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RF_WH_3_B_SUDHA
INDIAN COUNCIL OF MEDICAL RESEARCH
REPORT
Phase III- Clinical trial with once a month combined injectable contraceptive
“Lunelle/Cyclofem” (MPA-25 mg + oestradiol cypionate- 5mg).
Introduction:
Intramuscular
attractive
administration
and
of
a
long-acting
desirable contraceptive modality.
(LA) fertility
control
is
agents
an
It suits a significant sector of the
population as it fills a gap in the currently available technologies.
The injection as a
method of delivering drugs fulfills many of the features of an ideal contraceptive as they are
relatively long-acting, simple to use, unrelated to coitus,
and are highly efficacious.
Injectable contraceptives given every 2-3 monthly contain long acting progestins which
has
action such as norethisterone enantate
prolonged
NET-EN and
depot
medroxyprogesterone acetate DMPA. Although these formulations provide very high
use-effectiveness in preventing pregnancy, they induce menstrual cycle disruptions such
as heavy and prolonged bleeding, irregular bleeding including amenorrhea.
Such side
effects discourage women to accept these methods for long term use.
Long-acting
contraceptives delivered through
monthly
intramuscular injection
is an
alternate method for family planning which fills the desired gap in birth control methods.
The main
advantage of this approach over long-acting (2-6 months)
progestin only
injectables is better cycle control with their use.
Once-a-month
combined
injectable
contraceptives currently used or studied are
Deladroxate, Lunelle, Cyclofem, Mesigyna and Chinese Injectable No.1.
Chinese
Injectable No.1 is being used mainly in China; it has good efficacy when doubling the dose in
the first month of use.
The most promising once-a-month
Cyclofem/ Lunelle and
combined injectable Contraceptives at present are
Mesigyna. Both preparations are highly efficacious and compare
favourably with the efficacy of other available. One major advantage of both these once-amonth injectables is much better cycle control than with the 3-monthly injectable DMPA.
Cycloprovera/Cyclofem, combines 25mg of progestogen MPA and 5mg estrogen ethinyl
estradiol cypionate.
WHO in
The Upjohn Company developed Cycloprovera and turned it over to
1984. Lunelle containing the same combination
is marketted by Pharmacia
Pharmaceuticals USA and is registered in USA and few other countries and is available in
Indonesia and other countries as Cyclofem.
Mesigyna, developed by
valerate.
WHO, combines 50mg NET EN and 5mg estrogen estradiol
Schering AG is handling registration, distribution, and marketing of Mesigyna.
Mesigyna is manufactured in Mexico and has been registered in Argentina and Brazil as
well as Mexico.
Introductory trials of Cyclofem have been conducted in Chile, Indonesia, Jamaica, Mexico,
Thailand and Tunisia and many other countries
It is expected that the addition of a once-a-month combined injectable contraceptive to the
existing cafeteria of family planning methoos could possibly increase the
contraceptive
prevalence. However, one disadvantage of the monthly injectable is the need for frequent
visits and would also increase the staff work load. If well planned and with proper selection
of the users and with good counseling, the introduction of a once-a-month injectable
contraceptive should offer another useful family planning option for the couples.
In a WHO comparative multicentric study of Cyclofem and Mesigyna, a total of 2320 women
were recruited from 17 centres from Africa, Asia and South America (1108 Cyclofem, 1152
mesigyna). The data from over 1 year Follow up was collected; 10,969 woman months for
Cyclofem 10,608 women month for mesigyna.There was no significant difference between
the two
preparations.
occurred with mesigyna.
There was no pregnancy with Cyclofem
Discontinuation rate with
and two pregnancies
both the preparations were around
36/100 women users. There was some deviation from the normal menstrual pattern for
both these
preparations, eg. 23.3 and 25.2%
experienced rregular bleedings with
Cyclofem and mesigyna respectively and 13.3 and 11.0% of Cyclofem and mesigyna users
experienced prolonged bleedings at 3-6 months of use. Moreover
63% women had
acceptable bleeding pattern during the same period. Discontinuation
due to bleeding
irregularity and amenorrhea has been low in WHO trials; 6.3 and 7.5 % for Cyclofem and
mesigyna discontinued due to heavy /prolonged or irregular bleedings and 2.1 & 1.6%
discontinued due to amenorrhea at 12 months.
2
Trials with Cyclofem and Mesigyna have also been carried out in Egypt and China. All the
studies indicate
that both the preparations were highly effective and there was
no
significant difference between the two groups.
ICMR carried out a phase III clinical trial with once a
month injectable contraceptive
Mesigyna v/s two monthly injectable contraceptive NET-OEN 200 mg. The result indicated
that the monthly injection was found to be equally efficacious as two monthly injection
(pregnancy rate of 1.1/100 users at 1 yr). Although subjects using monthly injections had
better bleeding pattern as compared
to two monthly injectable but the
due bleeding related reasons were similar with both the
discontinuations
preparations, whereas the
WHO trials indicated better continuation rates with monthly injectables.
In order to study the efficacy , side effects and acceptability of monthly injectable
contraceptive Lunnele/Cyclofem in our population a clinical trial was conducted through
our network of Human Reproduction Research Centres (HRRCs) with the following :
Objectives
To
evaluate the contraceptive efficacy,
side
effects,
continuation rate and the
bleeding pattern of one monthly injectable contraceptive.
To assess women’s perception for monthly injectable contraceptive.
To study the return of fertility after discontinuation of the method .
Methodology
The study was carried out at 15 HRRCs of the ICMR through cafeteria approach.
Women attending family
planning clinic of
the
methods were given balanced presentation of the
participating HRRCs
advantages
seeking spacing
& disadvantages of the
currently available methods in the clinic namely IUD, OC, Condom, Sterilisation (Male &
Female) and one monthly injectable contraceptive Lunelle / Cyclofem. Pamphlets in local
languages and pictorial charts were used to explain the methods to the women. Special
efforts were made to find out whether they have
understood
the advantages &
disadvantages of the methods and help them to make right choice. Women were enrolled in
this study who accepted Lunelle / Cyclofem as a method of spacing after Screening for
inclusion / exclusion criteria.
3
All women accepting Lunelle signed an informed "consent form". A thorough systemic
and pelvic examination was performed to exclude conditions listed in subject exclusion
criteria.
