical procedures. Before Nor
plant is introduced, medical personnel must be trained to
insert and remove implants, and support personnel must be
trained to maintain aseptic conditions and to handle sup
plies. Appropriate providers must be prepared to counsel
clients about choosing and using Norplant. Sufficient num
bers of trained staff must be ready as the program grows and
as previously trained staff are reassigned. Systems of super
vision and record-keeping should be ready.
Interpersonal relations. Clinic personnel should see their job
as helping clients to use family planning. They should have
training in understanding the clients' point of view and in
communicating with clients in a helpful, friendly manner. If
clinic personnel have this attitude and these skills, they can
easily offer Norplant in a positive way. Providers should be
rewarded for their ability to satisfy clients' needs.
Mechanisms to encourage continuity. Clinics should be
prepared to offer clients family planning advice and care
over many years. Clients need help with their initial method,
and later they may need more information and support if they
decide to switch methods. Programs that introduce Norplant
need to help women who experience side effects and to
conduct routine follow-up visits (see p. 24 and p. 29). Man
agers must establish an adequate system for implant removal
and a strategy for reminding women that implants must be
removed after five years (see p. 26 and p. 29). Women who
POPULATION REPORTS
no longer want to use implants need help choosing another
method.
Appropriate constellation of services. Clients may prefer
that family planning services be offered along with other
kinds of services. For example, in some places women may
prefer a single service site that offers both family planning
and complete maternal and child health services. In other
places women may want family planning services offered at
job-training sites. Program managers should find out what
kinds of services clients would like to receive in combination
with family planning and where such services should be
offered. In Kenya, for example, Norplant and other family
planning methods are offered at clinics set up near market
places because that is most convenient for women. Norplant
services can be offered wherever technical competence and
asceptic conditions can be assured (see p. 28).
With these elements of high-quality care in mind, program
managers must assess their program's readiness to add Nor
plant to the methods already offered. Both the Population
Council and WHO provide detailed checklists of the factors
that managers should consider when deciding whether to
introduce Norplant (164, 258). In making their decision,
managers can base their estimates for the cost of training,
clinic space, and personnel time on their program's costs for
similar expenditures in the past.
Managers must be sure that they can provide their clients
with good services before they introduce Norplant. Some
family planning programs may decide that they do not have
the funds, personnel, or facilities to offer adequate Norplant
services now. Others may choose to offer Norplant in only a
few locations because of limited resources. Such decisions
are consistent with the desire to provide family planning in
a manner that serves clients well and uses program resources
efficiently. In clinical trials, where high-quality education,
counseling, and medical services have prepared women to
use Norplant and have given them the best of care, Norplant
has been popular. This suggests that Norplantwill be popular
when the quality of care is good. If clients are satisfied with
the care that they receive, they will keep coming back when
they need family planning, and they will tell others about
their good experiences. Thus managers must be prepared for
the costs of offering a popular new method and good services
to assure that clients' needs are met, which in turn will attract
more users. In contrast, if the quality of care is poor, many
people will not use the services, and others will soon discon
tinue use. If clients are dissatisfied, the money spent on
supplies and training will be wasted.
Who Can Help Support Norplant Services?
Donor agencies—particularly the United States Agency for
International Development (US AID) and, to a lesser extent,
the United Nations Population Fund (UNFPA)—provide most
of the contraceptives distributed by family planning pro
grams in developing countries. To date, donor agencies have
not supplied Norplant implants in large quantities or funded
large training programs because few national family plan
ning programs yet offer Norplant. Most donor support has
been for research and introduction activities.
US AID. Since 1981 US AID has helped to support Norplant
research and development. This support has primarily been
through the activities of the Population Council and also
through Family Health International (FHI), the Association
for Voluntary Surgical Contraception (AVSC), and other Co-
19
operating Agencies. US AID is focusing its assistance on 17
large countries, but other countries also may request assis
tance for Norplant activities, particularly training and tech
nical assistance (37). US AID'S Norplant strategy is based on
the following principles, set forth in 1990:
• S&T/POP (The US AID Office of Population! will work with
designated CAs (Cooperating Agenciesl to develop country
specific approaches for Norplant introduction in priority
countries.
• To ensure the best use of limited resources, designated CAs
will take the lead in training and service delivery, and
collaborate with other agencies in conducting related activi
ties.
• Program activities will be those for which A.I.D. has a
comparative advantage, such as counseling, training, quality
of care, and operations research as they relate to service
delivery. The focus of programming will depend in part on
the stage of Norplant activity that has already taken place.
• Programs will gradually be phased in with emphasis on
providing quality services.
• Widespread promotional activities will not be encouraged
since Norplant is a provider- and quality-dependent method
and demand for Norplant is expected to exceed AID'S ability '
to supply it.
• (The US AID Office of Population) does not see commodity
supply as its primary role and intends to collaborate with
other agencies for this purpose. Moderate quantities of
Norplant may be procured for assistance to priority pro
grams (244).
Before US FDA approval in December 1990, US AID sup
ported the supply of Norplant only to research programs. US
AID did not supply country programs with Norplant until it
was approved by the US FDA. In 1992 US AID is filling
requests for 29,600 implant sets from 12 countries and has
received one request for 3,000 sets in 1993. Plans beyond
1993 will depend on the growth of Norplant use (86).
UNFPA. Since 1986 UNFPA has supported the Population
Council's clinical trials and pre-introduction studies in more
than 20 countries (89, 242). Also, in Indonesia UNFPA
supported a program that provided training and supplies for
several methods including Norplant (137). UNFPA provided
Indonesia with 164,000 implant sets, the largest number
supplied to any country (243). Anticipating future requests to
fund Norplant clinical and pre-introduction trials, UNFPA
has developed the following guidelines:
• All Norplant trials require national government approval.
• All projects should be developed with an experienced exe
cuting agency such as the Population Council, FHI, or WHO.
• The executing agency will supervise all activities and
procurements.
• All programs will include wide dissemination of informa
tion in the Ministry of Health, other ministries, medical and
nursing associations, women's groups, relevant nongov
ernmental organizations, and other groups.
• All programs should conduct user-attitude surveys (89,185).
UNFPA supports the Population Council's efforts to intro
duce Norplant and to develop Norplant II (see p. 7). Activities
will include introductory trials, research on client follow-up
and cost-effectiveness, and preparation of materials for pol
icy-makers, program managers, and donors (242).
World Bank. The World Bank has made loans (o Bangladesh,
Indonesia, and Kenya for programs that include Norplant. In
Kenya the World Bank is lending funds for a program to
provide several family planning methods, and FINNIDA, the
Finnish development assistance agency, is funding the por
tion of the program that provides Norplant training and
20
supplies (85). The 1992-97 World Bank loan to Indonesia
for family planning and safe motherhood includes funds for
Norplant as part of efforts to widen the variety of family
planning methods offered (234). In Bangladesh the World
Bank is part of a consortium of donors that will fund family
planning and other health services (see p. 22).
IPPF. In 1985 the International Medical Advisory Panel of the
International Planned Parenthood Federation (IPPF) approved
Norplant and recommended that it be added to the IPPF list
of commodities (88). IPPF makes grants to affiliated family
planning associations worldwide and subtracts the cost of
commodities from the total grant. Between 1985 and 1987
IPPF received requests for Norplant from 35 countries but
supplied implants only to 12 countries that met criteria set to
ensure quality of care (88). These criteria are:
• At least one doctor trained in insertion and removal proce
dures, trained counselors, and a system for client follow-up;
• Government registration or else government approval to
import implants for clinical trials and training (88).
More recently, the number of sets requested has been small.
Requests peaked at over 8,000 sets in 1988 but in 1990
through 1992 averaged about 2,400 annually (88,133). IPPF
officials attribute the decline in requests to increases in the
price of the implants and the fact that other family planning
commodities are cheaper (88, 194). Some IPPF affiliates
receive implants from sources other than IPPF.
Donor coordination. Coordination among donor organiza
tions would improve the continuity of services—a key factor
in Norplant programs. For example, when a program plans
to introduce implants, one donor might fund training, a
second might buy supplies, and a third might provide long
term evaluation. Without assurance that other sources of
funding are available to sustain all elements of the program,
each donor is reluctant to become involved (99).
In Bangladesh the government has worked with a consortium
of donor agencies to develop a coordinated plan for improv
ing health services including family planning (143). Each
donor agency identified the most appropriate areas for its
participation. For example, US AID has experience in pro
viding resources for training, and the World Bank is able to
support the purchase of supplies. In all, 17 donor agencies
have agreed to the cooperative program.
In the Bangladesh agreement funds for Norplant are avail
able as part of the amount allocated to clinical trials and the
introduction of new technologies. The government of Ban
gladesh can spend part of these funds on Norplant training
and supplies, but the proportion is not fixed. Future demand
for each method will determine how much will be spent on
each commodity. The original agreement estimated that
20,000 to 30,000 Norplant sets will be needed each year (235).
The concept of a consortium of donors to fund family plan
ning activities, introduced in Bangladesh, is now being
applied in Nepal. Within this agreement Norplant would
again be offered as part of a much larger program. In 1991
US AID hosted a preliminary meeting of international donors
who might be involved in family planning programs in Nepal
and elsewhere; more meetings are planned. For organiza
tions such as the World Bank, cooperation is easiest to admin
ister on a country-by-country basis. Other organizations
such as US AID may prefer to set global cooperative strategies
(131,132). Similarly, UNFPA has urged a centralized system
for procurement and distribution of contraceptive supplies
(241).
POPULATION REPORTS
Keeping the Way Clear for Norplant Users
Where should programs draw the line between tests, proce
dures. and criteria that are necessary to use a method and
those that are unnecessary, arbitrary, and inconvenient barri
ers that discourage the user? Unnecessary medical barriers—
unnecessary or dysfunctional procedures, practices, policies,
and orientations at least partly based on a medical rationale”
(199)—diminish the quality of care and limit access to fam
ily planning.
There is a pressing need to review guidelines for the provi
sion and use of every contraceptive method and, where nec
essary. to revise them in light of current scientific knowledge.
Introduction of a new method, such as Norplant, offers the
valuable opportunity to alert providers so that they can avoid
unnecessary barriers from the start and at the same time can
assure standards for high-quality care. To date, most programs
have not imposed unnecessary restrictions on Norplant use.
Physicians James Shelton, Marcia Angle, and Roy Jacobstein have identified six types of unnecessary medical barri
ers imposed on various methods (199):
1. Inappropriate eligibility criteria, contraindications, or
precautions. Some programs or regulatory agencies may
want to apply the same contraindications, warnings, and pre
cautions to Norplant as to the pill. But some warnings about
pill use are unnecessary even for the pill, and others may not
apply to Norplant. The differences between Norplant and
combined estrogen-progestin oral contraceptives—such as
Norplant's lack of estrogen and its continuous slow release
of very low doses of hormone—may be as important as the
similarities. For example, evidence to date does not rule out
Norplant for women with thromboembolic disease who can
not use other methods. Eligibility barriers sometimes arise
because considerations that providers should weigh along
with other factors when advising a woman gradually come
to be taken as absolute contraindications.
2. Process hurdles—procedures that clients must undergo
that have little or no relevance to use of their method. For ex
ample, is an initial pelvic examination really needed for Nor
plant use? The manufacturer, WHO, US FDA, and some
other experts suggest pelvic exams for all women who choose
Norplant (94. 174, 258, 259). But a pelvic exam can detect
very little relevant to Norplant use except pregnancy, which
usually can be determined from menstrual history. Therefore
others argue that a required exam will unnecessarily discour
age women who, out of modesty, are unwilling to undergo
pelvic exams (134). Service sites should offer the best, most
thorough care that they can but not force it on clients. Facili
ties able to conduct pelvic exams can offer the exam to a cli
ent, explain the exam, its benefits, and its possible help in
selecting a family planning method, and let the client choose
whether she wants it. She should understand that the pelvic
exam is not required to obtain Norplant. Service sites that
cannot conduct pelvic exams can still offer Norplant.
Similarly, guidelines from a number of organizations assume
that service facilities routinely test blood pressure (94, 97,
POPULATION REPORTS
174, 258, 259). In clinical trials of Norplant, however, blood
pressure did not change significantly (see p. 8). Certainly,
the test could uncover an important health problem, but
should results influence decisions about Norplant use?
Other process barriers include requiring two clinic visits to
obtain Norplant or routine follow-up visits every few months,
or rigidly insisting on insertion only during menstruation de
spite other evidence that a woman is not pregnant.
3. Impediments to the eligibility of providers. Studies
show that midwives and nurses can insert Norplant as safely
as physicians (see p. 28), and they often communicate better
with clients. Requiring that only physicians insert and remove
Norplant would unnecessarily restrict the method. The qual
ity of care is better enhanced by training providers adequate
ly in the technical skills needed.
4.
Provider bias. Because of personal biases, a provider may
not describe methods to clients objectively or even may try
to override clients' choices. Providers’ biases can arise from
misinformation or from prejudging clients' preferences. With
a new method such as Norplant, providers need to be well-in
formed from the start so that they do not act on or spread un
founded rumors that discourage clients.
5. Age/parity barriers. No medical reasons prevent a woman
from using Norplant because she is young or has no children.
In fact, family planning agencies in Baltimore are collaborat
ing to promote and provide Norplant to unmarried, sexually
active adolescents who want to avoid pregnancy (264).
6. Regulatory barriers. Some regulatory agencies have
been reluctant to approve new contraceptives without local
clinical trials (199). Pre-introduction studies are valuable be
cause they develop a core of local expertise often necessary
for training and wider use. Repeated effectiveness and safety
trials, however, have discovered few if any differences among
women and are not likely to yield additional medical infor
mation that helps regulatory decision-making.
Avoiding unnecessary barriers enhances the quality of care
(199) (see p. 19). First, many of these barriers restrict a cli
ent's choice of methods, and convenient access to a choice
of methods is a basic element of high-quality care (35). Sec
ond. time wasted on unnecessary procedures could be spent
instead on important activities such as taking a relevant medi
cal history and thorough counseling.
Family planning programs and facilities vary widely in the
services that they can offer. At a minimum, to offer Norplant
along with other methods, personnel must be able to take
and to interpret a relevant medical history, to counsel poten
tial and current users, to insert the capsules correctly and un
der aseptic conditions, and to refer users to convenient
removal services. Other facilities can offer more, such as re
movals and pregnancy tests. Both kinds of facilities can of
fer high-quality care with no need for unnecessary barriers
that deny Norplant to women who could use it.
Client Fees
Programs may spread the cost of Norplant by charging users
some fee. Volunteer family planning organizations, such as
family planning associations, have long charged modest fees
for services and supplies (113). The fee must be based on an
analysis of what clients are willing and able to pay (125).
Clearly, some women are willing to pay for Norplant. In
Thailand some women pay as much as US$8 for their
implants, depending on ability to pay (96). In Sri Lanka nearly
85% of the women who were interested in implants were
willing to pay US$3 (236). Still, price affects choice of
methods. In the Dominican Republic researchers observed
that some women who preferred Norplant chose the IUD
instead because of its lower price. Because the commodity
cost of Norplant accounts for so much of the total price, the
Dominican researchers noted that the price of Norplant to
users would have to increase greatly if donors stopped
supplying the implants (12). In Colombia researchers are
studying whether women will pay more for Norplant if prices
start low and gradually increase or if they begin at a reason
able but higher level (239).
Planning
To
Introduce Norplant
Once program managers have decided that their clients will
benefit from Norplant and that their program can supply the
necessary high-quality services, they must prepare for intro
duction. For example, managers must consider:
• How big should the initial program be, and how fast should
it grow?
• How will people learn about Norplant?
• What does Norplant counseling involve?
• What do insertions involve?
• How should removal services be organized?
• How should Norplant providers be trained and supervised?
• Where should services be offered?
• What record-keeping and follow-up are required?
was available in the US, Dominican immigrants requested
Norplant at some New York clinics where services are free.
These clinics had a waiting list of 500 women by the time
Norplant became available (130).
In a larger program in Bangladesh, the Ministry of Health
plans to provide implants to 20,000 to 30,000 women each
year. Pre-introduction trials started in 1985 under the direc
tion of the Bangladesh Fertility Research Program (BFRP),
now the Bangladesh Institute of Research for Promotion
of Essential and Reproductive Health and Technologies
(BIRPERHT). At first only a few clinics offered Norplant, and
BFRP planned gradual growth to 12 and then 30 additional
sites. The Ministry of Health, however, now plans a large
program to provide long-term methods, including Norplant,
nationwide, supported by a consortium of donors (see p. 20).
Program managers need to decide how they can best estab
lish Norplant services that offer both high-quality medical
care and thorough counseling, and how quickly they can
meet clients' demand for implants. What are the relative
advantages of large and small programs and of those that
grow quickly or slowly?
In small programs and in those that grow gradually, it is easier
to ensure that clients receive high-quality service. Supervi
sors can monitor newly trained personnel more closely.
Training enough providers is easier if the clientele grows
gradually. Thorough counseling is easier, too, and women
may be able to learn about the method from experienced
users. Thus they may make better-informed choices about
implants. All of these factors—high-quality medical service,
easier management, and thorough counseling—lead to sat
isfied users.
Large programs and those that grow quickly also have a
rationale. Many national programs need to increase contra
ceptive use in order to lower high birthrates that endanger
women's health and impede socio-economic development.
In such places policy-makers may want to expand family
planning services rapidly, and they may see implants as a
valuable part of that effort. Such efforts will be undercut,
however, if clients receive poor treatment or are pressured
into using a particular method.
How Big, How Fast?
Large programs may be necessary to provide removals and
offer on-going service to Norplant users, especially if much
of the population is mobile. If services are not available
nationwide, Norplant users may move where local health
care providers cannot serve them. Indeed, in some countries
governments are committed to offering the same medical
services everywhere. Thus it may be against government
policy or politically impractical to offer implants in only a
limited number of locations.
Program managers face decisions about how to introduce
Norplant services and how quickly to expand them. In the
Dominican Republic, for example, the program is small. The
family planning association PROFAMILIA carried out clinical
trials in Santo Domingo and Santiago. Since pre-introduction trials ended in 1986, PROFAMILIA has continued to offer
Norplant. The staff from thepre-introduction trials, now very
experienced, continue to provide counseling, insertions, and
removals. Although women pay only part of PROFAMILIA's
costs, Norplant is still their highest-priced contraceptive
option (12, 33). Few women can afford implant's, and so the
number of insertions remains small. More women might
choose Norplant if the price were lower (12). Before Norplant
The pace at which Norplant services expand must ensure
thorough counseling and screening, safe insertions, proper
handling of side effects, and adequate access to removal at
any time. In most places this will require starting small and
growing gradually, learning from experience and adapting
the program as it develops. The quality of services depends
greatly on how many well-trained providers are available,
and training many providers well takes lime. Programs that
have an existing infrastructure for family planning services
with established counseling, conditions for asepsis, follow
up procedures, and communication programs will be able
to offer clients this new method more quickly. In any case, a
program that chooses to introduce Norplant widely and
The Population Council, the Johns Hopkins Program for
International Education in Reproductive Health 0HPIEGO),
WHO, and other organizations provide detailed information
for managers who are planning Norplant introduction (see
box, p. 27). Program planners can request these publications
for more information on these topics and others.
■
22
POPULATION REPORTS
quickly must be particularly attentive to maintaining highquality care.
■
How Will People Learn About Norplant?
People need to hear about this new method and to learn the
facts about it. To help them do so, program managers first
need to understand how clients learn about contraceptive
methods and then to use this information to communicate
with clients. Because women usually first hear about im
plants and other methods from current users or from medical
personnel not involved with implants, these groups need
accurate information about the new method.
Women are most influenced in their family planning choices
by what they hear outside clinics. Interviewed in Egyptian
health centers, 57% of Norplant users listed their relatives,
neighbors, and friends as their most important source of
information about Norplant (62). In the US as well, women
who chose Norplant were more often influenced by friends
and family members than by clinic personnel (51).
Thus satisfied users of a particular family planning method
often are influential sources of positive information. In Thai
land one-third of women who chose implants in clinical
trials did so because they had talked with Norplant users
(107). Satisfied users also can influence continuation rates.
Researchers in the Dominican Republic noted that the ear
liest users of Norplant were more likely to discontinue be
cause of side effects than women who chose the method
several years later. The researchers attributed this change to
users' sharing information and supporting each other as well
as to counselors' learning more about Norplant and giving
clients better information (13). Satisfied users—for example,
nurses who use family planning—are particularly credible as
providers and counselors.
Conversely, dissatisfied users can discredit a method very
quickly. In several countries poor service delivery, especially
refusal to remove the implants before five years of use, has
caused public opposition to the implant method.
Mass-media television publicity, as well as favorable opinion
-x among users, can attract potential clients, particularly to a
j) new method such as Norplant. In Brazil researchers studied
100 women who chose Norplant and 100 who chose IUDs
at the same clinic. They found that 80% of the Norplant users
and all of the IUD users had learned about their chosen
method before coming to the clinic. Half of the women who
chose Norplant—a new method—had heard about it on
television. About one-third had heard about the method from
friends, relatives, or other women. Of the women who chose
the IUD—a well-known method—9% had heard of it on
television, and 74% had learned of it from friends, relatives,
or other women. Although most women had heard of their
method before coming to the clinic, a great majority said that
clinic counseling answered questions about the method that
they chose (80).
Women also learn about family planning methods from local
leaders and community organizations. Government officials,
women's health care advocates, religious leaders, and others
with a constituency among the public need information
about Norplant. Often, they can help design services, too.
Informing other health workers. Health care personnel who
are not providing implants themselves nonetheless need to
know about Norplant (233). Many women ask questions of
family or friends who work in health care. In Brazil, for
POPULATION REPORTS
example, 20% ofthe women who came for Norplant or IUDs
had talked about the method that they wanted with health
care personnel outside the clinic (80). Some women ask
questions about Norplant when consulting physicians for
unrelated reasons. In several cases such physicians misin
formed and frightened women because they themselves
knew little about the method and were suspicious. In other
cases physicians gave women inappropriate care for side
effects (262). Health care providers need accurate informa
tion about the method including where women should go to
obtain implants and to have them removed. Programs can
inform health care providers about Norplant by sending
them information in special mailings and by including infor
mation in journals or newsletters, in in-service education
programs, in professional meetings, and in television or other
mass media that reach professionals. Conferences and bro
chures for medical personnel not providing Norplant were
part of introduction activities in Egypt and Colombia, for
example (111).
' ■
What Does Norplant Counseling Involve?
As with all family planning decisions, a woman's choice of
Norplant should be an informed choice, freely made. That
is, she must know the full range of methods available to her
and their characteristics, and she must be allowed to make
her own decisions, based on her own needs. The provider
must ensure that she has the information and makes her
decision without pressure from the provider or from anyone
else (42,172). At the same time, the provider helps the client
to recognize her own needs and wants as she makes her
decision (see Population Reports, Counseling Guide, J-36,
December 1987).
When counseling ac
complishes this, the re
sult is greater initial use
of contraception as well
as longer continuation of
use (see Population Re
ports, Counseling Makes
a Difference, J-35, No
vember 1987). In the Do
minican Republic, as
noted, investigators
found that, as providers
became more confident
in counseling, women
were less worried about
side effects and used
Norplant for longer peri
ods (13).
Initial counseling can
support women's con
tinued use of Norplant in
two ways: (1) By inform
ing women beforehand
of the method's features
and possible side effects,
counseling helps to
screen out women likely
to be dissatisfied with the
method and to abandon
it early. (2) For those who
choose the method,
counseling
prepares
"This woman is interested to see that her
friend has just received Norplant. "Most
women learn about Norplant from
other women. Therefore informing the
public accurately about Norplant is vital.
23
them for the side effects that they may experience so that they
are not frightened if side effects occur.
Telling clients about methods. Clients choosing among fam
ily planning methods need to learn the basic features of all
available methods. For implants, this includes what they look
like and the need for insertion and removal. Women who are
seriously considering implants and women who have cho
sen them need more information, of course. Essential infor
mation for both groups is outlined in the "Guide to Norplant
Counseling," published with this issue of Population Re
ports. More detailed information can be found in various
publications listed in the box on p. 27.
Counseling should emphasize that Norplant is effective for
five years and must then be removed, but it can be removed
sooner. It should cover the side effects that women might
experience. Providers can spend less time on information
that women need to hear but not remember, such as how the
method works.
Women are asked to understand a great deal of information
when they come for counseling. Showing as well as telling
can help clients remember. For example, when counseling
about menstrual changes with Norplant, some providers in
the US show clients calendars marked with possible men
strual patterns, and they point out which patterns are normal
for Norplant users as well as which patterns indicate that the
Norplant user should return for a check-up (51). Printed
material, designed for clients to take home, can be helpful.
So can repeating essential information at follow-up visits.
Helping women decide about Norplant. The central step in
the counseling process is helping the client choose a family
planning method (115). This step has two aspects: (1) helping
a woman decide which method fits her needs and (2) assess
ing whether the method that she wants is medically appro
priate for her—that is, medical screening. For both aspects,
the provider asks the client questions, and they discusses the
answers (see the "Guide to Norplant Counseling").
Questions that help a woman decide if a method suits her
needs draw her attention to the features of the method, both
positive and negative. For example, a provider might first ask
a woman whether and when she wants to have children in
the future. If the client wants to delay pregnancy for several
years, the provider can suggest Norplant as one of several
choices that might be appropriate. The provider should point
out that Norplant is effective for up to five years but allows
the woman to become pregnant after the capsules are re
moved. Asking about a woman's experience with contracep
tives also can be helpful. For example, if a woman was
bothered by irregular bleeding with another hormonal meth
od, Norplant may not be the best choice for her. But for a
woman who often forgot pills or does not want to take pills,
Norplant might be a good choice.
screening questions should focus on conditions relevant to
the contraceptive method and not on general health matters.
For Norplant, questions should address whether the client:
• Is pregnant;
• Has active liver disease, as evidenced by jaundice;
• Has cancer of the breast or reproductive organs; or
• Has active cardiovascular disease (see the "Guide to Nor
plant Counseling").
If questioning reveals that a client has symptoms or a diag
nosis of these conditions, or if there is uncertainty, she should
be referred to a doctor or nurse for diagnosis and, possibly,
treatment before she uses Norplant. The provider conducting
the counseling should discuss nonhormonal methods with such
a client, should help her choose another method at least for the
meantime, and should make sure that she has an ample supply
of condoms or spermicide when she leaves.
Prospective Norplant users also should be asked about dia
betes, hypertension, migraine headaches, and epilepsy. Clin
ical studies have not suggested, however, that Norplant use
will aggravate diabetes, high blood pressure, or migraine
headaches, or will increase the risk of stroke. Still, a number
of organizations advise that Norplant users with these con- '
ditions may need to be monitored or to monitor themselves
(174, 259). They should be referred to a nurse or doctor to
decide on this. The recommendation for monitoring is based
on findings in some studies that combined estrogen-progestin oral contraceptive altered carbohydrate metabolism
or blood pressure or increased the risk of stroke. Also, clinical
trials excluded women with diabetes or high blood pressure,
and therefore the effects of Norplants on these women have
not been studied. As for epilepsy, women who take seizure
medication should know that some medications used to treat
epilepsy make hormonal contraceptives such as Norplant
less effective. They may prefer a nonhormonal method.
Where referrals or monitoring of these conditions is not
possible, providers must decide what course of action best
protects a client's health, based on the availability of other
family planning methods and the client's willingness to use
a nonhormonal method such as condoms, spermicides, vol
untary sterilization, or an IUD. If she will not use a nonhor
monal method, a progestin-only method such as Norplant is
preferable to one containing estrogen (94). Leavinga woman K
without any contraception may be exposing her to preg
nancy. Pregnancy, especially frequent pregnancy, can en
danger a woman's health. It is particularly dangerous for
women with conditions such as cardiovascular disease,
diabetes, and cancer. In setting up Norplant services, pro
gram managers should take care not to establ ish strict criteria
that arbitrarily exclude certain women. Instead, providers
should make balanced recommendations, taking account of
an individual woman's situation (see box, p. 21).
The risk of sexually transmitted diseases (STDs), including
AIDS, is crucial to every choice of contraceptive methods.
Providers should always remind clients that Norplant and
most other methods do not protect against STDs. Providers
should politely ask each woman if she has more than one
■ sexual partner or thinks that her sexual partner has any other
sexual partners. If so, she needs encouragement and help to
try to persuade him to use condoms at every act of coitus
outside marriage. She can use Norplant at the same time for
highly effective contraception.
Explaining how to use Norplant. When a woman chooses
Norplant, the provider should explain how the capsules are
inserted and removed. The provider also should tell the client
that she should have the capsules removed after five years
but can have them removed at any time sooner. Also, the
provider should review common side effects, particularly
bleeding changes, so that the client is not alarmed if they
occur. Furthermore, the client needs to know the signs of
ectopic pregnancy, infection at the insertion site, and cere
brovascular problems that call for her return to a Norplant
provider. (See the "Guide to Norplant Counseling.")
Questions that assess whether a method is medically appro
priate ask about symptoms and previous diagnoses. These
Counseling returning clients about side effects. Providers
need to recognize Norplant side effects and know how to
24
POPULATION REPORTS
manage them. When a
woman reports a prob
lem, the provider should
determine, if possible,
whether it is due to Nor
plant or to some other
cause, and what course of
action to follow. Both
JHPIEGO and the Pro
gram for International
Training in Health (IN
TRAH) provide check lists
for diagnosing the causes
of common conditions
experienced by Norplant
users (94, 97) (see box, p.
27).
The most common Nor
plant side effects are men
strual changes—spotting,
amenorrhea, or frequent,
prolonged, or heavy
bleeding (see p. 5). For the
great majority of clients
whose bleeding changes
pose no health risk, coun
seling may be what is
needed. Some women
simply want an explana
tion. Others fear for their
health. In these cases, the
provider can assure the cl ient that these changes are
common and pose no
health risk. If the woman
is not reassured, she may want to choose another method.
Some women find that the bleeding interferes with their
religious obligations or their sexual relations with their hus
bands. When women have doubts about continuing Nor
plant use, the provider should help them weigh the advan
tages and disadvantages of switching to another method.
G 'Who can counsel? Various program staff may be responsible
)
for counseling. In most places nurses counsel women in
groups at the clinic and then counsel them individually. In
Indonesia the family planning field worker does much of the
preliminary counseling about the range of methods (253).
Physicians in private practice may counsel clients them-’
selves. Whoever has the chief responsibility for counseling,
almost all health care providers counsel clients, informally
■or formally, at some time, and therefore they need training
in counseling skills and talking sympathetically with clients (97).
implants on the woman's skin helps to insure correct place
ment of the anesthetic and the implants (82) (see photos
above). Placing the capsules just under the skin, not deeply,
helps to assure that they can be removed easily later (233).
When all six capsules are in place, the provider closes the
incision with an adhesive bandage—no stitches are needed—
and places compresses and gauze over the entire area. Inser
tion usually takes 8 to 10 minutes (6). The Population Coun
cil, JHPIEGO, INTRAH, and WHO have published complete
instructions for insertion and removal (94, 97, 149, 258).
What Do Insertions Involve?
Insertion and removal of implants are minor surgical proce
dures. The Population Council and Leiras Oy developed the
techniques for insertion and removal (149). As experience with
Norplant grows, practitioners are suggesting modifications of
these techniques (49, 51, 97). Most of the equipment for inser
tion and removal is commonly used in health centers. Leiras
Oy provides the specially marked trocar. Norplant insertion and
removal kits supplied by US AID contain all the necessary
equipment (37).
To set up services, managers must understand what Norplant
insertion requires. In brief, to insert an implant, the provider
anesthetizes an area of the skin on the inside of the woman's
upper arm. The provider then makes a 2 mm incision, either
with a special trocar, if it is sharp (49, 53), or with a scalpel,
and uses the trocar to insert the capsules just under the skin.
The trocar is marked to indicate how far it should be placed
under the skin to insert each capsule. The provider places
the capsules in a fan shape, radiating out from the incision.
Using a paper or plastic template to mark the pattern of the
Avoiding infection. Providers should wash their hands and
use gloves that have been soaked in a 0.5% chlorine solution
for 10 minutes or boiled in water for 20 minutes. Equipment
should be sterilized. Where sterilization is not possible,
high-level disinfection can be done by boiling instruments
for 20 minutes or by soaking them in chemical disinfectants
(97, 149, 258). If the health care provider wears gloves and
avoids cuts with instruments that have blood on them, he or
she should be safe from any infection borne in clients' blood,
such as AIDS or hepatitis 8.
■
POPULATION REPORTS
25
nancy; signs of possible cardiovascular disease; possible
anemia related to heavy bleeding; implant expulsion, which
will require replacement with sterile capsules; severe infec
tion or abscess at the insertion site; and cancer of the breast
or reproductive organs. In clinical trials some Norplant users
asked providers to remove their implants for conditions, such
as irregular bleeding or mild weight gain, that did not impair
their health. Initial counseling should try to screen out wom
en who think that they could not tolerate such side effects.
Good-counseling also may help a woman who has chosen
Norplant but now wants it removed. In some cases it may be
the husband who needs reassurance, and he should join the
counseling session. The provider can listen to the woman
and her husband, provide reassuring information, and dis
cuss their options, of which removal of the implants is one.
A pamphlet from the Philippines illustrates two choices for Nor
plant users: At left, after five yeairs using Norplant, a woman
receives another set ofimplants to continue contraception. At right,
another woman has the capsules removed to become pregnant.
Timing of insertion. To ensure that clients are not pregnant,
their implants should be inserted during or within a few days
after a menstrual period, or after abortion, unless other
information indicates that they are not pregnant. Norplant is
effective within 24 hours. Women who are breastfeeding are
advised to use a barrier method of contraception (97, 150).
Still, women can safely use Norplant after the first six weeks
of breastfeeding, and research may establish that even earlier
use is possible (2, 55, 56, 147, 188, 189, 196, 256).
■
How Should Removal
Services Be Organized?
Program managers must understand the procedure involved
in removing implants. To remove the capsules, the provider
finds them by feeling them, injects local anesthetic under the
capsules, and makes one 4 mm incision near where the inser
tion incision was made. With fingers, the provider pushes
against the skin, moving one capsule at a time toward the
incision and then, with mosquito forceps, pulls out the
capsule. Any fibrous tissue around the capsule must be
scraped away with gauze or a scalpel as the capsule is
removed. After all of the capsules are removed, the provider
places an adhesive bandage and compresses over the inci
sion site (97, 149).
Removals take longer than insertions, and they are more
likely to be difficult. They should be done in a clinic setting.
In an lndonesian study of removals, the mean time required
was about 22 minutes (6). Occasionally, removals can take
an hour or even longer (83, 107). Rarely, the provider may
need to ask the client to return for a second visit if removal
is so difficult that her arm becomes swollen (166). Removals
are more likely to be difficult if the provider is not skillful,
the implants are deep in the arm, or fibrous encapsulation is
extensive. The woman's arm may be painful and bruised
after removal (111).
When to remove the implants. The capsules should be
removed after five years of use or whenever a woman wants
them removed for whatever reason. In addition, providers
may recommend removal for such medical reasons as preg
26
Other women will request removal because they want to
become pregnant or they are moving to an area without
Norplant services. Again, initial counseling and screening
can minimize the number of such women who choose
Norplant. People's circumstances change unpredictably, how
ever, and women cannot be denied removal just because
they change their minds or their situations change.
Access to removal. After counseling, some women still will
want Norplant removed, and they should be accommo
dated. In focus-group discussions, however, some users re
port difficulty persuading health care providers to remove
implants (262). Health care providers have given various
reasons for refusing or delaying removals. Removals require
time and aseptic conditions, and clinic staff may not be able
to perform them whenever a woman comes in (233). In other
cases providers may not feel confident of their ability to
perform removals (262). In still other cases providers have
disagreed with women who complained that their side ef
fects were so severe as to require removal. Clinic personnel
also have refused removal because implants are expensive,
and they thought that women had had sufficient warning
about side effects before they chose implants.
Access to removal is a necessary part of high-quality service,
however. Women should not be forced to continue using
implants if they no longer want them. Such a policy is
intrinsically unethical, and word of such a policy will dis- (
courage women from trying the method.
As Norplant becomes available, managers must plan for
removals by ensuring that facilities and trained personnel are
ready’when needed. Program managers also mustensure the
following six conditions:
• During initial counseling providers must tell women: (1)
where to go for removal; (2) that removal is necessary after
five years of use but can be done sooner at their request; and
(3) that they must return to the clinic if they are moving
from the area. Staff should remove the implants if the
woman is moving to an area without implant services.
• Clinics designated as removal facilities must allocate time,
space, equipment, and personnel to removals.
• Staff must know either how to remove implants or where
to refer women.
• Staff must agree that women can have their implants
removed on request.
• Staff trained in implant insertion, removal, and counseling
should not be transferred elsewhere until other trained staff
are available.
• Clinics should have established back-up procedures for
difficult removals.
POPULATION REPORTS
Resources for Program Managers
Supplies
International Planned Parenthood
Federation
Regent’s College, Inner Circle, Regent’s
Park, London N'Wl 4NS, UK
IPPF provides supplies to its affiliates only,
at a cost of US $23.12 per implant set,
including one trocar per 50 implant sets.
US AID
Office of Population. Washington. D.C.
20523, USA
US AID provides supplies only for pro
jects supported by a US AID mission or
conducted with a Cooperating Agency.
UNFPA
220 East 42nd Street, New York, New
York 10017, USA
UNFPA provides Norplant supplies only
in the context of official projects negoti
ated with national government health
authorities.
The manufacturer also provides implants.
Leiras Oy Pharmaceuticals
P. O. Box 325, SF-00101
Helsinki, Finland
Publications listed below are available
free of charge unless otherwise noted.
General Information
Norplant: A Summary of Scientific Data.
The Population Council, 1990. 39 pp.
Norplant Worldwide (Newsletter). The
Population Council, Two 4-page issues per
year.
—.
)
•‘Norplant at a Glance” (Information
sheet). Population Information Program,
1992. 1 p. (See copy mailed with this issue
lines. World Health Organization, 1990.
134 pp. Cost: US$12.50.
Norplant Guidelines for Family Planning
Service Programs. The Johns Hopkins Pro
gram for International Education in Repro
ductive Health (JHPIEGO), 1992. Available
in English, French, and Spanish. 150 pp.
Cost: one copy free to US AID-funded pro
jects; write for cost of additional copies.
Training Materials
Norplant Contraceptive Subdermal Im
plants: Guide to Effective Counseling
About Norplant. The Population Council,
1989. 38 pp. Available in English. French,
and Spanish.
Norplant Prototype Training Curriculum.
The Population Council, Program for Ap
propriate Technology in Health (PATH),
Family Health International, and Associa
tion for Voluntary Surgical Contraception
(AVSC), 1990, revised 1992. Available in
English and French from the Population
Council.
Norplant Brochure for Physicians.
PATH. Available in English and Spanish.
Norplant Implants: Manual for Clinicians.
The Population Council, 1990.40 pp. Avail
able in English, French, and Spanish. Cost:
US$3.50 plus postage.
Norplant Training Course Outline:
Standard 3-Day Course. JHPIEGO, 1992.
Available in French and English. 40 pp.
Norplant Course Handbook: Guide for
Participants and Trainers. JHPIEGO,
1992.
of Population Reports.)
Guide to Norplant Counseling. Popula
tion Information Program, 1992. (Mailed
with this issue of Population Reports.)
Program Operation Guides
Prototype Client Record Form for Nor
plant. AVSC, 1992. 3 p.
Norplant Contraceptive Subdermal Im
plants: Managerial and Technical Guide
Norplant Slide Set. Insertions and remov
als. JHPIEGO, 1992. 100 slides cover ba
Organizing removal services. Removal services can be or
ganized in several ways. All clients requesting removal might
be referred to a central facility; a team of trained providers
could travel to service sites on specified days; or many
providers could be trained to remove implants at many sites.
In deciding how to organize removal services, managers
must consider the convenience of clients and how best to
train providers and to maintain good medical services. A new
program will generate few requests for removal and thus will
offer few chances for providers to perform or observe the
procedure. A centralized facility for removals or a traveling
team with a specific schedule would be suitable for a new
program. These skilled providers could schedule removals
so that trainees would be able to observe the procedure and
perform removals under supervision. Centralized facilities
POPULATION REPORTS
sics of Norplant counseling, insertion and
removal techniques, and troubleshooting for
insertion and removal problems. Available
in English, French, and Spanish. Cost: one
set free to US AID-funded projects; write
for cost of additional copies.
Norplant Training Video. Insertions and
removals. JHPIEGO. Available in late 1992.
Norplant Insertion and Removal Practice
Training Arm. PATH. Cost: $ 13-$ 16 each,
depending on quantity.
Norplant Prototype User Brochures.
PATH. Available in English, Indonesian,
Sinhalese, Spanish, Swahili, and Tagalog.
Norplant Training Videotapes. Leiras Oy
Pharmaceuticals. Available in English.
Slide sets available in English.
Addresses
Association for Voluntary Surgical Con
traception (AVSC)
79 Madison Avenue, New York, New York
10016, USA
The Johns Hopkins Program for Interna
tional Education in Reproductive Health
(JHPIEGO)
Brown's Wharf, 1615 Thames Street, Suite
200, Baltimore, Maryland 21231, USA
Leiras Oy Pharmaceuticals
P. O. Box 325, SF - 00101 Helsinki, Finland
The Population Council
One Dag Hammarskjold Plaza. New York,
New York 10017, USA
Population Information Program
The Johns Hopkins Center for Communica
tion Programs, 527 St. Paul Place, Balti
more, Maryland 21202, USA
Program for Appropriate Technology in
Health (PATH)
4 Nickerson Street, Seattle, Washington
98109, USA
World Health Organization
1211 Geneva 27, Switzerland
should be conveniently located, however, within easy reach
of most clients.
As the number of Norplant users increases, demand for
removal services will grow. At that point, most providers
could be trained in the removal procedure. Removal services
should'not be spread so thinly, however, that providers do
not perform enough procedures to maintain their skills.
0
How Should Norplant Providers
Be Trained and Supervised?
Health care personnel need different kinds of information
about Norplant. Those who are not involved in implant
services need a general introduction to the method so that
they can answer questions and refer clients (see p. 23). If
27
implants are to be widely available, information about Nor
plant should be part of all preservice family planning educa
tion. In Thailand and Indonesia all physicians, nurses, and
midwives receive a general introduction to Norplant and
other family planning methods while they are in school (75).