Haemoglobin estimation (done by
cyanmethhaemoglobin
method), urine for
albumin and sugar, B.P. and weight was recorded at registration and at three monthly
follow-up for a period of one year. Each women was provided with a menstrual diary
card to record the bleeding pattern and bring it along with her to the clinic for follow up and
for subsequent injections.
Injection Lunelle / Cyclofrm was given within five days of LMP / MTP as deep intramuscular
injection in the Deltoid / Gluteal region (gluteal maximus) or anterior thigh.
Women were
instructed to come for subsequent follow-up and administration of Injection of Lunelle /
Cyclofem at one monthly interval (28-30 days) ± 3 days.
Women were informed that they
would receive 12 injections provided she does not discontinue the method earlier for any
reason. All subjects who discontinued the use of Lunelle / Cyclofem and did not opt for any
family planning method including conventional methods were followed up for one year for
Return of Fertility. Those women who became pregnant (method failure) during the follow
up period of the study and continued with the pregnancy were followed until delivery to
record the pregnancy outcome. Women who did not wish to continue with the pregnancy
were offered medical termination of pregnancy. Special efforts were made to ensure that all
women are followed up at home by the Social Worker if they failed to report to the clinic for
any reason. To ensure this, the women's address as well as address of near relatives or a
friend was clearly recorded at the time of registration so that even if the subject migrated to
other place without information to the clinic she could be traced and followed up.
At any point during the trial if the women wanted to discontinue the injections she was
allowed to do so.
However, efforts were made not only to ascertain the actual reasons for
discontinuation but also to provide her with alternative method of contraception (whenever
injection was discontinued for reasons other then planning pregnancy).
As expected with combined Injectable Contraceptives bleeding problems are expected to be
few.
However,
some bleeding
irregularities are expected
in women
using these
contraceptives. If the women had amenorrhoea of more than 45 days urine pregnancy test
(mandatory) was performed to exclude pregnancy and reassure her that she is not pregnant.
In case of bleeding irregularities women were examined/reassessed and reassured. She
was provided with haematinics if she wished to continue with the method.
Women were
also provided with "Health Care" cards for all illnesses including those unconnected with
monthly injectable contraceptive use so that they are assured of good quality health care
4
services. This ensured a regular and timely
follow-up for
subsequent injections
reporting of any side effects or complications during the use of this method.
CRITERIA FOR SUBJECT SELECTION:
Subjects were recruited in this study only if they met the criteria specified below.
Married women exposed to the risk of pregnancy if they met the following criteria:
1.
Willing to participate in the trial.
2.
Age between 20 - 38 years.
3.
Has at least one living child.
4.
Had not used any long acting hormonal contraceptive for last 6 months.
Regular menstrual period (28 + 7 days).
5.
a.
If interval case, then menstrual cycles of 28 ± 7 days during last 3 months.
b.
If post delivery case who is not lactating, then at least two menstrual periods
following delivery with an interval of 28 ± 7 days.
c.
If post MTP, then either concurrent with MTP (first trimester) within 5 days
or after one menstrual period within 35 days of MTP. If first period after
MTP does not occur within 35 days then wait till
normal menstrual period
i.e., one cycle of 28 ±7 days.
d.
Lactating women enrolled after 6 months of delivery provided she has
at least one menstrual period following delivery.
e.
For those who had discontinued IUD or Oral Pills or any other steroidal
hormone at least two menstrual periods i.e., one cycle of 28 + 7 days after
discontinuation.
7.
8
Ability to maintain menstrual diary card.
Living within a distance of 10 km. from the HRRC, i.e. accessible for
follow-up for home visits.
9
Is judged to be co-operative for clinical assessment and clinic visits on
scheduled dates and is agreeable to home visits by Social Worker.
The following were the contraindications to the use of Lunelle/Cyclofem injection:
1,
Suspected pregnancy
2.
History of menstrual disorder (s)
3.
History of Thromboembolic disorders.
and
4.
Jaundice (during last 6 months) or during any pregnancy.
5.
Severe liver disease.
6.
Diabetes Mellitus.or any other metabolic disorder
7.
Heart disease.
8.
Hypertension (systolic> 130 mm/Hg, (diastolic>90 mm/Hg).
9.
Tuberculosis / Leprosy.
10.
History of allergies (e.g. Asthma, hay fever).
11.
Known or suspected malignancy any where.
12.
Depression, epilepsy,migraine.
13.
On Rifampicin, Phenytoin or Butazolidine.
14.
Haemoglobin less than 8 gm %.
15 . Cervical Cytology dysplasia moderate/severe.
16.
Known or suspected pregnancy
SAMPLE SIZE
The reported pregnancy rate with Lunelle/Cyclofem is 0.2 to 0.7 per 100 users at one year.
To estimate a pregnancy rate of 0.5 per 100 users (with an absolute error of 0.5 per 100
users ) the sample size required is 764 cases (a = 0.05 ).The reported continuation rate is
55 to 80 per 100 women. Assuming a continuation rate of about 65 per 100 users at the end
of one year, a sample of 1200 women will be adequate for the study.
Enrolment procedure:
The subject were screened for suitability for inclusion in the study after they volunteered to
use Lunelle/Cyclofem after being informed of the nature of the study and after signing the
informed Consent Form.
Complete medical history was recorded to ascertain any conditions listed in the exclusion
criteria.
A full medical and gynaecological examination was performed to ascertain the
suitability for inclusion in the study. Blood sample were taken for haemoglobin estimation
and urine examination was done for albumin and sugar. A pap smear was also taken at the
time of admission and at 6 monthly thereafter.
If the subject was found suitable to enter the study, the rponthly injectable contraceptive
Lunelle / Cyclofem was given within 5 days of onset of menstrual period taking first day of
the menstrual bleeding as day one
or concurrent with MTP or within 5 days of MTP.
Lunelle / Cyclofem was administered by deep intramuscular injection by a sterilised
6
disposable syringe following all a septic precautions. If the subject was not menstruating at
the time of screening, she was asked to report to the clinic within 5 days of the next
menstrual period. The subject was admitted to the study only after administration of the
injection and not in advance.
The registration record was completed at the time of
enrolment.
The study subjects were provided with a menstrual diary card and were explained how to fill
it accurately. The subjects were given appointment to report to the clinic at one monthly
interval (± 3 days) for the next injection provided she did not require to report earlier for any
other reason (unscheduled visit).