Personnel directly involved in implant procedures and coun
seling need special training and practice to develop skills.
In-service training is necessary to supply trained personnel
to an expanding program. In clinical trials the personnel who
inserted implants were trained at Population Council centers
in Indonesia, Egypt, and the Dominican Republic (25). These
providers, primarily physicians, in turn trained people in
their own countries. Other countries planning to introduce
Norplant need a similar core group of trained and experi
enced providers. The group can continue to train other
providers as the program expands (9). Some can receive
further instruction and become trainers, perhaps using their
clinics as training sites. A high-quality program depends on
well-trained providers, and managers should encourage good
training by recognizing and rewarding good trainers (134).
Formal training must continue as programs grow. As implants
become more widely available, more clinic staff will learn
both medical procedures and counseling informally, by watch
ing experienced personnel work. This informal training-by
observation is not reliable and must be supplemented with
formal training (9).
Training for removals presents special problems because,
when implants are first offered, few women request removal
(233). A trainer may demonstrate a removal, but trainees may
have no opportunity to perform one until months or even
years later. Strategies to help ensure high-quality removals
include referring all women to a central facility for removals,
providing trained practitioners with a videotape of the pro
cedure, having a trainer go out to clinics on request, encour
aging practice on
model training arms
or animal tissue
such as chicken
breasts, and retrain
ing clinic person
nel later as the need
for removals grows
(134, 233, 252).
In Indonesia, Thai
land, and else
where, nurses and
midwives, as well as
as physicians, have
performed Norplant
insertions and re
movals. Two Indo
nesian studies com
pared insertions and
and removals per
formed by physi
cians with those per
performed by nurses
and midwives (6,
212). They found no
A page in a Latin American pamphlet ex significant differ
plains to the Norplant user when to have the ences between the
implants removed. The provider writes the two groups in the
month and year on the blank line provided. length of these pro
cedures or in insertion-site infection rates. In the US, physi
cians, nurse practitioners, and nurse-midwives are being
trained (252). When nurses and midwives offer Norplant,
more women can receive implants, and the cost may be
lower. In many countries Norplant will be widely available
only if nurses and midwives provide the method.
Supervision. Good initial training is necessary but not suffi
cient to ensure continued high-quality service. In addition,
managers must continually supervise staff. Supervision should
cover clinic services, clinic management, and interaction
between client and provider (98). Different personnel may
have responsibility for supervising each of these areas. In
itially, trainers might supervise services, especially clinical
care. Program managers must develop service standards
(100). Manuals prepared by JHPIEGO and WHO suggest
standards for evaluating services (97, 258) (see box, p. 27).
Supervision of Norplant services will be most effective as part
of a good overall supervisory system. When a good supervi
sion process is in place, Norplant services can be reviewed
as all other services are reviewed (98). Separate supervision
of Norplant services may be necessary if there is no general
(
system or as the new method is Introduced.
Regular supervision helps maintain high-quality service. Re
searchers in Ecuador concluded that insertions seemed de
ceptively easy to some clinic staff. Eventually, overconfidence
led to carelessness and cases of infection at the insertion site.
With periodic supervision, the situation was corrected (126).
■
Where Should Services Be Offered?
In general, any facility that can offer voluntary sterilization
or IUDs also can offer implant insertions and removals (36).
The room must be clean and equipped with sterile or highlevel disinfected supplies (7, 97). In addition, a service site
should have the personnel and the space to counsel clients,
including a place for client and provider to talk privately.
Service points also need adequate record-keeping capabilities.
More service sites will make Norplant more available, but
quality of care must be maintained as services expand. In
Kenya 83% of women live in rural areas (103). To serve them,
clinics offering vaccinations, child health services, and several contraceptive methods have been set up in rural mar
ketplaces (66). Although these clinics lack on-site facilities
for sterilizing equipment, a physician has devised a way to
offer Norplant insertions there without sacrificing the quality
of care (153). Every Monday several presterilized packets,
each containing the equipment and supplies for one inser
tion, are delivered to each clinic where there is a trained
provider. On the following Monday the packets of instru
ments that have been used and any that remain unused are
taken back to Nairobi for autoclaving. New packets are left.
There were no cases of infection at the insertion site in a study
of the first 300 insertions performed at these marketplace
clinics (153). In Indonesia thousands of women received
implants and IUDs in temporary outreach facilities set up in
urban and rural markets, neighborhoods, or fairgrounds.
These programs reached many women who were not using
modern birth control methods (181). In 1990 more than half
of the women who received Norplant were served in such
clinics (92). Temporary clinics can present special problems,
however. BKKBN and the Ministry of Health have recently
discontinued Norplant insertions in temporary clinics be
cause of concern about the ability to maintain asepsis, to
screen clients adequately, and to keep records (92, 253).
POPULATION REPORTS
f
What Record-Keeping and Follow-Up?
What records must be kept about Norplant users? Initially,
clinic staff need to record the name of each implant recipient
and when her implants need to be removed after five years
of use. At any follow-up visits, any complications or side
effects should be noted. When her implants are removed,
that, too, should be recorded.
In addition to helping serve individual clients, record-keep
ing helps program managers evaluate the use of implants.
Records on infections at the insertion site and removals for
pre-existing conditions such as pregnancy help managers to
assess the quality of medical procedures and screening. Also,
managers need continuation rates to determine the cost of
the program per couple-year of protection from pregnancy.
Organizations involved in Norplant introduction suggest
follow-up visits about one month after insertion and once a
*C
ya thereafter (94, 97, 176, 198, 258). At the first visit the
ptjJder should make sure that there is no infection around
the area of the implants, answer the client's questions, and
again discuss possible side effects, the need for removal after
five years, and the availability of removal whenever the user
wishes. At the client's annual visits, the provider should
answer the client's questions and screen the client for con
ditions that might require removal of implants or monitoring
of the client (94, 97). Women with diabetes or high blood
pressure may require more frequent follow-up visits to moni
tor their condition (see p. 24). AVSC has developed a proto
type client record form for keeping track of the client's health
for the full five years of implant use. The form is a record of
the client's name and address, medical history, and physical
condition. It can be updated on each follow-up visit (17).
How will Norplant users recall when to have their implants
removed? If women come in fora yearly check-up, both they
and the program are more likely to remember removal after
five years. Most programs also give women some written
statement of the date for removing implants. In Indonesia and
Nepal, for example, program clients have family planning
cards, and Norplant users' cards show the removal date (28,
66). In Finland and elsewhere the provider attaches a re
minder card to the woman's file and gives her one to keep.
In other programs the provider writes the removal date on
the information booklet that the woman receives (151).
Keeping track of women who have received implants has
been difficult (7, 24,122,187, 262). Programs may choose to
emphasize the client's responsibility to return for implant
removal. To assist her memory, she could be given a colored
card that states the date to return. Each year's card would be
a different color. Radio announcements, clinic posters, or
other means would tell women that this is the year for women
with a particular colored card to have their implants removed
(20, 37). In some countries, particularly if the population is
mobile, broadcast announcements can remind women to
have their implants removed,
□
New Method, New Opportunity
Introducing a new family planning method such as Norplant
is an opportunity for program managers to improve clients'
satisfaction and thus program performance. Pre-introduction
trials have shown that women like the method if it is offered
with good medical care and counseling and if they can have
the implants removed when they choose. If a program pro
vides high-quality services and publicity that positions the
method to meet clients' needs, Norplant may become a
popular new family planning method.
• 8. AFFANDI, B., SANTOSO, S.S.I., DIAJADILAGA, HADISPUTRA, W.. • 21 BALOGH. S A., KLAVON, S.L. BASNAYAKE, S., PUERTOLLANO.
MOELOEK. F.A., PRIHARTONO, J., LUBIS, F., and SAMIL, R.S. Preg- N„ RAMOS, R.M., and GRUBB, G.S. Bleeding patterns and acceptability
among Norplant users in two Asian countries. Contraception 39(5):
541-553. May 1989.
36(2): 203-209. 1987.
9. AJELLO, C. (IHP1ECO) (Norplant use and training courses! Personal 22. BALOGH, S.A., (ADIPO. OA., EKWEMPU. C.C.. D1EJOMAOH. M..
FAKEYE, O. OTUBU, J.A.M.. OKPERE, E, OTOLORIN, E.O..
10. AKHTER. H.. DIAZ, S. CAMPODONICO, I., et al. Contraceptives
surveillance of Norplant." Sep. 1990. 19 p. (To lx
* published by World nmg17-103-107. 1992.
An asterisk (’) denotes an item that was 11. ALAN^GUTTMACHER INSTITUTE Special report.. Norplant—One 23. BALTIMORE SUN. Implanted protection: Women slowly turn to
particularly useful in the preparation of year later. Washington Memo, Dec. 20, 1991. p. I, 3-4.
24. BASNAYAKE, S, THAPA, S., and BALOGH, S.A. Evaluation of safety.
• 12. ALMONTE, D.. POLANCO. J.F.. PEREZ, S., CORDERO, M.. BRATT.
this issue of Population Reports.
Family Planning 19(11: 39-47. Jan.-Feb. 1988. .
through PROFAMILIA programs: Final report. (Santo Domingo, Domini 25. BEATTIE. K. (Population Council) (Norplantdevelopmentl Personal
1. AAKER. D.A. and SHANSBY. J.G. Positioning your product. Business can Republic, and Research Triangle Park. North Carolina!. Asociatidn
Pro-Bienestar de la Familia (PROFAMIHA). and Family Health Interna
z'aBDULLa/ka.. SAWSAN, I.E.. SALEM, H.S., and SHAABAN, M.M.
tional, |an. 3, 1992 33 p.
Effect of early postpartum use of the contraceptive implants. Norplant, ■ 13. ALVAREZ, F., BRACHE, V. and FAUNDES. A. The clinical performon the serum levels of immunoglobulins d the mothers and (heir breast
27. BENNETT. A.. FRISEN. C, KAMNUANSILPA. P„ and MCWILLIAM.
Studies in Family Planning 19(2): 118-121 1988.
fed infants. Contraception 32(3): 261-266. Sep. 1985.
ARSHAT, H„ RACHAGAN, S.P., KIM, K.S., SUAN, A.E., KARIM. H A..
3
AFFANDI. B. Kontrasepsi implant: Pengalaman klrnik serla prospek 14.
masa depan. (Contraceptive implants: Clinic experience and future and ISMAIL, M.TM. A study of the acceptability and effectiveness of
prospects.HINDI 1988. 9 p. (Unpublished)
4
AFFANDI, 8. Norplant introduction in Indonesia. Prepared for theJournal of Reproductive Health 8(1): 21-29. Jun. 1990.
amily Planning Association of
ASHBY, A. (Wyeth-Ayerst Pharmaceutical) (Norplant in the US|Nepal, 1990. 195 p. (Mimeo)
Workshop on Implementation of Large Scale Norplant Programs Sub 15.
sequent to Pre-introductionfClinical Trial Phase, Jakarta, Dec. 10-14. Personal communication, Dec 5. 1991
29. BHIROMRUT. P A study of the acceptability of Norplant implant in
16.
ASSOCIATION FOR VOLUNTARY SURGICAL CONTRACEPTION
5
AFFANDI. B., PRIHARTONO, |., LUBIS, F., and SUTEDL H. Clinical(AVSC). Development of permanent and longterm contraception in research). |n.d.| 54 p. (Unpublished)
trials of Norplant in Indonesia. In: Shaaban; MM., ed. The Norplant Nigeria, 1986-1990. New York. AVSC, 1990. 29 p. (Mimco)
30. BIALY. G. (US National Institutes of Health) [Capronor 2 and
subdermal contraceptive system. Proceedings of the Symposium on ' 17. ASSOCIATION FOR VOLUNTARY SURGICAL CONTRACEPTION.
Longterm Subdermal Contraceptive Implants: Egyptian and International Prototype client record form for Norplant. |n.d.| 3 p. (Unpublished)
Experience. Feb. 23-24. 1984. Assiut, Egypt. Assiut University. 1984. p. 18. BAKAMJIAN, L. (AVSC) (The Norplant program in Colombia! Per- •31J3RACHE. V., ALVAREZ-SANCHEZ. F.. FAUNDES. A.. TEJADA, AS.,
and COCHON, L. Ovarian endocrine function through five years of
• i^FFANDI. B.. PRIHARTONO. J., LUBIS, F.. SUTEDI, H and SAMIL. 19; BALOGH, SA. The role of research in contraceptive introduction.
R S Insertion and removal of Norplant contraceptive implants by phy Presented at the 118th Annual Meeting of the American Public Health
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BRACHE. V. FAUNDES. A.. JOHANSSON. E.. and ALVAREZ. F.
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MOELOEK, FA. PRIHARTONO. J, LUBIS. F„ and SAMIL, R.S. Five-year
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A.-.M., MIRANDA. P.. PERALTA, O.. and CROXATTO. H.B. Effects of
Norplant subdermal implants on lactation and infant growth, tn:
Philadelphia
1984. p. 397-403.
56. DIAZ. S., HERREROS, G. JUEZ, G., CASADO, M.E., SALVATIERRA,
A.M.. MIRANDA. P.. PERALTA, O„ and CROXATTO. H.B. Fertility
nd infant growth. Contraception 32(1); 53-74.
• 5Z dIaZ, S„ PAVEZ, M„ CARDENAS. H..
of Norplant subderm.il implants or Copper-T IUDs Contraception 35(6):
569-579. Jun. 1987.
58. DIAZ. S.. PAVEZ, M„ HERREROS. C. JOHANSSON. E.D.. and
59 DIAZ S. PAVEZ m miRanda I- Ri iBERFSON, D.N., SIV1N.
60. DORFLINGER.
[Norplant projections] [Notes from IHPEIGO
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m Egypt survey results of EFCS clientele: Summary report 1990. Cairo,
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A summary report of a two stage study. Feb. 1991.49 p. (Unpublished!
65. FAKEYE.O. Theeftectof low-dosec
6b FAMILY HEALTH INTERNATIONAL.
challenges:
, FAMILY PLANNING WORLD. Doctors, patients satisfied with Nor68. FAMILY PLANNING WORLD. Norplant <
69. FAMILY PLANNING WORLD. Norplant Foundalii
30
1 II M( r>( IN Al I) M Wnrid B.'.
land, )un 13,1991.
132. MCDONALD, M. (World Bank) [Norplant funding) Personal comnd Apr. 7. 1992.
.
133. MCGREGOR, K. (IPPF) )IPPF upply of Norplant
134 MCINTOSH, N. (JHPIEGO) (Raining for Norplant insertion and
removal) Personal communication. Aug. 5 and Oct. 2. 199) and Apr.
22, 1992.
135. MORENO, L. and GOLDMAN, N. Contraceptive failure rates m
developing countries: Evidence from the Demographic and Health Sur
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137. MUNTHE-KAAS, A. (UNFPA) JUNFPA support of Norplant acti
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138. NEPOMUCENO, T
—
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139. NIYOMWAN, v' Pre
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Contraception 37(1): 61-73. Jan. 1988.
14 3. PANNENBORG. O.C. (Wbrld Bank) (World Ba
144. PARIANI, S.. HEER. DAt. "nd VAN ARSOOL. AID.. |r. Do
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POPULATION REPORTS
Norplant Worldwide. No. 14, May 1990 p T“1 "“' ™"
' i™LlS^T'?SC?UraL<PC1- N»n>l«con«a«p<iwsubdermal
a^kManual for clin,cian*- New York. PC, Feb. 1990 39 o
imoia^C1^^ £OUNCIL (PC)- Norplant contraceptive subdermal
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,,
■151. POPULATION COUNCIL (PQ. Norplant levononjesrel implants,
A summary of scientific data. New York. PC, 1990. 30 p.
152. POPULATION COUNCIL Acceptors describe what they like,
4 Ap?' 198610 3 * 3bOUt Norp,ant
Norplant Worldwide, No.
153. POPULATION COUNCIL Bring pre-sterilized instruments and
"PP|'ies to ken1^i!ni” without electricity, water. Norplant Worldwide,
154 POPULATION COUNCIL. Comparing family planning methods:
Norplant fact sneet no. 5. Norplant Worldwide, No. 11, Aug. 1988. p.
190.
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226.
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191.
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SIVIN, I, DIAZ, S.. HOLMA, P, ALVAREZ-SANCHEZ, F„ and
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SEGAL, S.J., FAUNDES, A., ALVAREZ-SANCHEZ, F„ VILJA, P.
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157. POPULATION COUNCIL. Develop regional booklets as prototypes
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171 POPULATION COUNCIL. Update Norplant Worldwide, No. 16,
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’ 253. WARD, S.J., SIDI. I.P.S., SIMMONS, R., and SIMMONS, G.B.
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ADDENDUM
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POPULATION REPORTS
contraception. American Journal of Obstetrics and Gynecology 165(6,
31
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12
Development of a Contraceptive vaccine for use by the Human male -
Results of a feasibility study carried out in Adult Male Bonnet
Monkeys -NR Moudgal, G S Murthy, N Ravindranath, A <J Rao & M R N
Prasad.
MALE CONTRACEPTION
In the case of the male, as yet no method has been found that is
fully effective, safe, reversible and acceptable.
ere responsible for this constraint.
Several factors
Foremost among there is the
incomplete understanding of the physiology of the male reproductive
system and the relative lack of suitable targets for fertility
interference in the male as opposed to the female.
Another factor
is the debatable issue of the requirement of drug induced azoospermia
as a prerequisite for a male contraceptive.
On the question of safety
the risk versus benefit considerations of a male contraceptive
require greater safety standards than those accepted for therapy
of other clinical disorders.
THait may indirectly apply to
out there is reason to believe that future research will lead to a
better understanding of male reproductive physiology and to the
discovery of safe, reversible and easily acceptable male anti
fertility agents.
It is anticipated that with the advancement in the field of txaiscuke
molecular and cellular biology and genetics, a fuller knowledge of
the male reproductive system will create appartunities tor more
rapid development of better methods of male contraception.
The earliest report of attempts at chemical control of male fertility
was concerned with the use of the male hormone itself.
(Testosterone
years studied - 1949-52) This study was sucoffided ny investigations
of a variety of, non hotnmonial agents with testdcular action some of
f- eo c. e o
which res-cted clinical testing before being abandoned. With the
advent of oral contraceptives for women, the effect of new
progestogens was assessed in
- a non steroidal inhibitor of
pituitary function meth“-^‘also reached clinical trial,
more
recently androgenic steroids such as dan^zol or progestational
either alone, or in various
steroids and testosterone
combination nave been studied.
Steroidal Contraceptives:
□MPA injections in doses of 1000 mg per one or two weexs to numan
males induced azoospermia by 70 days which lasted for several.
months.
The effects were reversible by six to eight months
following withdrawal of treatment.
However libido and sexual
potency was affected.
Medioxy Progesterone Acetate in comoinations with andfogen were
conducted at several centres supported by WHO, Population council
and Ford Foundation.
sexual potency.
Testosterone was added to ensure libido and
Some centres evaluated the effect of DMPA plus
testosterone enanthate (TE) or cypionate (TC) both injected once
monthly with DMPA in monthly doses of 150 mg or higher plus TE of
250 mg or 400 mg.
This induced oligospernia or azoospernia in
majority of volunteers.
In another study a combination of
200 mg
DMPA plus 250 mg TC once monthly produced azoospermia in 56% of men
within 6 to 15 weeks the remaining men achieved oligospeimia within
CypKoterone Acetate also induced severe oligosper-hia or
■
azoospernia but affected libido in at least a few of the volunteers
20 weeks.
3
The NIHFW also administered Cyproterone Acetate orally at a dose
of 20 mg daily and testosterone enanthate at a dose of 250 mg every
fortnight to five volunteers.
The test were successful but the
efficacy of the pills cannot be proved unless multi-centre trials
are initiated and conducted.
Microsdose Intravagina 1 Levonorgested Contraception:A multicentric clinical trials - Contraceptive Efficacy and
side effects -WHO- Task Force on long Acting systems Agents
for Fertility Regulation.
Participants - Thailand, People's Republic of China, India,
Columbia, Switzerland, Cuba, Brazil, Pakistan, USSR, u K,
Zambia, Sweden, Tunisia.
A multicentric clinical Trial - 19 centres - (Largest
participation China, follwed by India and Brazil) in 13
countries - to assess the contraceptive efficacy and clinical
acceptability of silastic 382 vaginaijring releasing 20 mg of
levonorgestrel for at least 90 days.
1005 women, 8176- 74 women months.
Since 1918 vagina recognised as a suitable site for administration
of drugs that will reach the system^circulation.
In a patent
issued to Dr. Gordon Duncan of Upjohb-Ltd in 1968 it described
a vaginal ring composed of silicone polymer which could release
a number of progestational steroids for contraceptive purposes.
In the first study (1970) three women nad a vaginal ring releasing
medfoxy progesteron acetate placed in the vagina tor 28 days.
Although ovulation was suppressed the ring design was such that
the drug was [lomogeneously mixed with the pdlymer which resulted
in a pronounced initial release of the drug.
Research undertaken by the WHO special programme of&
2
Research Training in Human Reproduction has aimed at the
development of the low dose progestogen only approach with a
minimum of ovulation inhibition but relying upon local
C'S-f'U'i'CLoJ
pharmacological effects on the orviis.1 ?nucus and endometrium.