Follow-up procedures
Each women was followed up at one monthly interval for a period of 12 months for giving
injections and for return of fertility for another period of 12 months, if not using any method
of contraception, if women discontinued earlier for any reason she wasl also followed for
return of fertility and pregnancy outcome.
Each study subject was examined at the prescribed intervals. At each follow up visit, details
were obtained on the subjects menstrual history since her last visit and recorded on the
follow up form. Each subject was asked for symptoms or complaints that she can recall since
her last visit.
For each subject
breast examination, systemic examination and pelvic
examination was perfrmed after every three months. Blood pressure and weight were also
monitored regularly. Haemoglobin was estimated at 6 monthly interval or earlier if clinically
indicated.
Cervical cytology was repeated at 6 monthly interval ie. at admission, at 6 mths and at the
last injection (11 month) or earlier if clinically indicated.
Non-specific questions were asked, e.g. “How have you been since your last visit" If she
volunteers any complaints the same were recorded. Efforts was made to contact women if
overdue by more than two days
by making home visits by a health visitors/social worker.
Vigorous adherence to follow-up dates was done to minimize discontinuations due to “ Lost
to follow up" and "late for follow-up “. The women were encouraged to report to the clinic on
any day in case she has any complaints or side effects.
The filled menstrual diary card was collected and new one provided to record the menstrual
data.
A follow-up appointment was given and
it was emphasized
to come back to the clinic
within the stipulated date so as to avoid failure of the method.
Criteria for discontinuation
(i)
Discontinuation of a subject:
It is conceivable that Lunelle/ Cyclofem may be discontinued before the prescribed duration
due to side effects or method failure. If the subject develops any condition during use listed
under contra-indication, she was advised to discontinue the use of Lunelle/Cyclofem and
alternative method provided.
In addition the subject may request discontinuation for
planning pregnancy, switch over to other methods or for any other reason. If woman desired
to discontinue no further injections were given to her and the reasons for discontinuation
appropriately elicited and recorded in the data recording forms.
(ii)
Discontinuation of centre
The center to be discontinued from the study if women who are “late-to-follow-up” or “Lost to
follow up “exceed more than 10% in either category .
(Hi)
Discontinuation of the study
In order to safeguard against an unexpectedly high method failures, the number of women
becoming pregnant during the use of Lunelle 7 Cyclofem was monitored very closely.
The study to be discontinued if the lower limit of 95% confidence interval of cumulative life
table pregnancy rate exceeds 3 per 100 users. This was to come into effect only after (a)
100 women have enrolled in the study or (b) 1200 women months of experience has been
observed.
ADVERSE REACTIONS - In case of occurrence of any life threatening side effects directly
related to the method use, the women were instructed to report to respective HRRC who in
turn would report to the ICMR Hqrs, further Lunelle / Cyclofem injection was stopped and the
women were appropriately treated and closely monitored.
8
PREGNANCY - Any suspicion of pregnancy (amenorrhoea more than 6 weeks) it was
confirmed by a urinary pregnancy test or ultrasound. If confirmed, the pregnancy report form
duly filled was to be sent to ICMR Hqrs by fax or e-mail. Further injections of Lunelle were
stopped and woman advised to undergo MTP.
Return of Fertility:
All the women
who did not adopt any method of contraception after discontinuation of
Lunelle and were exposed to the risk of pregnancy were followed up at three monthly
intervals for return of fertility for a period of one year. Women who became pregnant were
followed up for outcome of pregnancy.
ETHICAL ASPECTS:
Toxicological studies have shown that monthly injectable has no toxicological risk to the
subject. Prior to the initiation of the study, approval has been obtained from the Toxicology
Review Panel, the Central Ethics Committee of ICMR and the Drugs Controller General of
India. All the participating centres obtained clearance from their local Institutional ethical
committees.
Results:
A total of 63784 women attended family planning clinics at 15 HRRCs of the Council, out of
these 26856(42.3%) accepted Tubectomy, 116(0.2%) couples opted for the Vasectomy ,
25% accepted Condoms, 15.8 accepted IUD, 14.7% accepted Oral pills and monthly
injectable Cyclofem was opted by 1330 (2.1%) of total family planning seekers (Table 1).
Table 1 : Relative acceptability
No of Subjects
%
Tubectomy
26856
42.3
Vasectomy
116
0.2
IUD
10049
15.8
Oral Pills
9358
14.7
Condoms
15865
25
Monthly injectable
1330
2.1
Others
218
0.3
9
Total acceptors
163784
A total of 1330 women have been enrolled in the study. Mean age of acceptors is 26.0±4.1
years and mean parity of 1.8±1.0. Mean weight and height of acceptors is recorded as
48.2±10.9 kgs and 152.3±17.7cms respectively. 87% of the acceptors are literate and 17.8%
are employed (Table 2).
Table 2: Profile of acceptors
No of acceptors
1330
Mean age (yrs.)
26.0 + 4.1
Literate (%)
87
Employed(%)
17.8
Mean Parity
1.&J 1.0
Mean age of youngest child (mths)
27.9 + 24.1
Mean weight (kgs)
48.2 + 10.9
Mean Height (cms)
152.3+ 17.7
These women have been observed fora total of 11518 women months of use. 539 women
have completed one year of use i.e. have used 12 injections. The continuation rates at 6, 9
and 12 months are 79.2, 73.9 and 70.3 per 100 users respectively (Table 3).
Table 3 : Continuation rate per 100 users
6 months
9 months
12 months
Continuation rate
79.2 %
73.9 %
70.3 %
Woman months of use
6759
9446
11518
No. of women completed
1056
953
539
Majority of the users discontinued the method due to personnel reasons 4.7, 7.0 and 8.4 at
6,
9 and 12 months of use. In contrast to progestin only methods discontinuation rates due to
10
menstrual irregularities was very less i.e. 9.2 per 100 users at one year. Discontinuation rate
due to ammenorrhoea was 2.2, 2.4 and 2.7 at 6, 9 and 12 months, discontinuation due to
heavy and prolonged bleeding were 1.9, 2.1 and 2.7(Table 4).
Table 4 : Net Cumulative discontinuation rate per 100 users
Pain at injection
0.1 ±0.1
0.1 ±0.1
0.1 ±0.1
Infection of injection site
0.3 ±0.1
0.3 ±0.1
0.3 ±0.1
Involuntary pregnancy
0.0 ±0.0
0.0 ± 0.0
0.0 ± 0.0
All menstrual reasons
7.1 ± 0.7
8.0 ±'0.8
9.2 ±0.9
Other medical reasons
2.2 ±0.4
3.5 ± 0.6
3.7 ± 0.6
Planning Pregnancy
0.7 ± 0.2
0.8 ±0.3
1.4 ±0.4
Opting permanent method
0.5 ± 0.2
0.8 ±0.3
1.1 ±0.3
Opting for other FP method
0.7 ±0.3
1.1 ±0.3
1.7 ±0.4
Other personal reasons
4.7 ± 0.6
7.0+0.8
8.4 ±0.9
Late for F.U
2.0+0.4
2.7± 0.5
2.7 ± 0.5
Lost to F.U
0.9± 0.3
1.2±0.3
1.2±0.3
Menstrual data on 1118 women was analysed and normal bleeding pattern (menstrual cycle
of 25 -35 days) was observed in about 38 per cent of acceptors and reduced infrequent
' bleeding was observed 60 per cent of the women. Infrequent and reduced bleeding did not
result in women discontinuing the method. No method failure has been reported in this
study. Discontinuation rate due to other medical reasons is 2.2, 3.5 and 3.8 at 6, 9 and 12
months( Table 5)
Table 5 : MEDICAL REASONS FOR DISCONTINUATIONS
Nausea, Giddiness and vomiting
7
High Blood Pressure
6
Rashes and itching
2
Dysmenorrhoea
2
Painful boils present at vulva
1
Weight gain
3
Breast tenderness
3
Atypical Squamous cells in cytology
1
Hair loss
4
Others
23
Total
52
Few women (116) discontinued from the study due to personal reasons like transfer to other
city (56), husband separated (18), objection from family members (16) and illness of the
husband (12) were the major personal reasons for discontinuations (Table 6).
Table 6 : Personal Reasons For Discontinuation
Husband illness
12
Transfer
56
Husband separated
18
Family objection
16
Religious reason
2
Feel shy for examination
1
Others
11
Total
116
33 acceptors could not come to the clinic at the scheduled,time for taking injection due to
illness in the family (5 cases), being out of station for social commitments (27 cases) and
family problem (1 case) Table 7.
Table 7 : Reasons for Late for follow-up
(28 to 33 days)
Illness in family
5
Out of station
27
Family problem
1
Total
33
Return of Fertility
■
,
All women discontinuing the use of the monthly contraceptive injection Cyclofem and
not
using any contraceptive method (exposed to the risk of pregnancy) were followed up for a
period of 12 months for return of fertility and outcome of pregnancy. A total of 223 women
12
were enrolled who have met the above criteria but majority of them accepted another FP
method after completion of study period and a total of 23,women were recruited for the
return of fertility as they met all the criterion for enrollment ie not using any method of
contraception and exposed to the risk of pregnancy. Out of these 23 women , all became
pregnant at the end of 12 months(mean 5.5 months) earliest at 1 month and the last at 12
months after discontinuation. Out of these 23 pregnancies 21 delivered normal live babies,
1 was a still birth and 1 women opted for termination of pregnancy( 8wks).
Vaginal bleeding patterns
The menstrual pattern was analysed using the approach recommended by Rodriguez et al.
Analysis has been done on 4 different menstrual bleeding indicators given below:
No of bleeding runs: Number of times the women starts bleeding in a reference period of
90 days. 2- 4 bleeding runs are taken as normal.
No of bleeding days: Gives the total number of days in which the menstrual bleeding
occurs in a reference period of 90 days. 6-20 days of bleeding are considered normal.
Average episode length: Gives the number of days after, which the next cycle starts. A
period of 22-35 days is considered normal in a reference period of 90 days.
Based on the above-mentioned indicators, another indicator is generated which summarizes
the bleeding pattern of a subject in a given reference period.
Frequent/prolonged bleeding: if a subject has either of the following:
1.
-
Bleeding runs > 5 number.
-
Average episode length < 21 days
-
Total bleeding days >20 days
-
Longest bleeding run >10 days
Reduced/infrequent bleeding: If the subject has none of the above but has either of the
2.
following:
Bleeding runs 0-1
3.
Average episode length > 35 days
Total bleeding days < 5 days
Acceptable/normal bleeding pattern: If the subject has none of the above.
Result of analysis of Menstrual Bleeding Pattern:
62.5% of the women using Cyclpfem had 2-4 (normal) bleeding runs in the first reference
period and increased to 70.3% at the end of 4th reference period (Table5).
54.6% of women had normal number of bleeding days (6-20) in a reference period which
increased to 61.7% at the end of 4th reference period- Average episode length (22-35) was
'13
seen in 35.3% of the women at 1s’ reference period which increased to ,46.8% at the end of
4th reference period.(Table-5), the data reveals that only 2.4 % women have frequent I
prolonged bleeding in 1 year use of Cyclofem. The majority of the acceptors have either
normal bleeding pattern (41.5%) or reduced I infrequent bleeding pattern (56.2%) (Table 5).
Table 5: VAGINAL BLEEDING PATTERNS OF CYCLOFEM USERS
Number of Reference Periods (each reference period = 90 days)
PARAMETERS
1st (3 mths)
2nd (6 mths)
3rd (9 mths)
4th(12mths)
No. of Diaries
1136
954
831
507
.0
13.6
I.13-3
1Q.3
11.6
1
21.4
14.8
16.7
16.5
2-4
62.5
70.5
71,6
70.3
5+
2.5
1.4
1.3
1.6
Mean ± SD
2.0 ± 1.3
2.2 ±1.2
2.2 ± 1.2
2.1 ± 1.2
No. of bleeding runs (%)
No. of bleeding days (%)
0
13.6
13.3
10.3
11.6
1-5
29.8
21.9
25.8
25.9
6-20
54.6
63.3
62.8
61.7
21 +
2.0
1.5
1.1
0.8
Mean ± SD
6.9 ±5.4
7.8 ±5.3
7.5 ±4.9
7.2 ±4.9
. 1-21
4.8
rj6
2.2
2.0
22-35
35.3
46.9
46.7
46.8
36-63
34.7
23.7
25.0
27.5
64+
25.2
25.9
26.1
23.8
Mean ±SD
63.1 ±62.7
70.6±76.7
70.4 ±77.8
65.0 ± 73.4
Average Episode Length (%)
Summaries of Bleeding pattern%
Frequent/prolong
7.3
5.2
3.4
2.4
Normal (Acceptable pattern)
29.4
42.3
41.6
41.5
Reduced/ infrequent
6313
52.4
55.0
56.2
Discussion :
14
Combined injectable contraceptives containing both progesterone and Oesterogens
were developed to overcome menstrual
irregularities which was commonly seen with
progesterone only contraceptives(l). Two very popular combined preparations Mesigyna
and Cyclofem have been clinically evaluated and programme introductive studies have
already been undertaken in different parts of the word including Latin America. Another
popular monthly injectable contraceptive Chinese No. 1 is vqry popular in China. Combined
once-a-month injectables contain a synthetic oestrogen in addition to protestogen.