Initially the WHO research concentrated upon progesterone itself,
norethtsterone and levenorgest£SJ..
u-d
f
However as a result of
excessive nonstrual disturbances and too many involuntary
pregnancies, progesterone and no|fethfsterone rings were abandoned.
These results led to the selection of a vaginal ring which released
20 mg/day of lev©norgestrd-l.
This multicentre study was undertaken between 1980-86 in 19
centres in 13 countries.
The trial was approved in all centres
by the local institutes xitheE ethics commijnittee and by the
national drug regulatory authority.
Women attending the
institutes family planning services were invited to participate
in the study and were £ully informed as to the nature of the
trial, its potential risKs and benefits.
Each ring weighed approximately 11 g. Manufactured from silastic
medical grade 382p' po lysiloxe r^elas tomen supplied by Dow Corning,
Midland, Michigan, USA.
AG, Berlin (West).
The levfinorges tiz?U. was supplied Schering
Rings were manufactured by Lemejy S-A- Mexico city.
A total of 1005 women were admitted only 2 and 4 subjects were
recruited in Bangkok and Karachi.
In these centres the vaginal
ring was perceived by the subjects as unaceptable prior to
admission to the study as its insertion required genital
manipulation.
3
Reasons - for discontinuation - The 12 month discontinuation rate
for all reasons is 50.3%.
Africa - 68.1%, Asia - 59.9%, China
31.7%, Europe - 45.8%, Latin America - 57.1%.
Contraceptive Efficacy A total or 26 pregnancies with the ring in place and one of
these was ectopic.
Six resulted from unprotected intercourse,
five cases the ring had been removed by the subject and in one
case the pregnancy was associated with unnoticed expulsion.
the combined total pregnancy rate at one year is 4.5%.
So
The
"protected" pregnancy rate of 3.7 is higher than that reported
for the Population Council's comoined levonorgestrel estradiol
releasing ring.
But this levonorgestrel only ring in this study
was designed so as to avoid the concomitant administration of
estrogen to the provia-4, and gaginal netrcoHSe.
This. ring
has a
pregnancy rate which is comparable with the low dose combination
pill and much lower than that found with the levo norges trad. mini
pill in previously published W H 0
Outcome of pregnancies -
randomized multicentre studies.
Of the 26 pregnancies that Occurred
with the ring in place, 19 were terminated by induced abortion,
one ended in spontaneous abortion, one was an ectopic pregnancy
and one patient was lost to follow up.
Reasons for discontinuation - Table III cumulative discontinuation
rates at one year.
4
Reasons for
d i s co ntinua tion
Rate at one year
per 100 women
Number of events
Pregnancy
32
4.5
Menstrual problems
-Rroble-ms
138
17.2
-1=09—
Other medical reasons
109
14.0
Non medica1reasons
77
10.8
Expulsion
57
7.1
Loss to follow-up
99
12.7
The principal reason for discontinuation was "menstrual problems"
and
with this group, intermenstrual bleeding (6.2%) xss and
prolonged mssji mensfis (4.670) were the commonest.
In comparison
the gross rates quoted for the population Council ring were
11.0% and 8.9% which are lower than the rate in the W H 0 trial.
This was to be expected as combination oral contraceptive rates
have much lower discontinuation rates for menstrual irregularities
than progestogen only oral contraceptives.
It is also reasonable
to expect that a vaginal method of contraception will have higher
subjective complaint rates as has been shown in the randomized
comparative study of the population Council vaginal ring and
the oral contraception in which the women using the ring had
complaint rates of 34.ly. and 37.8% compared to 9.6% in the 0 C
users.
Microdose Intravaginal Levonorgestra1 Contraception - A Multicentre
clinical Trial
Expulsion and Removals -WHO .
Expulsions - leading to discontinuation
57 discontinuations of method due to expulsion giving a one year
discontinuation rate of 7.1%.
Majority of discontinuation for
expulsion accurred within the first 3 months of ring use.
There
is considerable heterogenity with a rate of 1.7% for Europe and
22.9% in Asian women.
5
dumber of Expulsions -
In total 771 women did not expel their rings for a total study
years .
time of
The other 278 expelled the ring at least one although details are
not available for 44 women.
Thus 234 women (24.2%) experienced
a total of 504 expulsions of the vaginal ring.
Distribution of the number of expulsions of the vaginal ring.
no.
Of expulsions
No. of women (%)
0
1
771
150
(76.7)
(14.9)
2
40
24
(4.0)
(2.4)
3
women months of use
6186
1259
361
178
4
6
(0.6)
57
5
6
5
4
(0.5)
(0.4)
53
7
4
(0.4)
10
1
(0.1)
33
12
Total
1005
38
_8177
In 417 (83%) expulsion the circumstances of the event were noted.
The majority of the expulsions coincided with defecation (57.3%)
with for fewer at urination (11.5%) at mens tarnation (16.8)
during strenflous activity (5.3) and intercourse (1.9).
it can
be seen that there are large regional, differences, women k in
Asia and China have almost twice the first expulsion rates of the
other regions.
Therefore the particular reason for first expulsion
varies from region to region.
Removal of the ring by the. women herself was reported by 121 women
on a total of 201 occasions of which 190 had clinical details
6
provided.
The removals took place in 12 centres (there were non
in 7 centres
and 4 centres contributed 100 of the subjects
reporting one or more removals and 83% of the episodes of removal
The commonest "medical" reasons given
for removal were pain or
bleeding (26 subjects) or vaginal discharge or ur-rtaxtc'n (26
subjects; less than 1% of the subjects removed the ring because
of coital discomfort (dyspereUnia).
The vast majority (63/69)
of the removal took place for unrelated reasons occurred in
subjects in 4 centres.
There were no removals by the Asian women
low rates in Africa and China dnd high in Europe.
In Latin
America there appeared to be a large variation from centre to
centre.
It should be noted that the four centres in China, two of the
three centres in India (Chandigarh/New Delhi) and the Brazilian
centre contributed 52.2/0 of the subjects recruited and 55.1% of
the women months experience with the device but 71.5% of the
©omen who had an expulsion for which details are available.
>
I
\
t
to H 3 • 3^-
1
'■Microdos'e Intravagina 1 Levonorgestral Contraception:A Multi Centric linica 1 trial -
Bleeding patterns - comparison
with other reasons for discontinuation.
Cumulative discontinuation rates &c one year reasons—fer-dHsax
d iseontirraa ti o n
NO of
events
Rate at one
year per 100 women
<2
4.5
138
17.2
'-'ther medical reasons
109
14.0
Non Medical Reasons
77
10.8
57
7.1
99
12.7____
Loss to follow up
=lii==
Study on Bleeding Patterns:-
Out of the t3)tal of 1005 women who entered the study from 19 centres
702 were provided with a menstrual diary with a daily record of
occur^ance of bleeding ^spotting or neither.
the
The clinically unacceptable
patterns are no bleeding throughout the reference period prolonged bleeding;
at least one bleeding/spolting episode pasting more than 14 days;
frequent bleeding; more than 5 bleeding/spolting episodes;
infrequent bleeding; 1 or 2 bleeding/spotting episodes;
irregular pleeding; 3 to 5 bleeding/spo£ting episodes and less than
3 bleeding/spo£ting free intervals of 14 days or more;
combination of the above categories
2
Clinically acceptable pattern.
None of the above, that is a pattern with 3 to 5 bleeding/spo£'ting
episodes,none longer than 14 days and at least 3 bleeding/spotting
free intervals of 14 days or more.
Reference
\jo. of Diaries
II
I
Period
IV
XII
days 1-90
days 91-280
181 - 270
271 - 360
702
586
510
449
Number of women (percentage) experiencing different types of
bleeding patterns in each reference period.
Refere nee
Period
I
daysl-90
II
days90-180
irregular
157
(22.4)
164
(28.0)
145
(28.4)
116
(25.8)
Infrequent
54
(7.7)
52
<8.9)
52
(10.2)
33
(7.3)
Frequent
80
(11.4)
(9.0)
3
26 22
(5.5)
35
(7.8)
(0.7)
1
(0.2)
3
(0.6)
4
(0.9)
Prolonged & irregular
35
(5.0)
21
(3.6)
11
(2.2)
9
(2.0)
Prolonged & infrequent
5
(0.7)
4
3(0.7)
0
(0.0)
4
(0.9)
Prolonged & frequent
5
(0.7)
1
(0.2)
2
(0.4)
2
(0.4)
No oleeding
6
(0.9)
7
(1.2)
4
(0.3)
7
(1.6)
Unacceptable patterns
347
(49.4)
303
(51.7)
245
(48.0)
210
(46.8)
Acceptable patterns
355
(50.6)
283
(43.3)
265
(52.0)
239
(53.2)
■Bleeding patterns
Prolonged
IV
III
days 181-270 days271-360
3
This table shows the percentage experiencing clinically important
bleeding pattern irregularities as reflected by their menstrual
diaries in each successive reference period.
Approximately half the
women expeeience '‘unacceptable" patterns in each reference period,
the commonest problem being "irregular bleeding in one quarter of
all women.
It should also be remembered that women with more
disruptive patterns discontinue h use early and are therefore under
represented in the later reference periods.
The following table shows the no. of women experiencing clinically
important bleeding patterns in their discontinuation reference
period by reason tor discontinuation.
It is clear that even among
the 443 women who completed the study 230 (51.9S) of these experienced
"unacceptable" patterns, hair of these being irregular bleeding.
The table also shows that of the 9 women who became pregnant, 5 experi
enced an irregular bleeding pattern during the time preceding conception.
Of the 72 women discontinuing method use for"desires pregnancy" all
but four have "unacceptable" patterns but in the case of 75 who had v
vaginal problems, 41 were in the "acceptable" pattern.
4
Number of women experiencing different types of bleeding patterns in the discontinuation (1st) reference
period.
1
2
4
5
6
8
3
7
10
9
prolonged Frequent Infrequent Irregular Prolonged Prolonged prolonged Acce Total
NO
Discontinuetion
bleeding & infrequ &irregu- & fregu- ptab
bleeding bleeding bleeding bleeding
reasons
ent blee lar bleed- ent
le
ding
ing
bleeding patt
ern
6
3
57
32
117
4
10
1
213
Pregnancy
-
-
-
-
5
-
-
-
4
9
Bleeding problems
1
-
2
8
-
-
-
6
18
End of study
1
443
Amenorrhhea
-
-
4
1
2
1
-
-
7
15
Pain
1
-
4
1
5
-
1
-
9
21
Vaginal problem
-
-
11
6
17
-
-
-
41
75
Other medical
-
-
1
-
1
...
-
2
4
Desires pregnancy
-
36 ,
1
7
4
6
4
72
Other non medical
2
One expluIsion
14
-
1
4
3
1
1
-
5
17
-
2
1
2
-
-
-
8
13
Los4^ of followup
-
-
2
1
2
-
-
10
15
All reasons
10
3
120
48
169
10
26
7
309
702
%
1 .4
0.4
17.1
6.8
24.1
1.4
3.7
0.1
44.0
5
Apart from bleeding abortions which are being taken seriously and
treated as the prmary reason for the large discontinuation rates,
m
Other factors like other medical reasons (which I shall detail now)
non medical factors, loss to followup etc. are seen as deterrents
If we
which can be overcome by better consulti-ng motivation etc.
compare the discontinuation rate wex will find that uncertain
factors like loss to followup account from 12.7 percent per 100
women and in one instance where the menstrual diary of 15 such
subjects were analysed 10 of these loss to followup subjects had
‘‘acceptable" patterns of bleeding and only 5 were in the "unacceptable"
pattern.
In the category of other medical reasons vaginal related reasons were
pronounced.
Cumulative discontinuation rates for vaginal related reasons.
Discontinuation reason
3
Discharge
Irritation
Infection
months
6
9
12
rate
1.0
2.0
3.0
3.5
N
9
16
22
25
R
0.9
1.0
1.2
1.2
N
8
9
10
10
R
0.3
3
0.7
1.2
1.4
6
9
10
N
Similarly other factors like pain, dyspare4(nia, odour,
nausea,
dizziness, palpitations and ornsvcrl pain all played a role in case
where there was removal of xi rings.
6
Cumulative discontinuation rates for non medical reasons and loss
to followup.
Discontinuation reason
Months
3
6
9
12
R
1.3
11
2.0
16
2.2
N
1.7
14
R
0.4
3
1.1
6
2.7
N
18
3.8
24
R
Other non medical reasons
N
(This could range from
curiosity, to clean to
s how hus ba nd, va gi na 1
douche, unknown by mistake)
1.4
2.3
3.6
5.2
12
19
27
36
R
N
4.5
40
7.5
64
10.2
12.7
33
99
pa-tie-Frts request
Wish to become pregnant
„Loss to followup
-i!
17
So,jt it is obvious that a combination of factors have led to the high
discontinuation rate of 50%.
But according to this report on the
trial - this specific clinical trial showed a low rate of reporting
for trivial vaginal irritation and discharge.
Therefore from a
clinical point of view these minor side effects appear to be of
little relevance.
Adverse Reaction
Two discontinuations occurred due to adverse reactions caused by
the use of xp progesterone releasing ring.
In the first case the
subject became hypersensitive after six months of ring use and
following removal the blood pressure returned to normal.
In the
second, the subject discontinued at day 56 complaining generalised
itching and breast tenderness.
IaJ H 3-35"
Hormonal Contraception - New long acting methods - Injectables &
Implants K No.3 March - April 1937. —^/^Gp/kfx
*
The synthetic hormones used in both injectables were developed in
The progestin Medroxy progesterone acetate (MPA) the
the 1950's.
hormone in DMPA is derived from the natural hormone progesterone.
□MPA is prepared in a microcrystalline suspension.
dose of JMPA is 150 mg every 3 months6 month
to 450 mg DMPA are less widely used.
from testosterone.
/
Thus the
hormone is not aosorbed immediately after an injection.
The s-usa-k
regimens of 250
Tne progestin Net-EN is derived
Net-EN is prepared in an oily solution.
There are few known contraindications to the progestin only
injectables.
WHO recommends that women should not use injectables
if they are pregnant, have cancer of the breast or genital t-,ct
or have abnormal uterine bleeding.
WHO advises that women with
q//’CL
history of diabetes or during pregnancy should be followed carefully
since some laboratory tests have shown that DMPA alters carbohydrate
metabolism
'WHO - injectable hormonal contraceptives - technical & safety
aspects, Geneva, WHO, 1982 - WHO publication No.65 - P.45)
On menstrual changes - (Population Report states)
Amenorrhea most common and occurs more often with the DM?A.
In
the 1st year 55% of DMPA users do not menstruate for 90 days or
more compared with about 30% of Net-EN users.
very heavy or prolonged bleeding, a potential health threat is
uncommon.
In a WHO multicenter trial only 1200 women needed
treatment for heavy bleeding - in almost 14,000 women months of
2
Similarly in a 12 month field trial in paxistan only one of 2,147
women required
tor prolonged bleeding.
Generally amenorrhea and light bleeding/spotting do not require any
1 medical treatment.
that the
Most family planning.
:ind
i ajlj^ay women’s concern by counselling them before
an injection and reassuring them if menstrual changes occur. Oral
contraceptives or supplemental estrogens to regularize menstrual
bleeding are not
I
routinely.
For neavy oleedinq WHO recommends either
(1) one combined oral contraceptives daily tor 14 days or <2) an
inter muscular injection of a syneh<ttic estrogen - 5 mg estradiol
cypionate or estradiol valerate.
£
But most women stop using injectables because of menstrual
disturbances than for any othei reasons. In recent trials <j/.to 30%
of women discontinued the method in the first year because of
S5
changes in the bleeding pattern.
perhaps because of different cultural and religious attitudes towards
menstrual disturbances or because of the varying availability of
counselling and follow up.
On Reproductive Effect: -
In Thailand because of fears that
might cause permanent
infertility the national family planning programme do not allow
women to use JnPA unless they have at least one child.
Experience with injectable contraceptives in Thailand - British
journal of Family Planning - 6 -14 January 1987.)
3
months after the end of the presumed duration of effectiveness.
Despite this initial delay over 60/» of former dmpa users because
pregnant within 12 months and over 90;t> within 24 months.
With NET-EN return pf fertility can also ba delayed.
I
I
In a recent
study of 69 women who stopped using NET-EN to become pregnant and
who, were followed tor a year average time to conception was longer
than among 92 former T Cu-200 IUD users.
former ^El'-EN users had conceived.
After one year - 7 37<» of
(ICMR - TasK Force on Hormonal
contraception - Return of fertility following discontinuation of
an injectable contraceptive - More thisteron denanthate (nET^EN)
200 mg dose - contraception 34(6) 573-532 - December 1986)
On harmful effects on children exposed to injected progestin
contraceptives either in utero or during Dreast feeding.
Several
studies in the 1970's reported no increase, in birth defect or
prematurity when pregnant women were inadvertently given
contraceptive doses of injectable progestins (One of these studies
was conducted by Upjohn Company - Depo prove/a for contraception;
Information for Eublic3oard of Inquiry on Depo Prove^a; responses
to the Board’s questions - submitted to the US, FDA, Public Board
of Inquiry - Upjohn Company 25 June 1982 - P 155)
But in a recent study of Thai children by Tieng Paadthaisong and
colleagues, however children of former users of DMPA were two times
more likely to have peripheral limb detects and about five times
more likeLv to have chromosomal abnormalities than children of
>men who used no contraception.
• 4
r
'eontraceptive use and pregnancy outcome in Chiang Mai, northern
Thailand, 1986 Jun published)^ Yet another study is being conducted
in Israel - preliminary analysis from a study in Israel involving
nearly 200 adolascents who were exposed in utero to (MPA) and
over 950 controls found no evidence of retarded or precocious
development or any disturbance in sexual development, sexual behaviour
or growth among those exposed.
But these studies on Thailand and
Israel supported by WHO and Eamily Health International are continuing
to look at children exposed in xei. utero to DMPA, MPA or oral
contraceptives.
(WHO special programme on R, D & T in HR - Thirteenth
Annual Report, 1934, Geneva, December 1984 (152 p)~J
The very small amount of hormone transmitted in breast milk appears
to have no effects on children even when followed upto 10 years.
Unlike oral contraceptives that contain estrogen.
DMPA and MET-EN
appears to have little effect on the cardio vascular system.
There
been very few reports of bl(®od clots or other cardiovascular
complications in women using injectables.
But adequate epidemiological
studies have not yet been conducted.
Effects on
lipid metabolism are less clear since long term studies
are not finished.
A few' studies report an increase with cholestrol
with longer use of |MPA (Liebd JFM ng, CSA, Yong, Y M & Ratnam SS,
/ong term effects of Depo-provera on Carbohydrate and lipid metabolism —
£>n trace ption 31(1) - 51-64 January 1985)~j
4.S
/k -Al?/-
tete-dccroese Irr~trggh do an i ty—Hi rwi' '-pteins (HD^^ both possibly adverse
effects (Kandeel K M Jj Mayel, SA and Abeza MS^
The effect of
injectable contraceptives on lipid metabolism in women.
Biochinjica Act a - 43(1) III-115, 1984 Kremer j , De Bru^
n,
*
Biomedica
HUA end
Hindriks Ft, Serum high density lips proteins cholestrol levels in
women using a contraceptive injection of depot's- Med foxy progesterone
Acetate - Contraception 22(4) 359-367 - October 1980J rhe only
study involving ;ET-EN also found a decrease in hdZ- (FojfiherEebyV
K- Tretyner’ I, Howard G, Hcnwui A and Elder MG - Effect of injectable
Norethersterone Oenanthate (Norigest) on blood lipid levels Contraception 25 (4) 435-46 - April 1982
*)|
Because NET-EN is a
chemical similar to testosterone i t is likely that it would reduce
HOL Levels slightly,
Whether the small decreases in HOL sometimes
seen in women using injectables have any clinical importance is
not certain.
WHO trials are underway in five countries to measure
lipid metabolism in women using DMPA and jJEi-E/j for short and long
periods ! (WHO special programme of R, J & T in HR, fourteenth
Annual Report, 1985, Geneva WHO, December 1985 - 218 P)
CANCER - Major contraversy about long-acting injectables are
whether they cause cancer?
Main reason why DmFA has not been
approved for contraceptive use in the uS.
Two species of laboratory
animals - beagle dogs & rhesus monkeys given large doses of DMP'A
or ’-iET-a.M for long periods have developed benign and malignant
tumours of the breast or endometrium
(lining of the uterus
(UP John Report and WHO facts about injectable contraceptives 1982)
But until recently human studies limited.
WHO conducted a case-control study involving over 1,500 cases and
over 5,800 controls in Kenya, Mexico & Thailand.
The US centers
for Disease Control and other organizations conducted a smaller
study in <eos ta Rica involving over 700 women with breast cancer,
invasive, cervical cancer or cervical carcimonia in situ and over
760 controls.
Like other epidemiological and clinical research
in the. US, Canada and Thailand^the WHO case control study found
no link between DMPA use and cancer of the breast, endometrium,
ovary or liver (Memorandum from WHO 1986).
6
3ut che Costa Rican study found a two fold greater risk jf breast
cancer among former DMPA users than among non-users a statistica 1 ly
significant decrease.
But researches regard these results as
inconclusive however as the number of cases is small.
women with breast cancer had ever used DMPA.
Only 13
Furthermore there
is no indication that the risk increased with the duration of use.