This
allows them to keep the contraceptive effect of progestogen together with the added benefit
of oestrogen to provide bleeding simulating regular menstrual bleeding. Different combined
once-a - month injectable contraceptive formulations have been evaluated and used over
the last four decades. In China and neighbouring countries, the so-called injectable No. 1
has been developed,is made up of 17 a hydroxyprogesterone caproate and estradiol
valerate, and this has been used by approximately 1 million women throughout the world (2).
Deladroxate, an injectable formulation made up of dihydroxyprogesterone acetophenide and
estradiol enanthate, has been used for years in Latin America (3,4), It is known in different
countries under the names of Perlutal, Unalmes or Agurin. Two new combined once-a-
month injectable contraceptives have been studied by the WHO and others during the last
20-30 years, namely Cyclofem (previously known as , Cycloprovera) and Mesigyna
(registered in some countries as Norigynon).
Safety and efficacy studies for Cyclofem
began in 1968 and the first clinical trials with Mesigyna started in 1974.
Subsequent
introductory studies of these two combined injectable contraceptives, carried out in different
countries, confirmed the results of the clinical trials and supported their commercialization.
Cyclofem and Mesigyna have demonstrated benefits and advantages compared with other
once-a-month injectables, as indicated by the multicentre studies carried out by the WHO,
and they are currently being accepted by an ever-increasing number of countries as a good
and effective contraceptive option for women opting for spacing methods (3,5,6)
Once-a-month combined injectables
1.
Cyclofem / Cycloprovea : 25 mg. medroxyproges terone acetate and 5mg estradiol
cipionate.
2.
Mesigyna / Norigynon : 50 mg NET-EN and 5 mg. estradiol valerate.
Both preparations are administered by deep intramuscular injection.
The first dose is
administered during the first 5 days of menstrual bleeding and thereafter every 30 days, plus
or minus 3 days. None of the Cyclofem and Mesigyna studies have found them to induce
any adverse or clinically relevant metabolic changes. Once-a-month combined estrogen and
progestogen injectables do not cause any significant delay in return to ovulation.
Use in the post partum period
15
Progestogen only injectables have not shown any adverse effects on lactation with regard to
quality of the milk, duration of lactation and infant growth(7,8,9,10).
However, the
progestogen is present in maternal milk in the same concentration as in maternal plasma.
DMPA reaches concentrations of 10 ng/ml in the first'week after its administration,
decreasing to 0.5 ng/ml in the third month. The concentrations of NET-EN in maternal milk
are lower than those of medroxyprogesterone because of the 19 nor derivatives which are
less soluble in milk.
The estimated daily progestogen dose ingested by the infants of
mothers using progestogen only injectable contraceptives is 0.3-10 microgram DMPA and
0.5-2.4
microgram NET-EN.
These amounts have been estimated by taking the
concentrations in maternal milk and assuming that the infant ingests 600-700 ml. milk a day
(11,12).
No health problems were found in children whose mothers had used these
methods, but the possible long term effects on neuroendocrine mechanisms regulating the
reproductive process are not yet fully understood. More studies and long term follow up are
required to answer this questions ..
Oestrogen containing once a month combined injectables would behave- in the same way as
the oral combined contraceptive pill and are therefore not recommended during this period
due to their possible adverse effects on the duration of lactation and infant growth.(13,14)
WHO accelerated the development of Cyclofem for use in developing countries in response
to request from India, Mexico, and other countries in the 1970s for a safe and effective
monthly injectable (1). Today Cyclofem is available in 18 countries, mostly in Latin America
and Asia (31).
While even the newer combind injectables have been on the market for years, they have
become more widely known and used in recent years because new safety and effectiveness
data have become available. The US FDA has approved Lunelle, although it is currently not
available in the US (31). It delivers 25 mg of MPA and 5 mg estradiol cypionate.
The following discussion focuses on the newer combined injectables: Cyclofem®
(also
known as Lunelle®, Lunella®, Cyclo-Provera®, Novafem®). Combined injectables have
been studied since the 1960s, and several formations have been used in some countries for
the past two decades. Older combined injectable formulations that are still in use include
Chinese Injectable No. 1 (also known as Gravibinon®) and deladroxate (available in Latin
America under various trade names, including Pelutal®, Patectro, and Topasel®) (1,5).
16
In order to study the efficacy, side effect and acceptability, the Council initiated a
Phase - III Clinical Trial in 15 HRRCs located in the dept of Obs/Gynae of the medical
colleges in different parts of the country from 2001-2005
Efficacy
Both progestogen only injectables and once a month combined injectables are highly
.effective, with pregnancy rates between 0.1 and 0.4 after 12,months (5,15,16). The efficacy
of the injectable methods depends on the timing of the first injection, adherence to the
schedule and on the injection technique. A study carried out in Thailand shows that delaying
the first injection from the fifth to the eighth day of the cycle, increases the pregnancy rate
from 0.16 to 0.62 after 3 months of use (17).
The maximum delay for the next DMPA
injection should not exceed 2 weeks, 1 week for NET-EN and 3 days for the once a month
injectables.
In a programme introductive study done in Mexico on 3,457 women and
observed for 20,316 women months of use found only one pregnancy (rate 0.03%) (18).
This is comparable to what we observed in our study , no pregnancies have been reported
shows that the method is highly efficacious. In a systematic review by the World Health
Organisation of the once a month injectable contraceptives found the life table pregnancy
rates in 5 Phase-Ill Clinical Trials in which 9,793 women were observed for a total of
.102,058 women months of use were 0.2% for Cyclofem anpi 0.4% for Mesigyna (19). In a
review by Koetsawang have found
that monthly injectables to be very effective for
preventing pregnancy( 0.23 /100 women years of use).(16)
In an open label, non
randomised, parallel, controlled study compared the efficacy of Lunelle and Orthonovem
oral contraceptives conducted in the USA found no pregnancies in Lunelle users as
compared to 1 pregnancy reported in the Oral Contraceptive users.(20)
In a large
multicentre WHO sponsored introductory study of Cyclofem in Indonesia, Jamaica, Mexico,
Thailand and Tunisia revealed it to be highly efficacious with 12 months pregnancy rates
ranging from 0 to 0.7% (21).
In a review by Peter Hall and others of WHO
reported
Cyclofem to be highly efficacious in preventing pregnancies.(22) Another WHO sponsored
Phase-Ill Clinical Trial with Cyclofem in which 2,328 women were observed for a total of
10,969 women months of use found no pregnancies as compared to cumulative life table
pregnancy rate at 12 months of 0.18 per 100 users with a combination of norethistrone
enantate, 50mg and estradiol valerate 5 mg423)
In a comparative Phase-Ill Clinical Trial of
2 injectable contraceptives DMPA and Cyclofem in 600 Vietnamese women randomized
revealed no pregnancy during the study period.(24)
In a large multicentre comparative
clinical trial of Mesigyna, Cyclofem and injectable No. 1 in Chinese women showed that out
17
of 990 women who used Cyclofem, the life table pregnancy rates were 0 as compared to
0.4% with Mesigyna and 0.77% with injectable No. 1 showing very high relative efficacy in
women using Cyclofem.(25)
Acceptability
In a programme introductory study conducted with Cyclofem in Mexico in which
3457 healthy women participated (645 women from rural area and 2817 women from urban
and suburban areas) were observed for a total of 20316 women months of use over a period
of one year. The overall continuation rate was 36.6% in rural areas and 23.7 % in urban and
suburban areas. The most common reason .'or discontinuation was loss to follow up as the
women had changed their address and shifted to new places.(18) In our study the
continuation rates was observed to be 79 per 100 users at six months and 70 per 100 users
at the end of one year, which indicates a very high acceptability of the method in the
teaching hospitals where good motivation and counseling skills are available through the
trained research staff.
Another study on acceptability conducted in Cairo (Egypt) between Nov. 89 to July 92 on
1091 women using Cyclofem and Mesigyna. The overall continuation rates was more than
60% with the range of 45 to 87 in different locations. The logistic regression analysis showed
that the most important determinant of discontinuation was service dissatisfaction, the others
being desire for pregnancy and other personal reasons. (26)
A programme introductory study conducted in Indonesia between March 90 and Feb 92
showed a life time continuation rate of 80 and 66 percents at the end of 6 month and one
year respectively. Personal reasons accounted for most discontinuations followed by desire
for pregnancy and loss to follow up. (27)
In a study conducted in Egypt on a sample of continuous and discontinuous of monthly
injectable contraceptive Cyclofem and Mesigyna as well as with the providing physicians.
Providing dedicated staff and counseling were crucial to the success of clinical trial. The
most satisfied users were those who had tolerated well the oral contraceptives but had
difficulty in daily compliance.(26)
Side effect of injectable contraceptives
Irregular bleeding
Irregular bleeding is the main side effect of progestogen only contraceptive methods. The
initial use of injectables may cause irregular unpredictable bleeding,, with or without
intermittent spotting. Only 10% of women who use DMPA report normal cycles during the
18
first year of use. Irregular bleeding is usual during the first 6 months, followed by delayed
bleeding and / or amenorrhoea in the month: thereafter.
Menstrual irregularities with NET-EN are similar but of a lower intensity.
The rate of
discontinuation after 1 year is estimated at 15% due to irregular bleeding and 12% due to
amenorrhoea, but these figures vary considerably from one area to another.(5,15,25)
Once a month combined injectables
There are no major differences between the bleeding patterns of cyclofem and mesigyna
users.
During 10-15 days after the first injection, most women have a bleeding pattern
similar to menstrual bleeding and then they will bleed very 30 days in a regular manner,
differentiating once a month combined injectables from progestogen only injectables. During
the first 3-6 months of use, only 25% of women experience 'some form of irregular bleeding
and 12% develop prolonged bleeding. The discontinuation rate due to irregular bleeding is
between 5 and 12% per year. (5,28)
The most common side effects observed with Injectable contraceptives are menstrual
irregularities which includes irregular and prolonged bleeding, heavy bleeding and in
frequent bleeding. The idea of adding oestrogen is to reduce these side effects and make
them more acceptable to women. In a large multicentre study by WHO in collaboration with
Family Planning Research Institute and Academy of Medical Science in China, 41.4% of the
women using Cyclofem had bleeding patterns similar to their untreated pattern in first 90
days of observation as compared to 63.7% of mesigyna user and 60.6% using injectable No.
1.
This
percentage increased to 67.8, 82.2 & 75.0 in the forth reference period of 90
1
■days.(2)
Between October 1988 and July 1990, a randomized multicentered Phase III Clinical Trial
was conducted in three provinces of China to compare three monthly injectable
contraceptives (Mesigyna, Cyclofem and injectable No. 1.
A detailed analysis of the
menstrual diaries of 5098 women aged 18-35 years compared the vaginal bleeding patterns
associated with the injectables.
Women
in
all three groups experienced
more
bleeding/spotting days, more bleeding episodes, shorter bleeding free intervals, and larger
variability during the first 90 days than during the following three 90-day periods. 90% of
Cyclofem users had 1-4 B/S episodes. 90% of Mesigyna users had 2-4.2 B/S episodes.
Cyclofem users had more spotting days than did Mesigyna users in each 90 day period.
Acceptable bleeding patterns predominated, on the most part in all four periods.
Acceptability increased with each 90 day period for all three injectables. Acceptability of
19
bleeding patterns was much higher among Mesigyna users than Cyclofem users. Prolonged
bleeding, followed by irregular bleeding and frequent bleeding, were the most common
bleeding disturbances.