(Lee N C, Rosero L, Oberle M W, Grimaldo C, Whaterly A, Rovira E
DMPA use in costa Rica and the risk of breast cancer (abstract)
presented at the 114th annual meeting of the American Public
Health Association, Las Vegas, Nevada, September 23roctober 2, 1936.
In the WHO study the risk of invasive cervical cancer appeared to
be slightly higher for former DMPA users than for controls.
The
study found that women younger than 36 who had used Di-ii-A for more
than four years were two times more likely to develop cervical cancer
than controls younger than 36.
But interpreting this finding is
difficult because the number of cases is^ But the Costa Rican study
found no increased risK
invasive cervical cancer or cervical
carcinomia is situa-te' among former DMPA users of any age or with
any duration of use (Oberle M
Irwin K, FortneyJ
Rosero L.
Cervicaf cancer and hormonal contraceptive use in Costa Rica (Abstract)
presented at the 114th Annual Meeting of the American public Health
Association has Vegas Neveda, September, 28 - October 2, 1936.
Tests ’Underway on New Long Acting Ester Injectables
A 12 year collaboration between the WHO and the (US NICHD) and
scientists fheough®Jthe world has led to several new injectable
compounds that may prevent pgegnancy for two or three months.
In 1975 WHO convened a group of chemists and biologists to be gi n
ie development of a new contraceptive steroi
ds.
Research focussed
7
on two progestins.
Norethindrone and Levonorgestra1 and scientists
synthesized over 230 esters derived from Net or Levonorgestra1 (an
ester is a combination of steroid and an acid)
these compounds in animals.
US NICHD then tested
Four compounds ail derived from
Levonorgestra 1 were selected for further testing because they
consistently inhibited ovulation in animals and appeared to be
long acting.
Trials with one compound designated HRP002 suggest that a 20 mg
dose will prevent ovulation for three months.
Preliminary
effectiveness trial planned to begin in 1987.
Second compound
HRjpOll chemically similar to another progestin, norgestimate that
does not cause marked endometrial or menstrual changes in animals.
WHO plans to begin small effectiveness trials of HRpOll in women
which will determine whether it will have less effect on bleeding
patterns than dhpa and NET
*EN.
Initial studies of HRP011 in a
small number of women in the US are oeing planned for late 1987.
Advantages - The chemical properties of esters the new injectables
are released from the injection site at a fairly constant rate
.without the initial high release that occurs with DMPA & NET-EN•
These injectables can be administered in a simple aqueous micro
crystalline suspension like that used tor DMPA.
manufactured easily and inexpensively.
They can be
Like DMPA and NET-EN
administered with a simple injection which any health worker can
administer without special training.
RU a86 ?
A steri&d derivative synthesized by Roussel Company is being
increasingly used in France to regulate human fertility and
it acts by competing with progesterone at the receptor level.
The contragestational or early abortifacient activity during
early and mid pregnancy could involve interference with the
decidualized endometrium.
RU Zj.86 has now been shown to
influence the placenta as assessed by its effect on cell •
The addition of RU 486 decreased
cultures from human placenta.
the production of ECG, hCL and progesterone by these cells
under culture.
There are three anti-progestins RU 486 (Wife prestone) ZK
98.736 (lilo pristone) and ZK 98.299 which have been studied
in some detail but only RU 486 has been tested clinically
on a wide s cale.
The first clinical trial of RU 486 was
daily for four days to a group of women in early
All but J of the 36 women with intra uterine
(pregnancy started to bleed during RU 486 administration.
In
subsequent investigations a variety of treatment regimens were
Jso
,LAlJ
I
g K
/employee to improve efficacy ... It was airsi found that by,/
. 1 (? w
i
aU5iinistering synthetic pros taglandilxfes7 raised to 95$.
Simil;
results were got by a vaginal administration of another prostag
landin gemeprost i.e. immediately after treatment with RU 486.
3n defence of RU 486 in the third world.
Specifically India.
Dr. Banco Coyagi, Director of K.E.M. Hos >ital, Pune.
2
2
Defends RU 486 on the plea that there is a basic acceptability
of such methods in rural India. Quotes a particular incident
to support it. "
a women's .meeting was in progress
in pimpale Jagdat a small village of the Vadu Rural Health
project of the K.E.M. Hospital} Pune, Maharashtra.
Into that
small room walked Professor Sune Bergstrom the Nobel Laureate
and father of Prostaglandins accompanied by the project staff
the Professor hesitatingly assed them if tiey had
delayed periods would they use pills to bring on menstruation ?
At once they put out their hands for the pills. Although he
advised them to go home, talk to their husbands and then make
their decision, the community health wfirker stood up and
said that it was not necessary
"There are three women
in their room who have missed their periods they want the pills".
This spontaneous response to a male foreigner by illiterate '
village women revealed more succintly to him than any research
project the need and acceptability sbf such a pill in India ....."
Three-quarters of Third World Women live in countries where
abortion is Legal at least on health grounds.
Take the example
of India where abortion has been permitted since 1972 for a
VsY-oe-0!
Eeard range of health reasons including contraceptive failure.
Yet in 1982 compared to an estimated 3,76,000 of legal abortion
were four to six million abortions performed outside ..approved.,.
facilities.
Accordingly to Dr. Banco Coyagi what is payiodoxical
that while million of women die of abortion services-with increase
in the 1990
*
s given at 25 5 increas in the number of women aged
15 - 24 - a safe and well researched drug like RU - 486 has
cause a rumpus between drug manufacturers, politicians,
bureacrafts and women's groups.
2U - 1^86 or Mifepristone it is argued is extremely effective in
j lx J IA.C. j 6 A
i-n—dnsing- early abortions .•■hen associated with prostaglandins-
apart from being safer and more effective.
- It can be used in relative privacy
- is more acceptable culturally
- can be used on an outpatient basis by trained para medics
only backed up by medical personnel and no need facilities like A
theatres and anaesthetics which are in such short supply.
..ost of the research on liftfe x ristrone and allied drugs has
been done so far in the first woild byjg/HO's special programme
Human Reproduction and Researchers in France, Sweden, Hungary
and ^ritain.
Some trials have been carried out in China and
are now starting in my hospital,
there are many questions that
needs answers, the minimal optimal do£@_, the interval between
RU 486 and prostaglandins the safety and efficacy in anaemic.
women, the acceptability^ the logistics and so on.
Other questions that third World Government will need to Un
answered are public sector costs.
Supply on' the large scale
required and the transfer of technology.
RU 486 v.- India.
uoae facts about
Around end of October ICMR will begin conducting
rtU 436 will in reality induce a "chemical miscarriage" by
discouraging the fertilized egg from fastening on to the wall
of the womb.
In 80 out of the 100 women tested in Mance the
embryo was expelled through what was the equa'valent of heavy
^ut if its efficacy needs to oe increased
menstrual bleeding,
to be 96 70 it needs to be combined with a cose of prostaglandins
in injectable or pgssary for^’/ith the help of prostaglandins
the incidence of heavy bleeding occurring with mifepristone
is reduced.
In fact the com any - Roussel
is very
sceptical about the use of RU - 486 in the Third World.
Roussels's
Head of clinical Research Sr. Andre (llmann who was closely
associated with the drug's development stated bluntly that there
was no possibility of using RU - 486 as it is used in France
in a developing country setting.
The synthetic prostaglandins.
necessary (whether injections or pessaries) require a freezer
chain (-2OoC) although iroom temparature prostaglandins are currently
under development.
If I were Minister of Health in a developing
country, I would prefer to spend my money on training nurses
■in vacuum aspiration
So in India to circumvent this difficulty a vaginal route
suppository will be used. The attempt is to evolve a single
day administration of the pill, together with a delayed acting
prostaglandins.
Moreover in India during the trials the women
will be administered only .a third of the dose that is, normally
prescribed abroad that is 2J0 Mg as ICMR studies adrso- aware
that this Igind of ab.rtion is not a simple "do it yourself
V\
it will require close medical supervision especially
method,
as it can only be used only till the seventh week of pregnancy
thus making it imperative to pin point the exact date of
concept! n.
In France the /omen must sig
an aspiration in case of nethod failure.
has to be monitored carefully.
causes severe bleeding.
a form agreeing to
So, obviously this
'.'/hat about cases where RU 486
One French women said after using the
method "A. long orocass which requires time and supportive clinic
/, (L.Utv coaLZa- -/ t
----- —" ..
acq-a
Zch is exh^usttn3y^
^e
*
I have also had)
>vacuum as•;ir''.tiu7r-g“-.'.ich—■
" Given the average Indian, women1 s
anaemic condition the side effects of heavy bleeding can be.
dan serous.
Dr. Saxena assures that the "clinical trials will
look into the problem, of effects on Indian women (as opposed
t
French women) based on pnarmogenetic differences’.'.
Institute for Research in Reproduction (ICMR) Bombay, India
and Schering AG, West Berlin.
Effects of progesterone Antagonist ZK 98299 on Early pregnancy
and Foetal outcome in Bonnet Monkeys.
I
,
ZK 98.299 (Onapristone) is a progesterone and gluco cort6cod tP
ii'Cfi1'
antagonist like RU 485 its preferential target calls are those
of the endometritt/o_ and deci o/u^_
The study demonstrates that ZK 98.299 at the dose regimen used
terminates early pregnancy in 62% of animals.
Since in the
three cases in which treatment tailed ZK 98.299 induced a decease
in progesterone levels and in two of the animals transient
episodes of vaginal bleeding it is possible that an increase in
the dose or trequency of administration might improve the
abortifacient efficacy.
But what is important to note that in the failure the pregnancy
did not ccfatinuefi unaffected.
The decease in the circulating
progesterone levels after treatment, the presence of haematoma
and blood clots in the placental tissue and the retarded foetal
growth suggest that the treatment disrupted at least partially
the conceptus.
However the induced uterine activity was not
sufficient enougn to expel it.
Therefore given the (fact that
it the treatment fails and the pregnancy continues the foetus
is exposed to tne risk of malformation.
RU 486 has been tested clinically for termination of early
pregnancy on a wide scale and its abortifjacient efficacy is between
60 to 80% depending upon the
and frequency of administration.
f- amenorrhoea and dose
But its clinical efficacy is
Lower than prostaglandins.
Moreover there is no information on
the xh foeto-toxicity and foetal outcome in RU 486 treated failures.
Therefore e it is essential that in such cases pregnancy is teEMinarec
terminated oy alternate methods as these drugs at present have
teratogenic effect.
Moreover it is not clear why ZK 98.299
treatment to monkeys and RU 486 to women does not induce abortions
in all cases.
Since ZK 98.299 induced vaginal bleeding in most of the animals
and similarly in RU 486 treated cases most of the women start to
bleed during the treatment period it appears that the insufficient
release of prostglandi&s might be the plausible cause of failure
to expel the conceptus.
AC/AA
A
(&</•<
QL
RU ,486 - The French Experience.
RU 486 is now fully licensed in France where it ordered and used
by hospitals and licensed abortion clinic.
Mifeflyne.
Bears the trade name
Its use is so tightly controlled that each box is
numbered and must be accounted fon. Mifepristone.— ihe geneic name
for the drug is an antiprogestin which renders progesterone^
h^>ne
-star-
rr^~
hormone secreted during the second part of a women's menstrual
cycle inert has three main effects when given in the early part
of pregnancy.
It causes the lining of the uterus to break down as it does
during a menstrual period and the implanted egg is lost with the
•
cervix.
It causes the uterus to contract.
It dittos the
If the appropriated dose is taken up to 41 days of ameno-
rrhoea (since the beginning of the last period) and if the dose is
followed 43 hours later by a prostaglandia in injectable or
form the efficiency increases.
But what is interesting and significant is the complicated French
procedure for conducting an RU 486 abortion in France.
ISS/
After aurs-i-ng' her period the women must visit her doctor and ask
for BHCG blood test and an official request for an abortion.
This visit must effectively take piece within 2 weeks of the
nurses period because under French Law there is a "coiling off"
period of five days between requesting an abortion and having
the abortion .
Mifepristone can only be taken up to the 49th day
of amenorrhoea .
An appointment must then be made at a suitable
hospital or clinic.
The women must take the results of her
bliod test and the doctor's letter to the clinic undergoing an
ultrasound examination to check the gestation of the foetus and
to the ensure that the pregnancy is not ectopic be questioned
for possible counter indications (eg. Asthama, cardio vascular
£ /V)6 A9-
problem, allergies and women over 35 who s-poke) sign a form
agreeing to an aspiration in &se of method failure and finally
swallow three 200 mg mifepristone pills.
two
days IS ter return the
cl-inic to receive an injection of prostaglandin and stfiy there
for three or four hour until pains and contraction have ceased.
Ten to fifteen days later must return for a compulsory check up
with either a ultrasound examination or BHCG blood test to ensure
that the abortion has been completed.
Despite some obvious advantages in tnat no hospital oeds,
anaesthesia or surgery not all gynecologists and hospitals are
using it widely because it is rather complicated for hospital
administrators to manage.
The gynecologists may have less of
a role but nurses and other paramedical staff must be involved
and well trained.
Krom the nea1th point of view infections have
not entirely disappeared fragments can be retained and cause
infection but traumatic complications of surgery perforations of
the uterus and scarring have vanished.
Roussel Uclaf. not beer1- on launching the drug in the united States.
Possibility of confrontation1 with antiabortionists problems of
liability and distribution
pxs peculiar to the U.S.
Next country
to apply for product licence is likely to be the u K where
extensive trials have taken place followed by Scandinavian countries
and Belgium.
GoH 3-33-
The two major questions regarding the safety and efficacy of
the vaccine are; (1) Could an anti-hCG vaccine break material' ,
tolerance to the hortnoue and elicit an immune response of
sufficient magnitude to neutralize the hormorje in the ma tcrialcirculation at the peri-implantation stage of "gestation".
cu/d
.
2) Could an anti-hCG response so produced be restricted to
*
th
the intended target so that cross sections with other normal
body constituents particularly endogan^ous pi tu atopy normo^e
would not 'gccur and endocrine and metabolic disturbances
and the potential risk of immunopathology avoided.
Phase I clinical evaluation of the 1st generation^nti-hCG vaccine.
A
1st generation anti-hCG is a synthetic peptide representing the
B-hCG carboxy terminal -> 160-145 peptide (B-rhCG CTP) coupled
to the diphtheria toxo rq carrier (DT) molecu/e mixed with a
dipeptide (MDP) adju<64Lnt and suspended in a
squalene arlacel - saline emulsion vehicle.
Objective of Phase I clinical trial to determine what, if any,
side effects were produced by this vaccine. Also to measure
and compare the levels of anti-hCG antibodies elicited by the
vaccine.
30 previously sterilized women volunteers were recruited. Six
of the 30 women volunteers were assigned to each of the five doae
groups. The highest of which, group being the dose expected to
elicit a level of immunity. Sufficient to confer anti-fertility
efficacy of the six women in each dose group four received the
complete vaccine and two received a *‘place£#' preparation consisting
of the MDP adjuvant and emulsion vehicle only. Immunization was
effected by two injections into the gluteal muscles at an
interval of six weeks and the subjects were followed up on an i
in-patient and out-patient basis for a total of six
*
months.
A
Majority of vaccine recipients in all dose groups produced
anti-bodies to i)CG as well as to the DT carrier compensate of
the vaccine The only side effects considered significant by
the resident physicians were transient muscle and ptrt pains
reported by a tew subjects.,.■
'
/-
So far as the Phase I clinical trial is concerned the primary
objective has been successfully acnieved in that the desired
type of immunity has been elicitein most of the vaccine recipients
without the production of unacceptaole side effects.
Given this success it was proposed that the next stage was a
limited study with the B-hCG CTP vaccine formulation in a small
number of fertile women volunteers to determine if anti-hCG
antibody levels in excess of 05
of hCG binding capacity
will provide an anti fertility effect. But before seeking
approval to conduct this study in women animal experiments will
have to oe conducted to determine if any fecal abnormalities are
associated with the vaccine's use.
2
Protocols for animal experiments and for the clinical study
have been conducted in consultation with TasK Force scientists
and clinicians and with representatives of the pharmaceutical
industry and national drug regulatory authorities.
Valuable additional information has been obtained in the Phase I
clinical trial relevant to the development of asafe, effective
ar;d acceptable anti-hCG vaccine suitable for wide scale
application particularly in the developing countries.
Defects in this system:
In the current formulation the long
peptide is more expensive and difficult to manufacture and
characterize ,so future vaccine production would be greatly
■^cilitated if one or more
snort peptides of B-hCG could be
identified.
Out of total of approximately 80 injections with the B-Acg CTP
vaccine that were made during the course of the trial, adverse
reactions to the DT component were seen in two instances,
whilst
this may appear to be a very low incidence it would probably be
regarded as an unacceptably high level when large scale (use of
the vaccine is considered.
To limit the MDP dose and improve on the vaccine delivery systems
are necessary.
The complex^ and viscous emulsion used as a vehicle for the current.
vaccine is obviously not suitable for use beyond the preliminary
stages of clinical testing.
3
Future Directions
The Task Force is proposing to carry out the following activities
during the 1988/89 biennium.
Subject to a satisfactory outcome of animal teratology studies
approval will be sought to carry out a limited efficacy evaluation
of the current anti-hCG vaccine formulation in fertile woman
volunteers.
Also aim to develop an improved version of this
vaccine using a slow release delivery system designed to elicit
long lasting immunity from single course of immunisation as well
as the development of a second generation of anti-hCG vaccine that
will represent a viable product prototype.
Anti-sperm vaccines and to evaluate prototype anti-trophoblast
vaccine are other areas of study of the Task Force.
A Meeting on vaccine safety in order to develop guidelines for
preclinical & clinical safety evaluation of vaccines in general
and for anti-fertility vaccines in particular will be convened
by the Task Force.
The Task Force steering Committee meetings include representatives
of CONRAD, the Population Council, The Indian National Institute
of intnunology and the US National institute of Child Health &
Human Development.
(/CH 3>-3S
International experience with Norplant & Norplant - 2 Contraceptives.
Iruing Sivin
Studies in Family planning - vol. 19 - No.2 - 81 - 94 (1988)
Menstrual problems & pattern change with time.
Alterations in periodicity of the menstrual cycle, changes in the
duration volume of menstrual flow and spotting are the most
pervasive side effects of implant contraception,
in initial and
subsequent studies few women have terminated implant use because
of amenorrhoea or oligomenorrhea but termination of use attributed
to menorrhagia or metrorrhagia (i.e. Mtea
v
bleeding) have been more
frequent.
There have instances in which vaginal bleeding has been extremely
severe.
©ne woman among 3,700 implant acceptors monitored by the
population Council recorded uneventual use of Norplant - 2 rods for
several months and then suddenly experienced very heavy vaginal
bleeding accompanied by a precipitous drop in her haemoglobin levels.
The rods were removed, she was trans fered and had an uneventjaal
recovery.
Two steep falls in haemoglobin levels have been reported
among the first 12,000 implant users in China.
IPiedical Problems unrelated to Mens trnation.
On the basis of the data for the "three country" study which involves
Chile, Dominican Republic & Finland and single country trials from
the Dominican Republic, United States & China it was felt that with
the exception of China all the countries registered between half
(51.0%) and 2/3rds (64.9%) of all terminations were attributed to
symptomatic complaints rather than to well defined diseases.
In
contrast in the People's Republic of China, subjective complaints
accounted
for between one fifth (21.1%)
Norplant - 2 to one-third
(33.1%) Norplant)
all medical terminations.
Hegdache one of the pronounced reason or symptom that led to
removal.
in the U.S. between 19 (Norplant) end 25 (Norplant - 2)
per cent of medically related terminations were attributed to
headache.
in the three country study about 21% opted out due to
headache.
In China also although headache was the most frequent
cause of termination among Norplant capsule users it accounted
for only lift,,Complaints about weight changes both increases and
Americans terminated largely due to w
ro^ti'o
weight gain (19.3) the Dominican women by a nature ot 14 to 4 were
decreases were also common.
more disturbed by weight loss,
Mood changes, anxiety, nervousness
and depression were also associated with the use of the method.
The remaining symptoms and complaints that led co termination are
diverse in nature; among the most frequent nave been ver tig o,
nausea, nus cu los ke le te 1 pain and abdominal pain.
But unlike American where circulatory and cardiovascular problems
leading to termination were infrequent i.e. the American figures
were 1.3 and 5.4% of all medical terminations for Norplant and
Norplant - 2 respectively.
<China these factors played a major role,
in China cardiovascular
and circulatory problems represented 11.2% medically related
terminations of Norplant use and 28.9 per cent of these terminations
from Norplant - 2 use.
Mild hypertension and heart rate problem
were the most common of these conditions.
A few cases were
diagnosed as myocarditis.
Similarly in the three country study mild hypertension was the
single diagnosis reported in this category of medical terminations.
Although anaemia was not common it did happen to one woman in
3
California and two Chinese women.
But Chinese physicians also
reported a number of cases of low platelet counts during implant
use including one of
and one of chronic thrombo cytopenia.
Endocrine problemsreported in the Dominican Republic and in China
for Norplant capsules were primarily thyroid proolems.
in China in
addition to hyperthyroidism en case of pituitary tumour was reported.
Skin problems resulting in removals were rashes, dermatitis and
, •
0ne case of breast cancer discovered in the first year of
use led to removal of rod implants in U.S.