Irregular bleeding decreased with time.
79.1% of Mesigyna and
Cyclofem users who finished the study had an acceptable pattern. 70.7% of women who
stopped for non-bleeding reasons had an acceptable pattern compared to 31.3% of those
who stopped for bleeding reasons. These findings show that Mesigyna users experienced
better cycle control and more acceptable bleeding patterns than did the users of the other
two injectables. (2)
In our study 62.5% of the women using Cyclofem had 2-4 (normal) bleeding runs in the first
reference period and increased to 70.3% at the end of 4th reference period (Table5).
54.6% of women had normal number of bleeding days (6-20) in a reference period which
..increased to 61.7% at the end of 4th reference period. Average episode length (22-35) was
seen in 35.3% of the women at 1st reference period which increased to 46.8% at the end of
4lh reference period.(Table-5), the data reveals that only 2.4 % women have frequent /
prolonged bleeding in 1 year use of Cyclofem. The majority of the acceptors have either
normal bleeding pattern (41.5%) or reduced / infrequent bleeding pattern (56.2%) . The
menstrual pattern in majority of the users indicates a shift towards normal bleeding pattern
from frequent and reduced / infrequent bleeding pattern.
In our study the other common reason apart from menstrual reasons was, other personal
reasons like transfer to another place, objection from husband/other family members etc.
which rose from 4.7 per 100 user at six month rose to 8.4 per 100 user at one year. These
rates are comparable to studies conducted elsewhere. Other predominat reson was late for
follow up to get their monthly supply of injectable. This rate increased from 2 per 100 user at
6 month to 2.7 at the end of one year.
Most of the side effects associated with the use of progestogen only injectables are
subjective and difficult to quantify. Some users gain weight during the first year of use and
some may subsequently continue to gain weight at the same rate [7-8]. (15,25) Between 3
and 19% of users report headaches or dizziness, a percentage similar to that seen in the
general population; few women discontinue this method for these reasons.
Side effects are less common than those reported with progestogen only injectables and are
similar to those reported by the users of combined pills: headaches, dizziness, mastalgia,
changes in body weight, etc. (29)
Medical reasons like Nausea, Vomitting, High Blood pressure, weight gain, breast
tenderness observed in a total of 52 cases L an acceptable number and none of these side
20
effects were serious or life threatening and were transitory. These rates are comparable to
other studies in which it was found to be decreasing with increased duration of use.
Return of Fertility
After discontinuation of progestogen only injectbales, there is generally a delay in the return
to fertility in comparison with combined pill or with non-hormonal methods. The extent of this
delay varies between different regions, communities and women. After discontinuing use of
DMPA 50% of women became pregnant in the 9 months following the last injection. After
discontinuing once a month combined injectables, ovarian function recovers quickly 39% of
women ovulated within the first 3 months and 78% within 6 months after discontinuing the
method. The return to fertility is considerably shorter with these injectables, most women
becoming pregnant during the first 6 months after discontinuing
the use of injection.
(2,7,8,13,30)
In the present study a total of 23 women were recruited for the return of fertility as they met
all the criterion for enrollment ie not using any method of contraception and exposed to the
risk of pregnancy. Out of these 23 women , all became pregnant at the
months(mean 5.5 months)
end of 12
earliest at 1 month and the last at 12 months after
discontinuation. Out of these 23 pregnancies, 21 delivered normal live babies, 1 had a still
birth and 1 women opted for termination of pregnancy ( 8wks).
Service
delivery
issues
play
an
important
continuations/discontinuations. The family planning
role
in
acceptability
and
programs which have responsive
service delivery and good quality of care in contraceptive service delivery have managed to
motivate women in accepting and continuing with method. Changes are needed in
techniques and content of counseling and information provision, technical provision of care,
training of staff, supervision, record keeping, logistics and supplies and the support from the
program and policies.
Research is required in service delivery of the injectable
contraceptives to assess managerial requirements/adaptations that would be required if
these are to be introduced on a large scale especially in the public sector. There are issues
of accessibility and availability of these contraceptives as the women will have to leave the
family and work to go to a facility to get injections on a regular basis
Conclusions
The results of the study indicate that the method is highly efficacious as no pregnancy is
reported in the study and the method is acceptable method of contraception for women
desiring spacing (continuation rate 70.3%) at the end of 1 year. The menstrual bleeding
21
pattern is not very significantly disrupted and women experience near normal menstrual
cycles.
■As the present study was conducted at teaching hospital in which trained staff and
researchers conducted the study, the continuation rates may not be replicable at other
service delivery systems. The data on return of fertility is not enough to make conclusive
inferences although the studies conducted elsewhere have shown that most women would
become pregnant within first six months after discontinuing the method. In order to validate
the results of the present study and to study other logistics and supplies, training
requirements, follow up needs and mechanisms it is imperative
that a pre- program
introductory study is carried out at the post partum (B&C) centres,community health and
primary health centres through the existing health care delivery system.
REFERENCES
1.
Newton JR, D’arcangues C, Hall PE, A review of “once-a-month” combined injectable
contraceptives. J Obstet Gynaecol. 1994;4 Suppl 1:S1-34.
2.
Snag GW, Shao QX, Ge RS, et al. A multicentred phase III comparative clinical trial
of mesigyna, Cyclofem and injectable No. 1 given monthly by intramuscular injection
to Chinese women. Contraception 1995; 51:185-92.
3.
Newton RJ, D’Arcangues C,
Hall PE. Once a month combined injectable
contraceptives. J obstet Gynecol 1994; 14 (suppl. 1): 41-53.
4.
Facts about once a month injectable contraceptives: memoran dum from a WHO
meeting. Bull WHO 1993; 77: 677-89
5.
6.
Lande RE. Popul Rep. 1995; 23(2)
Garza Flores J, Hall P Anticonceptivos injectables mensuales. In: Perez Palacios G,
Garza Flores J, Hall P, eds, Avances recientes an regulacidn de la fertilidad. Vol. 1.
Mexico: Editorial Piensa SA de CV, 1987.
7.
Zanartu J, Aguilera E, Munoz G, Peliowski H. Effeqt of a longpcting contraceptive
progestogen on lactation. Obstet Gynecol 1976; 47:174 - 6.