The other breast related
removal was mastalgia (pain in the breast) which occurred in two
women.
Terminations because of pelvic related conditions focus on a few
Li
omo~problems^functional ovarian cysts, uterine fibroids or myeaia and
lower abdominal pain. / Another complication observed in the three
country study^two Norplant capsule acceptors had epileptic
seizures as some drugs used in the treatment of epilepsy counteract
the contraceptive effect of levonorgestrel.
It was concluded that all this data from various implant studies
"represents prima-facie evidence that Norplant implant do not
present major health concern to users.
Given the efficacy of the
implants in preventing pregnancy the ensuring health benefits are
likely to outweigh by far the risks of Norplant Contraception".
Q
OA/
G6A/7X/?ct-/y m
fifj C>FF-ic^<~
-
-
T-P'-s sbuiss
TECHNOLOGY PAST - PBBSBNT & ?VTVRS - STATUS
—
M
I
S//?/^^
R.S&A)
H-F-w
u
.
*NTHE
- Dr, R,P. Das Associate Proiessor, Department
of Reproductive Bio medicine, National Institute of Health
and Family J.'elfare, New Delhi - 1989 »
UJh. 3- 3©
Contraceptives of today nd tomorrow. Field of population
control emerging as one of prime importance in bio-medical
research.
I
I •
I C_e. rA L i
o/-~
A variety of progestogens ?.nd cont±nua^tion of progestogens
and estrogens have now been used as injectable preparations
or as subdermal implants.
Two long acting injectables are widely available a depot
medroxy progesterone acetate (DMPA - trade name Depo
Provera, the Upjoha Company, USA) and worethi idrone Enanthate
' NET- ’ ), trade name 'oristeJ&at Schering AG, ",’est Germany)
' ' are hi hl; eff ctive spacin (reversibl ) methods -•
DM ' is i roved 'o - use in ore than 90 countries
NET-EN
in more th.-n 4? (but not in India).
Ths lon_ actin'- inject- bins abolish th.? cyclic.--.!
’ H -..-o' ably y
ctic
-v?.,o Ch
level
-v d i.t c bi Cion of oral pills. However ICs
re less effect on over all bodily physiology eg.
liv r o..- thyroid function than do the oral? pills.
; srious adverse reactions. Major side effect is on patterns
of menstruation irregularity to amenorrhoea. The over all
blood loss is reduced but occassionally there are episodes
of heavy bleeding. Many women gain 'eight on DMPA or NET-EN.
Numerous studies have shown that che use of injectable steroids
is associated with a slow return of fertility. The median time
to conception is about 10 months after the last injection witfla
fertility returning to 75% of women within 15 months and to
95% in 24 months.
0^
■ No adverse effect on the amount and duration of lactation.
'Vllnfects- of 'DMPA and NET-EN treated mothers_gained weight more
rapidly, than controls.
The greatest debate concerning the use-of long acting steroids
has revolt ' around possible carcinogenicity. I
some studies
a hi.'
prevaWbe .
'
-. i ccrvicr
*
rs has bee recorded
DM” ■; u
■ bit
t in other.
irevalen
>: te
cl
s
itl dur ?
: us 'nd
svidence of any change in
ris'. c ' 1 evasive cervical concern.
^oo0
In :h possible relationship between the continuous ;>*■
levels
o ‘ progestogens and incidence of breast corner,r—Only two
Cp.^4,
cases of bre: - t
among DMPA. users re >orted.
Qn. a ce. C
Since 1980 regulatory agencies, in Sweden, the ' .K. France and
-:,est Germany have approved DM'0/', for contraception. Several
i ti lai -nd international s scientific groups have also
endorsed DMPA, including HO, HRP & IPPF.
Monthly injectables - widely used in Lutin, America and China.
They contain an Oestrogen and progestinr&omibned
’7H is
currently supporting research on two new/nonthly injectables
and conducting trials on them alongwith-Family Health International
in three countries. 1':
- 2 -
■
COT!
1
ICMR ( TASK FORCE ON HORMONAL CONTRACEPTION) (PHASE II)
/k/o rplo >\t:
Randomized comparative clinical Trial of Norbeft (R) Six
capsules with Norplant (R) - 2 (Two covered Rods)
SubdeTmal Implant for Long Term Contraception. Report of
a 24Amonth study.
Research Centres.
A.I.I-M.S., S'afdarjung Hospital, Kasturba Hospital, New
Delhi, Rafta Krishna Mission^Seva Prathisthan Calcutta,
ICMR, New Delhi.
The need for a highly effective reversible estrogen - free
contraceptive method in which a single administration
sufficient for several years need not be stressed, subdermal implants offers the possibility of a long-term
contraceptive without frequent medical intervention or conti
nual attention by the user. As a result of several years of
research by the Population Council, New Yox^T~Uie~NQ£:Qlani (R)
'contraceptive system has been developed which embodies several
of the desirable features of a long-acting reversible fertility
regulating method.
Jhe ICMR (New Delhi) which actively collaborates .in con trace-,
'ution research with International Committee for Contraception
"Res ■
of HlEZ2p..p.ul tion Council/ Neu Y rk initiated
apHase II randomized clinical trial comp ring
>rplant (R)-
2 with Norplant (R) in August 1982 at ly of its Human Reprouction Research Centres. The present report s unn arizes the
results of this study upto 24 months of use of these implants.
For the trial of the implants, Norplant (R) -2, and 'lorpl nt /
(P) provided by the Popul; tion Council, New, York based on the ///'7«Z
hormone levonorgestrel a total of
- subjects were enrolled /
in the study, while 84 subjects were allocated to Torplant (R)
- 2, 88 were allocated to Norplant (R), The subjects were
observed for 1590 & 1777 months of use respectively.
A total of 8 subjects, 5 with Norplant (R) - 2 and 3 with ■
;Torplant (R) had expelled .ne of the rods or capsules ,
Analysis of the menstrual pattern indicated that the proportion
of subjects with menstrual irreguloMHtfes continued to be
high (more than 60%) throughout the study, since menstrual
irregularities were mainly excessive or prolonged or irregulai?
bleeding only 20 per 100 users discontinued the method at the
end of 24 months. This is unlike the observations made in conn
ection with another clinical trial with NET0-0'rN (200 Mg) given
as either two or three monthly intermuscular inject ion in which
42 per 100 users had discontinued the method due to bleeding
problems at 24 months of use.
<
O/z
Thus it appears that an obigonoc.vor oho-evc menstrual pattern
is more acceptable to thestudy propulation and discontinuation
was more due to amenorrheea. In fact 47 % of the subject had
cycle length of more than 35 days with both the devices during
the 1st reference period The figure continued to be higfr (i.e.
abdut 55 %) -until the 8th reference period. The above
2
observation indie tes that the majority of women using norplafct
e Lees experienced oligomanorrhoea. As result of the success
of these trials the ICMR has recently initiated a phase III
multicentre clinical trial with (ibr'aplant (R)-2 to confirm
the observations of this study.
v
Insertion and removal of Norplant Implants require a minor
surgical procedure under local anaesthetic and a small inciscon.
Removal is more difficult than insertion. Although the status
report of N.I.H.F.W. claims that infections are rare. Dr. Pramila
^ranayeket Medical Director of International Planning Rarenttood
Federation Points out that trained health workers are required
to insert the capsulesin a clinical setting and the method is
therefore not suited for community based programmes-
Dr» Somnath Roy, Director of N.I.H.F.W. admits that the hormone
levenorgestrol while suppressing ovulation canM also cause a-c—ke-j
hair growth, weight gain, headache, nervousness and depression.
Dr Roy also apprehended the possibilities of infection due to
the leekrof hygiene on the par£ of the paramedical staff.
According to Dr Roy "Experience gained from the clinic
based trials does not provide adequate guidelines and preparation
for programme operation. This is absolutely true in cases of
hLnjectables and implants". In order to be successful "it
would be important to.make the technology suitable to the
culture of the people and capability of the service system".
Although Dr. B.N. Saxena, deputy D.G. of ICMR and a coordinator
for the Norplant trial ba—d that it would change the whole
complexion of contraceptive .use in India" the women, activists
saw the menstrual irregularJUywas the greatest impediment or the
worst fall-out.
-J
Norplant - An account of its use in Bangladesh.
Bangladesh Fertility Research k-rogramme (counterpart of ICMR)
attempted to start Norplant trials in 1981.
But due to resistance
from various groups trial postponed by BFRP to February 198J£
They were financially & technically assisted by the population
Council
Family Health International.
In an article by Dr. Ha £ida Hanum Akhter the then Director of
BFRP she openly acknowledged that, "It has been found by researc~\iers
that contraceptive pills containing progestin and more commonly
used other reversible method necessitated continuous motivations
inoolvement invs by the user.
in a country like Bangladesh
this fact is more true than in the developed world.
It is therefore
necessary to introduce methods in Bangladesh which can continue
to be effective for long periods without continuous motivation
by Family planning Workers.
Norplant is perhaps the most
effective method which is likely to prove successful here."
Again even before the BFRP undertook the trial in February 1985
the third Five Year vlan justified the use of Norplan^on the
grounds that this “
longlasting method has the potential
advantage of not requiring day to day use and therefore nay be
particularly suitable for our semi Qitcsate population
the programme for its wider use can be decided according to the
experience of the trial.
Here again the effectivity question
is mentioned and is specially targetted towards the semi literate
population, in other words the poorer section of the population
so that population control can be assured".
(In these statement you have a blatant profession of the
discriminatory principles of age-noics.
Although the ICMR is
wary of such indiscretions and in fact takes care to pose the
issue with a“pro-women“
bias explaining its rationale
from their inner urges and needsthere is no doubt that
the very basis of long acting contraception like inj-ectables
and implants etc is to prompt women from having control over
these issues).
Critique about the " Tacts about an Implantable contraceptive" bulletin of the WHO -(1985)
1.
Insufficient Animal Experiments
(a) Levonorgestrel and the half actived I, Norgestrel isomer was
used interchangeably and theYieifore the interchangeable use of two
subs cances is confusing.
Comparison of the doses given to animals and humans is misleading
as there are big differences between species in terms of
bioevailability and terminal half lives of the drugs.
3.
On the one hand the beagle bitch is considered an unsuitable
model for studying proges tagins but experiment with this animal
are included and no replacement experiments were carried out.
In the majority of the experiment Levonorgestrel was given by
the oral route and comparison with implanted doses is misleading
co difference in bioavailability.
5.
As t which is a poor model for testing of
anima 1
implants is used in
Areas of insufficient clinical Research.
1.
Effect of Norplant on lipid metabolism experiments carried
out are contradictory.
And fat metabolism is associated with
risK of cardiac problems.
2.
Relationship between Norplant use and an abnormal glucose
tolerance test (According to WHO only six examined in this
3.
Safety of long term use of Norplant.
4.
Effect of Norplant on blood coagulation.
5.
Use of i.orplant during lactation and its effect on the growth
end development of the child.
6.
Use of Norplant during pregnancy.
7.
Its effect on the level of testosterone and ros tened^one.
d.
Its effect on systolic and diastolic blood pressure in the
4th and 5th years of use.
Inadequacies about the existing areas of investigation.
1.
Women who had used injectable contraceptives were e1imina ted
from this experimental series.
2.
The results were often compared with those of women who use
oral contraceptives and not with women who use no hormonal
IaJ H 3- It
Indian Data - on Norplant Tria Is :-
Note;-
only got data for the Phase-Il trial.
3ut the ICMR has
completed the entire protocol submitted its report to the Govt.
of India., As stated by Dr. 3 N Saxena
(ICMR) Norplant (R-2)
vU-.’O covered rods) has been recommended for use on a clinical
basis i.e. by a trained gynaecologist.
it has also been
suggested that from the point of view of economies of production
the rods would be cheaper to manufacture and clinically easier
to insert.
Otherwise all other clinical and metabolic effects
as well as bleeding patterns were similar in these two groups
What is important about this trial data is its
- concentration
on its efficacy and as a fall out of this the impact
menstrual cycle is given maximum importance.
the
Even the menstrual
irregularities which was high throughout the period of study
(i.e. about 60%) was considered more in the context of continuation/
discontinuation rates and not as a serious gynaecological problem.
Moreover in comparison with Net-EN since discontinuation rates
were lover it was concluded that the nature of menstrual disturbances
i.e. excessive, prolonged or irregular bleeding were more
acceptable to the Indian women,
“nd therefore it was amenorrhea
or less bleeding which was more problematic.
What is pertinent
and necessary to ask is whether Indian women with their anemic-
prone conditions can risk methods which can lead to excessive,
prolonged ox frequent bleeding.
spotting which
And Whether the intermittent
62 to 80% of the subjects experienced with both
the devices is merely a physical inconveniences for women or a
health risk.
In fact one of issues (as stated earlier) by the
US FDA committee was whether irregular bleeding could imply or
lead to"endometrial cancer"
2
It was also realized that apart from a more “acceptable" bleeding
pattern another factor which contributed to the higher continuation
rates was the “inherent characteristic of the Norplant
contraceptive method".
The realisation that any discontinuation
cf the method would mean a repeat surgical procedure for its
removal may have been a disincentive.
It is . here that the issue
of the woman losing control over her own body or reproductive
rights becomes crucial.
It is not certain as what extent the
official claim that the higher continuation rates due to better
counselling and follow up is xixak valid.
It is -mite possible
that in the guise of counselling there may have been professional
refusal to remove or a veiled refusal to remove unless backed up
by strong medical evidence.
And it is here that the periodic
motivation which played a crucial role in the steep fall in
continuation rates of NET-EN injections.- was not necessary.
All that the medical professionals had to do waste discourage removal.
There is a lot of data to substantiate these fears in Bangladesh
where scores of women have testified that despite suffering from
severe bleeding, itching in the vagina, and other unbearable side
I
effects^ (The family planning workers, doctors etc.
to remove it.
disinclined
They are either evasive or in some instances bluntly
refusing to remove it.. In fact one of the justification given by
Ik
A
iee doctors for refusing to remove it is that it is such an
expensive method equivalent to ik 2000 (US
55) that the women
do not have the right to " ta Ik about removal".
"How dare they
when such an expensive medicine is given tree of cost to these women".
Negative EFFECTS OF NET-EN/DMPA/ or injected Progestins;1.
DMPA alters carbohydrate Metabolism
2.
no
’.ray to control menstrual irregularity except to prescribe
supplemental estrogens which defeats the xme purpose of an estrogen
free contraception.
3.
Delay in return fertility - some as late as 2 years.
4.
Thai children of users of DM? A two time more prone to limb ;
defects and five times more, liable to have chromosomal abnormalities
5.
increase in cholestrol with longer use of DMPA.
6.
Decrease in high density lipaprotein (Both DMPA and NET-EN)
7.
Costa Rican study found two fold greater risk of breast cancer
among former DMPA users .
8.
Similarly WHO also found risk of invasive cervical cancer higher
in the case of former DMPA users.
9.
Following an injection of Net-En the serum zinc level in the
system decreases significantly.
As zinc is an essential component
of blood platelets a reduction in the zinc level could mean
abnormalities of the blood platelets - a symptom that is common
among pill users.
10.
This is regarded as a potential risk to users.
Net-En reduced prothromb^fl activity (a substance present
in the plasma and essential for clotting of blood.
There is also
a suspicion that Net-En affects the hepatocellular functions of
the liver.
Which means that women suffering from jaundice or
other liver ailments should not use the injection.
2
11.
One detremental feature of progestogen based contraceptives
is the effect it has on lowering the body's resistance to infection
termed as immuno suppresant effect.
The Dutch Medical Bulletin
writing about DMFA says, ".^ike all other progestogens DMPA has a
slight immunosuppressive effects.
Clinical effects of this has
never been written about."
WHO also advises that the use of injectable contraceptives such
as NET-EN should be avoided if at all possible among young
adolescence women who have not yet had children but may wish to
do so in the future and women over 40.
WHO notes that (a) the
consequences for sexual development of interrupting pituitary
activity in the first few years of adolescence are not fully
understood; (b) and neither has the effect of DMPA and NET-EN on
the subsequent fertility of women who have not had children been
studied carefully.
So women who wish to have children have been
advised to use another method of contraception.
Finally women over 40 are also cautioned against the use of such
in jectables.
in addition WHO lists several "special proolems" where great car~ee
in the use of injectables should be taken.
These include (1) abnormal liver function or recent history of
liver disease
*
history or evidence of cardiovascular disease,
congental hyperteipidaemia, diabetes mellitus or history of
gestational diabetes.
In all these cases WHO recommends very careful monitorying.
fact the checklist in as follows:-
3
Check the following by history and examination
Yes
no
Above 40 years of age
Above 35 years of age and heavy smoker
Seizures
Severe pain in the calves or thighs
Symptomatic Varicose veins in the legs
Severe chest pains
Unusual shortness of breath after exertion
Severe headaches and/or visual disturbances
Lactation (For less than 6 months)
Intermens trua 1 bleeding and/or deeding after
sexual intercourse
Arnenorrhoea
Abnormally yellow skin, eyes
Blood pressure (above 140 mm HG Systolic?
and/or 90 mm 1 HG diastolic?
Kass in the breast
Swollen legs (oedema)
Only if all the above are negative the woman may be given injectable
contraceptives.
Are these guidelines observed in India?
In India the procedure for testing a drug is that it must have the
approval of the central Drug controller. Govt, of India.
For
this approval an initial toxicology, safety and efficacy tests are
made which in turn are reviewed by a panel of experts.
Once found
suitable after testing the drug it is released to certain medical
institution for further research.
Here the institutional Ethical
Committee which is made up of professionals representing medical
legal and religious faculties must be involved in reviewing the
before we examine the issue of trials - a debate should be encouraged
on the more fundamental issue of medical experimentation.
here that hawks “*
It is
Or. BN Saxena assume importance.
"How
can we advance in this field of population control without human
experimentation and trials?
Can we prescribe a drug on the basis
of its efficacy data from another country?
In fact given the wide
difference in the metabolic impact of these hormonal drugs
(many
LC
recent studies proved
is absolutely essential that we marshall
our own data and therefore these trials are in the interest of
our people".
t
Granted that such a need exists then why not recruit articulate,
well informed literate volunteers who can not only extend informed
ow/so
consent but will be.vocal in exposing any misdeeds and negligence
jA-t'V
' of the medical community and demanding a back up medical care?
It would be professionally most honest if the medical community
offered itself as volunteers for the trial.
"Nobody will be
prepared to tolerate side effects like spotting.
venient and giving their lack of need for it-r
they will not fall a trap to the "
med ica1 community.
11 gu-i n rL
it is most incon
it is obvious that
11 or needs of the
says Or. Kamla Ganeshan (Senior
Gynaecologist) "Then what about the poor people how do you justify
their involvement in the trials?" .
"They are desperate and many of them express a desire to be given
an injection to solve their problem.
And since all contraceptives
for that matter drugs have side effects
tolerate it".
Moreover
they are prepared to
like all Govt, doctors she belong
to the "benefit outweigh risks school of thought injectable are a
5
boon to these women and hence these trial$is ethical.
(It is this kind of argument which makes it imperative for women’s
groups to ensure that a far wider informed debate takes place
because if these injectables are included in the family planning
programme it is very likely that many sections of women may
opt for them) .
Another related but equally important issue is that the Thrid
World population (again because of its objective need) are ideal
research material for fields trials especially since norms for
such research are extremely rigid in the advanced countries and
the people too well informed and articulate to
permit any kind
For instance in the Multi National
of misuse of trials.
Comparative clinical Trial of long Acting Injectable contraceptives -
NET-EN given in two dosage regimens and DMPA the final report of
which was published in 1983 we will find that out of 13 centres
included for the trialy
four in developed.
9 •■.■ere in developing countries and £xz>Mr
Even in terms of the number of woritn
recruited
for the trial and women months used in the trial of each treatment
group reveals this discriminatory attitude.
In the case of DMPA
No.of women recruits from developing countries were 1377 as against
as 210 in the developed countries ( dZ-'-'-xX-of which 130 women
volunteers belonged to
months it was 18, 167 against 2,
(Yugoslavia),
in terms of women
383 in the developed countries.
Similarly in the case of NET-EN (60 days) it was 690 women from
developing countries as against 99 from developed countries and
NET-EN (84 days) 693 from developing countries as aaainpt 103 from
.oy ACk
developed,
from
here again the majority of the women were recruited
c^k-(Yugos la via) .
,
There is no doubt that the research establishment collaborates
quite willingly with the drug multinationals in conducting the
trials.
At present while the 1CMR is launching the trials of
Ru 486 - an anti progestin or a progesterone antagonist - a
steroid synthesized by the French company Roussel - The institute
for Research in Reproduction (Bombay) is collaborating with Schering
AG, West Berlin in conducting trials on Bonnet Monkeys with
another anti progestin - 2K.-98.277-But to return to the issue of
trials as conducted in India and the question of informed consent
it mus tRioted that in India the testing is done mainly in government
run public hospitals and in rural areas where women are uneducated
and from the low incomegroup.
Although on the question of consent
the doctors on the programme insisted that consent was sought
before the injection was administered, it was more in the nature
of informing or alluring them to adopt this new method of
injectables, since the IUD does not suit them.
But nowhere are
they explicitly informed that they are a part of a trial in which
the drug is being tested.
As far as side effects are concerned^
they are only told about menstrual irregularities
(an effect
which they cannot suppress) but otherwise none of the other
dangers or risk are even mentioned.
The Doctors admitted that "the class of people are like that they
won't understand.
Educated people would understand that there is
nothing wrong with a trial but not these ignorant people.
If
we told them it is a trial then no one would be willing to have
an injection" .
Even the routine and more serious clinical examinations to
investigate the women's medical history for diseases, hypertensions
7
and bleeding problems were not conducted in the manner desired.
According to CEO report "During our visit we found that a women
is asked if she has any problems.
No specific questions like do
you feel depressed, have headaches etc. are asked.
The Doctor
justified it on the grounds that if they went by the checklist
the answer '-'OuId be yes to everything.
The woman on trial when
spoken to^stated that they had no problems except irregular
bleeding.
But when probed they admitted that they had giddiness
and headaches,
h.oreover during the thase-lll Net-En two
monthly trials it was noticed that even simple -.-uidelines of the
ICMR that women_who were br eas t feeding their child should not be
recruited was not observed.
Therefore considering the fact that
the medical staff were unable to erttmifterte regulate or monitor such
a simple but vital rule to prevent lactating women from joining
the trials makes one very sceptical about whether the more
serious contraindications ranging from liver or cardiovascular
disease to abnormal uterine bleeding and breast and genital cancer
were examined to the necessary extent a rd on the basis women
precluded from the trials— What is known as the preliminary
tc
screening eliminate high risk clients.
And while referring to lactating women WHO report (1982) admits
that a breast fed infant of a mother on NET-EN would receive
about 0.05>o of the maternal dose over a two month's interval.
This according to another report may prove very harmful as the brain
is not fully developed and may be sensitive to hormones.
In additio
the immature livef-and the consequent slower elimination may lead
to a higher accumulation of hormone in the blood (War on-Want,
norethisterone Enanthate, Dec. 1984 U.K.)
But apart from all the above medical lapses it was also noticed
that there was no effort to keep track of the patients once the
trial periods were over.
The doctor felt that, "if there were
any problems the woman would come back to us" .
But besides the disregard exhibited by the medical and paramedical
staff there are other problems related to the timely distribution,
administering and storage of drugs.
If the injection is not
administered within five days of its due date the contraceptive
efficacy is lost.
Which implies that the paramedical staff must
be sufficiently motivated to follow up each case of injection at
AS far as the issue of storing and
the right timeinter va Is .
I
administering the drug safety is concerned, the health ministry's
1/l’S Cocl-S
special guidelines states that the NET-EN being an oily vtscotfcsS
solution should be aspirated carefully in the syringe to ensure
use and prevent leakage and also that the vial
containing the drug should be warmed before injection if it has
been stored in low temperatures (Too much to expect from our over
worked health centres and govt, hospitals)
vaccine deaths have
Occurred due to wrong administration of the drug, faulty storage
and negligence.
Therefore in the wake of many incidents some
major tragedies with ifc triple antigen polio etc.^ it is necessary
to oe wary of it.
In fact the ICMR in its trial report stated
that "as the leakage of the drug" may be a "factor responsible for
the higher pregnancy rates"
it was recommended that at " pamph
centres it would be useful to prepack in sterilized disposal
syringes" .
Injectable
contraceptives and -s£exis t bias—jthe seventh Plan period
was seen by the Govt, as a phase which was preparing for "conceptua
9
breakthrough.
Apart from short and long term demographic goals
like a crude birth rate of 27, crude death rate of 10 infant
mortality of 87/1000 and a couple protection rate of 42% by 1990
and net reproduction of one by 2006 to 2011 and a zero growth rate
by 2,05 0 they will strive to achieve other- social goals like raise
the marriage age
increasing literacy, employment of women,
child s urv iva 1 a nd o Id age security.
is the govt1 s shift in emphasis.
But what a 11 this concea Is
it began after the Emergency
when women increasingly Became the victim of the official FT programme.
Reduction in vasectomies, increase in tubectomies,
the camp approach of laproscopic sterilization.
leading to
Although the
maternal and child health (ICihf) component is a major plank of
the FT programme^ all available data on the health of women and
children indicates that it continues to be poor.
India reports
lower life expectancy for wonen than for the men.
It is also
observed that the gender gap is widening with lesser share of gains
received by women.
Nor does "averting birth" improve quality of
life for instance the nutritional level of children in Kerala
which reports a high acceptance of family planning
than that of children in u.P.
is far worse
in fact the Ft Programme
has seen
the woman not as major and human component of the family unit out
only a breeder in society whose fertility must be controlled to
achieve govt, targets even ata considerable risk to her health.
Added to this has been the role of development agencies who since
the 1970's have extended their welfare policies to include
population control through family planning programmes.
They have
identified women in their reproductive role as essentially
responsible for limiting the size of the family.
They went to
the extent of ass txAhiing that poverty can be reduced by simply
limiting= ffr<-;-j
t achieved
£t-rtility
through widespread dissemination of
10
contraceptive knowledge and technology to women.
Only the obvious
failure of this approach led population planners (including Dr.
B N Saxena
to recognize that variables relating to
women's status such as education and labour force participation
could affect fertility differentials and consequently needed to
be taken into consideration.
^(Jhis
change of approach partly
of world sank which in its development
took place at the
Report of 1984 states that by reducing infant & child mortal!ty,
educating parents
/aCoauua
(especially wooen) and raising
women's employment and legal and social status will prove a key
incentive to fertility decline)
But even in this very "women centred approach" what strikes one
is that women continue to be treated in an instrumental manner
in population programmes.
The recognition of links between women's
autonomy over their lives and fertility control is not widespread
or in the case of our country totally absent.
The lack of
satisfactory birth control methods and the introduction of more
invasive techniques like injectables and implants is
birth control even more
"women centred" .
making
As DAWbJ (1985) has
argued this lets men off the hook in terms of their responsibility
for birth control while increasingly placing the burden on women.
A position which is also held by women's groups in India.
And
as stated by Dr. Raja baxmi of AIIHS in the interview (which is
•--------------- -------------------------
M
a part of the material) that there is a fundamenta l^even in the
scientific and medical data on the male reproductive system.
This coupled with the fact that controlling their cycle is more
difficult and motivating them near impossible - has only made it
.easier to "let them off the hook".
But as we analyse the trial data it
■’Omen have developed their own version of
contraceptive technology.
towards th&A
is evident in the high
discontinuation and drop out rates and unless the efficacy of
= ny . technology is proved in terms of positive hea 1 th
better adapted to the environment in which it
be oooosed in -stwo=bts-fe&- teews-.
’
Anti Sterilization:
A recent editorial in Lancet has pointed out that “in third world
countries like India where govts are so committed to the goal of
population control there is often a neglect of basic ethical
standards".
Given the conditions where surgeon
t/y with one another to complete
larger and larger number of operations there is bound to be a
failure to maintain standards op hygiene as well.
As a result a
large number of cases where patients have either lost their lives
or have sutfered damage due to lack of care at mass sterilization
camps.
Between 1986-88 there were 844 sterilization deaths in the country.
447 - 1986-87 and 397 in 1987-88.
Health Ministry reduces everything
to statistics—death rate only 7.1 per one lakh sterilizations.
In
Orissa, Madhya Pradesh, Rajasthan and Gujarat the sterilization death
toll is even higher.
13.5, 11.9, 11.8 and 11.2 per lakh sterilizations
respectively.
All ICMR guidelines viola ted.Zaproscope not sterilized.
No life
saving drugs - no screening of patients with aneemia, hypertension
and diabetes.
Equipment not properly sterilized.
In 1388 delegates
from Karnataka, Maharashtra, Uttar Pradesh, Gujarat and Orissa who
(attended a meeting of Family planning representatives fromStates
which had more deaths than the national average (7.1) identified
‘6'-S
the main causes of death as septiceaia, peritonitis,
nemi-siteis and ■
tetanus .
An editorial in Lancet refers to a paper written by a surgeon who
claims to have performed a total of 2,50,136 laparoscopic operations
2
in the course ot Less than ten years in camps.
A commentary on the
same paper in the same journal indicates that the surgeon spent less
than a minute on each operation.
“The women were numbered by small
stickers on their foreheads and then arranged in two long lines
on the verandah of a school each leading to an operating bench.
Even apart from the human angle, what of the post operational
complications.
Now there is enough epidemitfiologica 1 information to
show that pelvic inflammatory diseases (PIVS) contribute
significantly to gynaecological mortality. PIVS are a contra
indication tor surgical intervention.^Report of the Comptnoller Sc
Auditor
General of India, 1933-84
for Maharashtra.
In a test
check the CAG has come across two ineligible cases of tubectomies
on women whose spouses had already been sterilized.
The report found the state Govt, guilty of ignoring the G.OI
guidelines specifying that laparascopic sterilization should be
conducted only in well equipped hospitals and not in camps.
In
Maharashtra 94;-<> of the laparoscopic tubectomies have been xmex
conducted in camps.
In several centres tne operations has grossly
violated State Govt, norms which Lay down that not more than 50
operation should be conducted in one day with one surgeon and one
laparascope.
For sterilisations the State has recorded 90%
achievement in 1983-84.
Only half of the medical officers
appointed for conducting sterilisation have received training.
Similarly on 53% of the nurse midwives have been trained in the
insertion ot IUDs.
Given these findings in a state with is reputed
to have one of the better run health programmes it is not surprising
that planners have started talking of a "target holiday" .
Sterilisation Abuses in New Seema Puri resettlement Colony:
3
One classical abuse - 20 year old Putali who has no children was
asked by the Doctors of the MCD dispensary in New Seemapuri
resettlement colony that "If you want medicine for your headache
you must get sterilized first".
C_
A protest against such forms of coercion was organised by the
Sabla Sangh-Putali and a few hundred women from this working class
colony came together and demonstrated outside the dispensary.
The Sbla Sangh conducted a survey of four settlement colonies.
Sunder Nagri, New Seemapuri, DaKshinpuri and jahangirpuri to assess
the state of health services in these areas.
The data collected
over a period of four years clearly showed that women were the worst
affected and the direct victim of family planning methods and
drives,(gpnera 1 complexwas that there was no follow up care.
Tubectomies Copper Ts and laproscopic methods were commonly used
by Govt, hospitals-Chronic gynaecological ailments have developed
in mos t women forcing them to depend on private medical help at
costs
great and usually unaffordable expense tee—them. Men are rarely
sterilized.
The medical authorities are using free medical health
as a weapon for coercion.
New Seemapuri has a large refugee population from Bangladesh and
Nepal.
Rickshaw pulling, rag picking, construction work and the
recycling of waste are the primary occupations of the residents.
Backache weakness, giddiness, abdominal pain, breathlessness and di
distension of the abdomen are the common ailments suffered by the
women after the operation and 20/o of the women surveyed had spent
Rs.100-1000 on private medical care.
According to this study fifty per cent of the women' sterilized
failed to receive medical assistance after the operation resulting
in medical complications.
In Rajasthan, Minister of State for Health admitted in the
Assembly that 94 women had died following sterilisation operation
since 1985.
Of these 24 had succumbed to post operative complications.
International Family Planning Perspective - Vol. 15,
Sept 1989:-
Assembly-line Sterilization;
One Indian physician has in the course of 10 years performed 250, 136
laparoscopic sterilisations.
Reporting on his experience in the
British journal of obstetrics and Gynaecology.
Previl.V.Mehta
described having sterilized 40-50 woman per hour in special sterilizati
camps with high levels of effectiveness failure rate of O.lyi and low
V
levels of associated mortality 48 deaths per 100,JOO procedures^/
Furthermore rate of reported surgical and post operative complications
were no greater than those in other large studies of female
sterilizations.
A British Family planning expert John Gullebaud who
observed Mehta1 s technique comments that "if the main criteria of
success of a mass sterilisation program x
efficacy and cost
effectiveness than Dr. Mehta and his team are to be congratulated.
However he notes several reservations the greatest being the
apparent
(ry of counseling,
lack of a human touch during the
surgery and the risk of cross infection.
British Journal of Obstetrics and Gynaecology - 96-. 1024, 1989
96: 1019, 1989.
/
3-U.qPeople - 12 th May 1989 Norplant's US approval recommended.
The subcutaneous contraceptive implant, Norplant (Levonorgestrel)
P
should be approved, the US, E'tfA's facility and maternal health
drugs advisory committee unanimously recommended on 29th April.
The Population Council presented the results of the seven phase-IIl
470 women between the ages of 18 and 40
clinical trials involving
from the US, Sweden, Finland, Denmark, Brazil, Chile, Jamaica and
Of this total over 300 were from the
the Dominican Republican..
US.
Two of the trials compared the product with an IUD.
The
Council also presented the findings from the use of the product
in over 14,000 women who received it through "pre introductory"
ctb MW
studies mainly in developing countries which were designed to
give physicians experience with the system prior to approval.
j
Of the 2,470 women 400 completed the first g-ive years of continuous
use.
Major reason for termination was irregular bleeding (17.4%)
with menorrhagia.
More than 12% of the women experienced 18 or
more onsets of bleeding.
Some women also reported amenorrhoea.
14.67o of women discontinued therapy for other complaints including
placement related problems depression, mood changes, weight gains
and headache.
Problems with placement in 1.2/0 of women included
infection and expulsion of one or more rods.
Some women also
complained that the rods were visible under the skin.
potentially serious problems included hypertension (24 cases) ovarian
cysts (14) cervical cancer (8) gall bladder problems (7) and
aneamia (5) 6.7% of 992 removals resulted in complications.
101
accidental pregnancies occurred and the outcome of 27 pregnancies
is unknown.
One case of a Cir th defect was reported which
consisted of ambiguous male
iajh
Az
W\
3 h
A WOMAN-CENTERED APPROACH TO CONTRACEPTIVE RESEARCH AND
DEVELOPMENT
Mahmoud F. Fathalla
A historical perspective
"When the woman is afflicted with a large wound as a
consequence of an abortion,
or the womb is damaged by strong
suppositories, as many women are always doing,
themselves ,
doctoring
or when the foetus is aborted and the woman is not
purged of the afterbirth, and the womb inflames, closes and is
not purged,
if she is treated promptly she will be cured but will
remain sterile. ”
Hippocrates, 400 BC
Throughout human history, women have felt a need to regulate
and control their fertility. Until the modern era, they neither
had the power nor the safe and effective means to do so. The lack
of tools did not prevent them, as the writings of Hippocrates
(see Box) indicate, from trying to "doctor themselves", often
risking their health, future fertility, and even their lives in
the process.
In almost every culture historians have found ancient,
traditional recipes which women have used. Egyptian papyri dating
from 1850 B.C. refer to plugs of honey, gum acacia and crocodile
1
dung, used by women as a contraceptive vaginal paste (Speroff and
Darney, 1992). Women traditionally had only one genuinely
effective biologic method at their disposal to postpone
pregnancy: prolonged breastfeeding. Whatever the effectiveness of
these and other methods, their use by women throughout history
demonstrates the serious intent with which women have pursued
control of procreation.
Men, on the other hand, had the power and the means, very
early in human history. The biblical story of O-nan is a case in
point:
"And Judah said unto O-nan, Go in unto thy brother’s wife,
and marry her, and raise up seed to thy brother. And O-nan
knew that the seed should not be his; and it came to pass,
when he went in unto his brother rs wife,
on the ground,
that he spilled i_t_
lest that he should give seed to his brother.
And the thing which he did displeased the LORD: wherefore he
slew him also”.
(Genesis 38: 8,9,10).
The actions in the story are those of Judah, O-nan and the
LORD. O-nan's brother's widow, Ta-mar, had no active role to play
in this story. Withdrawal, or coitus interruptus, one of the most
ancient methods, enabled men to exercise control over
reproduction.
The condom, another effective contraceptive method, has also
been available to men for a long time. The history of the
2
development o£ the condom is lost in antiquity but most versions
indicate that it was a method developed by men for use by men. A
popular version attributes its discovery to a ”Dr. Condom", a
physician in England in the 1600s (Speroff and Darney, 1992). The
story goes that Dr. Condom invented the sheath in response to the
annoyance displayed by Charles II at the number of his
illegitimate children. Another version attributes the invention
to a medieval slaughterhouse worker who conceived the idea that
covering the penis with the thin membranes of an animal would
protect promiscuous men from sexually-transmitted diseases
(Himes,._X9.70L^_
In many societies, the predominant objection against
contraceptive use was really to contraceptive control by women.
rather than against contraception itself. Male-dominated
societies resented giving control of the process of reproduction
to women. Patriarchical societies reasoned that if women had
control over their reproduction, they would also have the
unthinkable - - control over their own sexuality.
Publications about the diaphragm first appeared in Germany
in the 1880's. A practicing German gynecologist, Dr. C. Haase,
wrote extensively about the diaphragm. Although Dr. Haase was
prescribing the diaphragm for unhealthy women to protect them
against undesired and risky pregnancies, he had to publish under
a pseudonym of Wilhelm P.J. Mensinga (Speroff and Darney, 1992).
3
The diaphragm was named after the pseudonym.
The fact that women did not have control over their
fertility affected their ability to enjoy mutually fulfilling
sexual relationships. Marie Stopes noted that a popular demand of
women at the time was for a simple pill or drug to make their
husbands less rather than more passionate (Stopes,
1928). Women
often said they liked everything about marriage, except "the
going to the bed side of it" (Eyles. 1922).
Fertility by choice, not by chance, is a basic requirement
for women's health, well-being and quality of life (Fathalla,
1993a). A woman who does not have the means or the power to
regulate and control her fertility cannot be considered in a
"state of complete physical, mental and social well-being",
the
definition of health in the constitution of the World Health
Organization.
She cannot have the joy of a pregnancy that is
wanted, avoid the distress of a pregnancy that is unwanted, plan
her life, pursue her education, undertake a productive career, or
plan her births to take place at optimal times for childbearing,
ensuring more safety for herself and better chances for her
child’s survival and healthy growth and development.
The Contraceptive Revolution
Widespread contraceptive use is a very recent phenomenon in
4
human history. The first demographic transition was accomplished
in the Northern industrialized countries in the 18th and 19th
centuries largely by men using coitus interruptus. Fertility in
Europe and North America has declined gradually, and today has
reached very low levels, in some places below replacement
fertility.
The second demographic transition is taking place now
largely in Southern developing countries. This transition began
only in the past few decades and has depended substantially on a
revolution in contraceptive technology. Among other things, women
for the first time had methods which they could use, even
independent of the cooperation of their male partners, to
regulate their fertility and to enjoy sexual life without fear of
unwanted ill-timed pregnancy. The consequent decline of fertility
has been even more steep in the Southern than compared to the
Northern countries. In__the USA, it took.58 years for fertility to
decline from 6.5 to 3.5; the same level of decline took 27 years
in Indonesia. 15 years in Colombia. 8 years in Thailand and
merely 7 years in China (UNFPA. 1991).
Contraceptive users in
the developing world increased ^tp^e-fold from an estimated 31
million couples in 1960-1965 to 381 million in 1985-1990 (UNFPA,
1991).
Before 1960, people had a very limited choice in
contraception: between coitally-related methods (condom and
5
withdrawal for the male; diaphragm, cervical cap and vaginal
spermicides for the female; and- periodic abstinence for the
couple/ and permanent methods (female and male surgical
contraception). The contraceptive revolution of the 1960s and
1970s led to significant improvements in existing methods,
including the simplification of methods of female surgical
contraception, to the extent that they no longer require general
anaesthesia nor hospitalization. For the first time.in—human
history, contraception could be taken out of the bedroom and out
of the genital area, with the development of systemic hormonal
methods.
In addition to the systemic oral hormonal contraceptives.
which are short acting and administered daily, recent development
of lonx-actinx hormonal methods and the introduction of the
intrauterine device (IUD) have freed women from taking a
precaution at every sexual act^and/provided an alternative to
permanent contraception. Women now have methods that offer
protection for 1-3 months (injectables), 5 years (Norplant
),
*
or
up to 8 years (IUDs).
A third major development is effectiveness. While in the
past, people had the choice only between coitally-related methods
that are associated with relatively lower levels of use
effectiveness, and surgical contraception which is effective but
permanent? |$fcmen now have the choice of modem methods that are
6
highly effective and also reversible (pills. injectables.
*
Norplant
and IUDs),
The fruits of the contraceptive technology revolution have
hundreds of millions of people all around the
world: people living in the most varied circumstances £ Jpa/the
slumsf^Latin Americ^>
skyscrapers of Manhattan, /Iff peri-urban
rural communities of the Indian subcontinent; people in all
socio-economic strata; people with different cultures, religious
beliefs and value systems; and people at different points in
their reproductive lives (postponing a first pregnancy, spacing
children or putting /the limit on childbearing).
Whatever the underlying factors for fertility regulation,
modern contraceptive technologies have given people the safer/ 7
“ o
more effective means to implement their decisions. Clinic and
supply "modern" methods (defined as methods requiring supplies or
clinical services and including male and female sterilization.
IUDs, the pill, injectables, condoms and female barrier methods)
account for approximately 80 percent of contraceptive practice
worldwide (United Nations, 1988). The non-supply or "traditional"
methods include rhythm or periodic abstinence, withdrawal (coitus
interruptus), abstinence, douching and various folk methods,
(It
mayi_be noted.. that...th.e_broad... classification, of. clinic, and .supply.
methods as "modern" and of non-supply methods as "traditional" is
not exact. The condom is an old method. Periodic abstinence
7
includes some new methods, J
The group of clinic and supply methods, which includes the
highly. effective methods that have revolutionized contraceptive
practice over the past few decades and the methods most often
offered by family plannning programs, make up a larger fraction
of contraceptive use in developing than in developed countries -
about 90 and 65 percent respectively.
(See Table/Chart X - pie
chart on worldwide contraception - page 7 of Fathalla. 1992b, in
Reproductive health: A key to a brighter future, based on United
Nations,1989). Indeed, the prevalence of traditional methods
differs much more between developed and developing countries (24
and 6 percent respectively) than does the prevalence of clinic
and supply methods, which is estimated to average 46 percent in
more developed and 41 percent in less developed regions. This
reflects the differing history of contraceptive practice in the
two groups of countries. Whereas in most developed countries
marital fertility reached low levels before modern contraceptives
were invented, in most developing countries contraception was not
widely practiced until modern methods were available, and these
methods tended to be preferred by new users from the start
(United Nations, 1988). In addition, these methods, particularly
the, clinic methods, were, more widely promoted in family planning
programs.
8
An Unfinished Agenda
Box: "Ifall the people of the world are to enjoy the highest
possible level of health and basic human rights, it is imperative
that research on contraceptive developm_e_nt_.continues unhindered."
Declaration of the International Symposium on
"Contraceptive Research and Development for the year
2000 and beyond"
In the early days of the contraceptive technology
revolution, the scientific community dreamed of an ideal
contraceptive that would fit the needs of everyone, everywhere,
every time. The field soon realized that a "magic bullet" is only
a dream that cannot come true. The diverse needs of different
people cannot be met by any single method but must be met by
broadening contraceptive choice. A wide range of contraceptives
is needed tailored to different human circumstances and desires:
for people who are different, for circumstances that are
different and for the same individual at different phases of life
(Fathalla, 1990). Broadening contraceptive choice is thus a key
to improving the quality of family planning services.
Contraceptives should not be looked upon as a temporary
measure to ease the world population problem. Contraception will
be a permanent feature of the way of life of all succeeding
9
generations on this planet. Our reproductive function is being
voluntarily adapted to dramatic new realities. What we are
witnessing is a major evolutionary jump that is science-mediated,
rather than imposed by Nature.
The contraceptive technology revolution still has an
unfinished agenda. The range of contraceptive choices needs to be
broadened to meet the vast expanding and diverse needs for
fertility regulation. Moreover, with all its benefits to the
quality of life
of women, the currently available contraceptive
technology has left women with some genuine concerns as well as
unmet needs. The qualities of convenience, effectiveness and use
by women in modern contraception were not without trade-offs.
The modern contraceptive revolution has been largely
demographic driven. Women have benefited in the process but were
not in the center of the process. As far as policymakers are
concerned, women were often means to an end, objects and not
subjects. This has accentuated the suspicions of women's groups
and resulted in a feminist critique of the medicalized
contraceptive technology (Dixon-Mueller,
1993). Whether justified
or unjustified, the critique must be voiced and must be heard,
because the concerns are genuine.
Who is in control?
10
Women have more at stake in fertility control than anyone
else. Contraceptives can be used by women to empower themselves
by maximizing their choices, and controlling their fertility,
their sexuality, their health and thus their lives. The
convenience of long-acting and permanent methods is welcomed by
many women. These methods, however, can be used and have been
used by governments and others to control rather than to empower
women. Some governments are short-sighted, not to see that when
women are given a real choice, and the information and means to
implement their choice, they will make the most rational decision
for themselves, for their communities and ultimately for the
world at large.
Safety concerns
Without safe abortion as a backup, the use of less effective
contraceptive methods will not meet the needs of women in
fertility regulation (Germain and Dixon-Mueller, 1992). As with
any drug, increasing the effectiveness of contraceptives commonly
has a trade-off in decreasing the margin of safety. From a public
health point of view, contraceptive drugs and devices have an
excellent record of safety. They have been used by hundreds of
millions of women over extended periods of time and under varied
circumstances. Few drugs have been, and continue to be, subjected
to such scientific scrutiny as regards safety. This scrutiny is
particularly Important because, unlike those who use drugs to
11
cure illness, women (and men) who contracept are undertaking
preventive action.
Safety concerns will loom particularly large if a service
system is more concerned about demographic targets than about
health and welfare of clients. Nonetheless, a contraceptive can
be safe or unsafe, depending on who is using it and the quality
of the service system delivering it. The technology "software” is
as, or even more important than the "hardware" (Fathalla, 1991).
Moreover, the concept of safety should be demedicalized to
reflect client concerns. A quality service should not define
safety simply as survival. Nor should safety mean merely the
absence of serious physical complications. Safety should be
defined from a woman's perspective. So-called minor
inconveniences or side effects such as menstrual bleeding
disturbances, headache or weight gain may not threaten life, but
can be of extreme concern and often significantly affect the
functioning and quality of life of the
woman (World Health
organization. 1991).
The abortion dilemma
The contraceptive technology revolution has emphasized
development of methods that are so effective that they can
prevent the need for abortion. The rationale for this emphasis
12
derives more from political concerns than from health or
scientific concerns. This focus on preventing abortion to the
exclusion (until very recently) of work to develop post-ovulatory
methods has serious implications for both health and fertility.
The abortion issue has implications for barrier method use
that are particularly important given the STD/AIDS pandemic.
Where safe pregnancy termination services are available and
acceptable, the need for highly effective contraception becomes
less, and women can more comfortably use barrier methods which
will also protect against infection. Where abortion is illegal or
unsafe, use of barrier methods can be associated with a high
health risk to the woman.
A review of current abortion laws shows that some 52
countries, with about 25 percent of the world’s population, fall
into the most restrictive category, where abortions are
prohibited on any grounds or allowed only when the woman’s life
would be endangered if the pregnancy were carried to term. 42
countries, comprising 12 percent of the world’s population, have
statutes authorizing abortion on broader medical grounds - e.g.,
to avert a threat to the woman’s general health and sometimes for
genetic or juridical indications such as incest or rape- but not
for social indications alone or on request. Some 23 percent of
the world’s population lives in 13 countries which allow abortion
for social or socio-medical indications. The least restrictive
13
category includes the 25 countries or about 40 percent o£ the
world's population where abortion is permitted up to a certain
point in gestation without requiring that specific indications be
present (Henshaw,
1990). Even where abortion is legal, however,
safe pregnancy termination services are not always available or
affordable.
Unsafe abortion is one of the most neglected health and
human rights problems in the world today. If there were a crisis
in which 500 people died daily, in the world, there would be news
coverage and perhaps a world uproar. Yet, no uproar has been made
about the 500 women who lose their lives every day in pursuit of
their reproductive freedom, because of unsafe abortion (Fathalla,
1992).
The current technology for pregnancy termination, even for
medical pregnancy termination using mifepristone (RU-486), is
still clinic-based. Its availability is limited by the
ay_a.iJabi.l_iXx_o.f__clxnic_al__sexYi.ces, It can., also be an easy target
for political opposition. Clinical facilities can be targetted
for funding cuts, for p icketing or for worse. An effective,
simple, affordable and safe technology which a woman can use in
the privacy of her home, outside the health care system, is yet
to be developed.
The unfair burden of fertility regulation
14
Women now have more reliable methods o£ birth control, but
at a price. They have had to assume full responsibility for the
inconveniences and risks involved. The role and responsibility of
the male partner have receded when contraception was considered a
woman’s business. According to UN estimates, the percentage of
different contraceptive methods among contraceptive users
worldwide is as follows (United Nations, 1988):
Female:
Female sterilization
_
26 percent
Intrauterine device
19
Pill
15
Vaginal barrier methods
2
Injectables
1
Other methods
2
Male sterilization
10
Condom
10
Withdrawal
8
Male and Female:
Rhythm
7
Women, therefore, assume responsibility for about two-thirds
of contraception in comparison to men's 28 percent. For each male
contraceptor, there are about three female contraceptors in the
world. Not only do women have an undue burden of responsibility
15
in fertility regulation, but the methods which women have
available for use that are associated with potential health
hazards. The importance of male participation and responsibility
has become much more with the emergence of the AIDS pandemic and
the increasing prevalence of sexually-transmitted infections,
where the use of the condom is the only effective strategy other
than abstinence.
Reproductive tract infections: the silent tragedy
Fertility regulation is an essential component of
reproductive health, but is not the only component. Women have
other needs and other concerns that are often neglected. Of these
needs, prevention and control of STDs is the one most linked with
family planning. Both unwanted pregnancy and infection are
transmitted through the same act of sexual intercourse, and women
need effective protection against both.
One trade off to the wider use of modern, non-coitally
related methods has been the decline in use of barrier methods
that offer some protection against sexually-transmitted diseases
(STDs). Reproductive tract infections, mostly resulting from
STDs, are not only a major cause of morbidity in many women, but
seriously undermine the quality of life of much larger numbers of
women, particularly in developing countries (Germain et al.,
1992). The worldwide spread of STDs has been one of the major
16
challenges to public health in the past few decades (Fathalla,
1992). While the burden o£ a number of traditional first
generation venereal diseases like gonorrhoea, syphilis, and
chancroid has declined, particularly in the industrialized
countries, they have been amply replaced by new bacterial and
viral syndromes associated with Chlamydia trachomatis, human
herpes virus, human papilloma virus, and the human
immunodeficiency virus (HIV). These agents, regarded as the
second generation of sexually-transmitted organisms, are more
difficult to identify, treat and control. Moreover, they can
cause serious complications, which can result in chronic ill
health, disability, or death. Both groups of STD's (the first and
second generation) remain major health problems in most
developing countries.
Reliable data on the worldwide incidence of STDs are not
available. Minimal estimates by WHO of the annual number of new
cases (not including HIV infection) are as follows:
Gonorrhoea
25
Genital chlamydial infections
50
Infectious syphilis
3.5
Chancroid
2
Genital herpes
20
Genital human papillomavirus infection
30
Trichomoniasis
120
17
million
STDs are now hyperendemic in many developing countries, including
the rural areas where facilities for diagnosis and treatment are
usually inadequate.
By definition, STDs affect both men and women. However, STDs
have more serious sequelae in women than in men. Early detection
and hence early treatment of STDs is easier in the male. In
women, the lesions often occur in the inner genitalia and are
thus hidden and quite often remain asymptomatic. Moreover,
ascending infection in women has much more serious consequences,
leading to pelvic inflammatory disease, higher risk of ectopic
pregnancy, and permanent infertility. Cancer of the cervix is
also a possible late sequela. Another consideration is the
transmission to the foetus of several pathogens of STDs. It is
also not widely appreciated that the risk of transmission of STDs
is much greater from man to woman than the other way round.
Finally, the most effective method available for protection
against STDs, the condom, is controlled by men. An effective
method of protection, that a woman can use without the need or
necessity of her partner's cooperation, simply does not exist.
The female condom, under development, requires male cooperation
and is also likely to remain prohibitively expensive.
18
Contraception-21
To meet the closely interrelated needs for birth control and
disease prevention, a^^se^^^^contraceptive technology revolution
must occur, driven by women’s needs and women's perspectives. A
woman-centered approach to contraceptive research and development
requires a clear mission, a' reinvigoratedjs,C2enc’e, and sustained
resources (Fathalla,
1993b).
’
The mission
The first contraceptive technology revolution was
demographic driven, with emphasis on the development of methods
that can have a demographic impact, by being effective, longacting and widely available. The field of contraceptive research
and development is best described now as opportunity-driven.
rather than goal-driven. Because of poor funding, scientists
follow whatever leads present themselves, and industry seeks only
to make marginal improvements or modifications in already
existing products. For the second contraceptive technology
revolution, the field must again be goal-driven, and the goal
should be set right. The field should sharply focus on a
sustained effort to develop contraceptives that address the still
unmet needs of women. The demographic impact will not be lost; it
will, be enhanced. The message for all of us concerned about
19
population growth should be clear:
know best. It is their
bodies, their.J,iyes..and. their..chiIdren's lives that are at stake
LTaylort_1.993Xt
Respecting,women__and,_respo_nding . to their unmet
needs .1 s one of the best strategies for saving the planet.
A recent survey of the field of contraceptive research and
development has come up with a list of 94 product leads that are
currently being pursued (PATH, 1993). Many of these are variants
of existing methods or alternatives within existing contraceptive
approaches. They include, among others, 4 IUDs, 7 hormonal
implants, 5 hormonal injectables, 5 oral hormonal contraceptives,
6 vaccines, and 6 techniques for female sterilization.
Given financial constraints among other reasons, a strong
case can be made for the field to focus its efforts on these
urgent needs that are met poorly, if at all by existing
technologies (protection against infection, postcoital/ post
ovulatory methods, male methods). The field must have the courage
to drop leads, even if they are scientifically feasible, and to
break new scientific ground. Scientific opportunity should not be
the sole driving factor; rather scientific work should be pursued
within priority areas of need.
Creating common ground
Collaboration between the users of the technology and the
20
creators of it is essential. This requires development of
communications and trust through honest and straightforward
dialogue. For example, the WHO Special Program of Research,
Development and Research Training in Human Reproduction and the
International Women's Health Coalition initiated such a dialogue
in 1991, by convening a meeting of women's health advocacy groups
from developed and developing countries and scientists engaged in
contraceptive research and development. The meeting proved not
only that scientists and women's health advocates can listen to
each other and respect each others’ views even when they differ,
but also that a common ground can be created for future
collaboration (World Health Organization, 1991).
It is time that this dialogue is moved forward and that
mechanisms are institutionalized to ensure that the voices of
women are not only heard but also heeded. Women’s health
advocates and potential users should be represented in all
decision-making mechanisms and advisory bodies that are
established to guide the research process - including definition
of criteria for safety, determination of research priorities,
design and implementation of research protocols, setting and
monitoring of ethical standards, and decisions on whether to
pursue a fertility regulation method from one stage to the next,
especially decisions to move from clinical to introductory trial
to introduction of a method into family planning programs (World
Health Organization, 1993).
21
Priority needs
An international symposium on "Contraceptive research and
development for the year 2000 and beyond" was convened in Mexico
City in March 1993. The symposium brought together senior
managers of all the international and some national public sector
agencies that undertake contraceptive research, along with
program directors and senior staff of international and national
agencies that support or are otherwise involved in the field of
fertility regulation research, together with women’s health
advocates. A clear recommendation was that "Particular emphasis
and priority should be given to methods that coincide with the
women's perceived needs and priorities, including among others,
methods that are under the user’s control and that also protect
against STD's, post-ovulatory methods, and safe male methods that
enable men to share responsibility for fertility regulation and
disease prevention. " (World Health Organization,
1993)
The need for methods which women can use to protect
themselves against STDs, including HIV, has become urgent.
Available female barrier methods are not very effective as
contraceptives, and are even less effective for protection
against STDs. Moreover, their use still depends on cooperation of
the male partner. There is also no method which can protect women
from infection while still allowing them to become pregnant. It
is quite common, for women to get the infection from their
22
husbands who have multiple sexual partners. The need is for
effective methods which women can use and control without the
necessity for partner cooperation. It is possible that if such
methods become available, women will do better than men in
compliance, providing more hope for the control of the pandemic
of STDs.
Carl Djerassi, a father of the oral contraceptive pill, has
recently remarked that if he were to choose one single new
contraceptive to develop, it would be a once-a-month pill
effective as a menses-inducer (Djerassi, 1991). Instead of
currently used oral contraceptives, which are taken daily for
most of the month, a menses-inducer would be taken by a woman
only during those months when she had unprotected coitus. Instead
of waiting to see whether she had missed her period, a woman
would take a single pill (containing a short-lived and rapidly
metabolized drug) to induce menstrual flow at the expected time.
Although not acceptable or suitable for every woman, such a
regimen would be an enormous improvement for many (Rimmer et al.,
1992). At most, a woman would take 12 pills annually, rather than
the present 250 or more. With such a pill, women would not know
whether they carried a fertilized ovum. A most important feature
of such a method is that the decision to contracept is made post-
coitally. For some women, the menses-inducer would be an
attractive back-up to barrier contraceptive methods, thus
encouraging their wider use. A menses-inducer would also be
23
suited to the particular needs of adolescents. A menses inducer,
that is completely user-controlled, could also provide a
technological response to the abortion controversy. It could
transfer the issue from the public domain to the privacy of the
individual's moral code. To have a real impact, a menses-inducer
must be safe enough to be used at home outside the health care
system.
Women for?—b-i©Teg-fea-l--reasons have to carry all the burden
and risks of pregnancy and childbirth. This, however, is no
reason that they should also carry most of the burden of
fertility regulation. A sustained research effort is needed if
men are to have broader contraceptive choices to enable them to
share effectively in the responsibility for fertility regulation.
For biologic reasons, regulation and control of the male
reproductive process is more difficult than in the female.
Hormonal suppression of spermatogenesis may be feasible, but
unless associated with replacement hormone therapy, sexual
potency will also be suppressed. A better understanding of
mechanisms involved in the post-testicular maturation of sperm,
without interference with spermatogenesis and testicular hormonal
production, utilizing the new tools of molecular and cell biology
and biotechnology. can provide promising leads for the systemic
male contraceptive of the future. The ease with which clinical
studies on methods of male fertility regulation attract
volunteers is an indication that the new generation of men is
24
more ready take on its responsibilities than has., been genera.llx
believed (Waites, 1993)
Reinvigorating) the science
This Contraceptive 21 Agenda requires that advances in cell
and molecular biology and biotechnology be applied to fertility
regulation. While such advances have opened new frontiers in the
medical and biological sciences, contraceptive research and
development have yet to exploit them. Major and sustained
investment in human resources is required to build up a critical
mass of scientists active in the field. Investment in the field
of reproductive endocrinology provided most of the leads for the
first contraceptive technology revolution. The field is now ripe
for another major initiative.
Resources
Although estimates of global expenditures for contraceptive
research and development are difficult to obtain, it is clear,
contrary to what some people believe, that contraceptive research
and development are poorly funded. The most complete study of the
levels and sources of worldwide funding for contraceptive
research and development reports on trends only up to 1983
(Atkinson et al., 1985 ). That study estimated that $63 million
was spent for contraceptive research in 1983. This figure
25
included funding for the evaluation of long-term safety of
existing methods. Of this total, private industry spent an
estimated $22 million or about 35 percent, and specialized public
sector agencies spent, out of funds given by international
donors, an estimated $26 million or 41 percent of worldwide
expenditure. The remaining 24 percent of expenditures was
provided mainly by national governments that funded missionoriented research. Less developed countries, especially China,
India, Chile and Mexico contributed about one percent of the
total. There is no evidence that the overall picture has changed
very much since then. An assessment in 1993 estimated the
worldwide annual funding for contraceptive research and
development at about $57 million (PATH, 1993).
Global expenditure on contraceptive research and
development, from all sources, is less than 3 percent of global
contraceptive sales, estimated to be between $2.6 billion and
$2.9 billion (PATH, 1993). The funding of public sector programs
of contraceptive research and development represents about 3 to 4
percent of the international assistance for population and family
planning, estimated in 1990 to be $802 million (UNFPA,
1992).
Another figure to note in these budgetary considerations is that
about $230 million is estimated to be required to bring a new
chemical entity for human use from research to the market.
(See
figure of steps of the process of contraceptive research and
development)
26
Public resources available for family planning and
reproductive health are limited and badly needed to expand access
and improve the quality of fertility regulation services. Thus,
any major infusion of resources in the contraceptive research and
development field will have to come from private industry, which
has finance and expertise far greater than other sources. The
pharmaceutical industry in the developed world invests about 16
to 19 percent of revenues in research and development of new
products (Pharmaceutical Business News, 1992). U.S. and European
companies report total revenues of over $90 billion per year and
a projected annual growth of 9 to 10 percent over the next five
years, implying that significant resources could be made
available
for research activities. The constraints that earlier
led to the retrenchment of industry from the contraceptive field
must be addressed, however, to mobilize their vast resources
(PATH, 1993). Foremost among these is a perception of the market
as being "mature" i.e. saturated in developed countries and not
profitable in developing countries, as well as a perceived dearth
of dramatically new product ideas. Product liability, drug
regulatory requirements and a hostile political climate played a
secondary role as disincentives to industry. The market is
changing. High rates of unwanted pregnancy, as well as a heavy
reliance on sterilization among the younger population, suggest a
"latent demand" for new contraceptives. Public sector provision
of contraceptives in many developing countries is now giving way
to a mor significant role for the private sector, and as market
27
pnnnonii.es in developing countries evolve, there will be a.
progressive increase in the share of the private commercial.
sector, brightening_future.profit prospects. Drug regulatory
requirements are now more streamlined and rationalized. The
political climate, particularly in the US, seems to be easing.
Public sector contraceptive research and development programs are
needed for re-engaging industry on a larger scale, by focussing
on long-term strategies to develop new product ideas that respond
to currently unmet needs of women, and that whet the appetite of
private industry. Public and private sector collaboration needs
to be promoted.
Conclusion
Will women get the contraceptives they still need to pursue
their reproductive rights and reproductive health?. The answer is
yes, when the contraceptive research and development field
becomes mission-oriented....when women participate actively in the
process, when science is re-invigorated, and when the required
resources are mobilized particularly industry resources. Women in
the 21st century deserve a better deal. Political will can make
it happen, and the time to start is now.
28
Fig. 3
Steps in Contraceptive Research and Development
leads dropped
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