8.
Toddywalla VS, Joshi L, Virkar K. Effect of Contraceptive steroids on human
lactation Am J. obstet Gynecol 1977; 127: 245-9
9.
Karim M, Ammar R, el-Mahgoub S, et al. Injected progestogen and lactation. Br Med
J 1971; 1:200-3;
10.
Peralta O, Diaz S, Croxatto HB. Planificacion familiar durante el periodo de lactancia.
Rev Chil Pediatr 1989; 60 (2 Suppl): 19-23.
11.
Koetsawang S, Nukulkarn P, Fotherby K, et al. Transfer of constraceptive steroids in
milk of women using long acting gestagens. Contraception 1982; 25:321-31.
22
12.
Saxena BN, Shrimanker K, Grudzinskas JG. Levels of Contraceptive steroids in
breast milk and plasma of lactating women. Contraception 1977;16:605-13.
13.
Diaz S, Peralta O, Juez G, et al. Fertility regulation in nursing women: III. Short term
influence of a low dose combined oral contraceptive upon lactation and infant growth.
Contraception 7983; 27:1-11
14.
Peralta O, Diaz S, Juez G, et al. fertility regulation in nursing women: V Long term
influence of a low dose combined oral contraceptive initiated at day 90 post partum
upon lactation and infant growth. Contraception 1983; 27: 27-38.
15.
16.
Declaration of IMAP on injectable contraception, IPPF Med Bull 1999; 33(2).
Koetsawang S. Once a month injectable contraceptives: efficacy and reasons for
discontinuation. Contraception 1994; 49: 387-96.
17.
Gray RH, Pardthaaisong T, McDaniel EB, et al. The timing of the first injection of
Depoprovera. IPPF Med Bull 7975; 9 (5)
18.
Garaza-Flores J., Introduction of cyclofem one-a-month injectable contraceptive in
Mexico. Contraception. 1998 July..;58(1): 7-12.
19.
Facts about once-a-month injectable contraceptives: memorandum from a WHO
meeting, Bull World Health Organization. 1993;71(6):677-89
20.
Kaunitz AM, Garceau RJ, Cromie MA, Comparative safety, efficacy, and cycle control
of Lunelle monthly contraceptive injection (medroxyprogesterone acetate and
estradiol cypionate injectable suspension) and Ortho-Novum 7/7/7 oral contraceptive
(norethindrone/ethiyl estradiol triphasicP. Lunelle Study Group, Contraception. 1999
Oct.;60(4):179-87.
21.
The introduction of Cyclofem into national family planning programmes: experience
from studies in Indonesia, Jamaica, Mexico, Thailand and Tunisia. Task Force on
Research on Introduction and Transfer of Technologies for Fertility Regulation
Special Programme of Research, Development and Research Training in Human
Reproduction, World Health Organization, Geneva, Switzerland, Contraception. 1994
May;49(5):489-507.
22.
Newton JR, D’arcangues C, Hall PE., A review of “once-a-month” combined
injectable contraceptives. J Obstet Gynaecol. 1994;4 Suppl T.S1-34
23.
A multicentred phase III comparative study of two hormonal contraceptive
preparations given once-a-month by intramuscular injection: I. Contraceptive efficacy
and side effects. World Health Organization. Task force on Long-Acting Systemic
Agents for Fertility Regulation, Contraception. 1988 Jan;37(1): 1-20.
24.
Cuone DT, My Huone NT, Comparative phase III clinical trial of two injectable
contraceptive preparations, depot-medroxyprogesterone acetate and Cyclofem, in
Vietnamese women. Contraception 1996 Sep;54(3): 169-79.
25 Liskin LS, Blackburn MS. Hormonal contraception: new long acting methods.
23
Popul Rep Ser K 1987; 3.
26.Hassan EO, el-Nahal N, el-Hussein M, Acceptability of the once-a-month
injectable contraceptives Cyclofem and Mesigyna in Egypt, Contraception
1994 May;49(5): 469-88.
Pandi
27.
SP, Hadjar LN, Prihyugiharto T, Introductory trial of the once-a-month
injectable contraceptive, Cyclofem, in Indonesia. Adv Contracept. 1993
Mar;9(1):33-40.
28.
Fraser IS, Vaginal Bleeding patterns i women using once a month
injectable contraceptives. Contraception 1994; 49: 399-1120.
29.
Hall PE. The introduction of cyclofem into national family planning programmes :
experience from studies in Indonesia, Jamaica, Mexico, Thailand and Tunisia. World
Health Organisation Task Force on Research on Introduction and transfer of
Technologies for fertility regulation. Contraception 1994;49;489-507
30.
International Planned Parenthood Federation. Directory of hormonal contraceptives.
(<http://contraceptive.ippf.org/(rlyna245m2vhrijfqdj304v45)/Default.aspx>)
International Planned Federation, Accessed Oct. 30, 2003.
31.
United Sates Food and Drug Administration (US FDA), Birth control guide.
<http://www.fda.gov/fdac/features/1997/babytabl.html> Accessed Aug. 12, 2005.
24
Supply Meets Demand With
Forecasting and Ingenuity
"No product, no program,"say logistics professionals (53).
Increasing demand for injectables challenges programs to
maintain a steady flow of supplies and to respond quickly
as more clients ask for injectables. Maintaining a continuous
supply of injectables—vials of the contraceptive, needles,
Choosing which injectables to offer. Programs forecast
demand for each type of injectable that they offer. A number
of organizations involved in international family planning sug
gest carrying one or at most two injectables (142).Carry!ng
multiple injectables complicates forecasting, distribution
of supplies, training, and service delivery. Differing injection
schedules can confuse providers and clients (18,156).To avoid
syringes, and sharps containers for disposal of used
equipment—requires adequate supplies at the warehouse
and a well-run logistics system to distribute supplies to clinics
confusion IPPF recommends that programs offer one progestinonly injectable and, if available, one combined injectable (84).
and other service delivery locations (see Population Reports,
"Family Planning Logistics: Strengthening the Supply Chain,"
Series J, No. 51, Winter 2002).
Some programs offer DMPA and NET-EN because donors sup
ply them or clients ask for both (121,156,177).The two inject
ables differ in several ways. NET-EN requires more frequent
injections than DMPA, which increases costs (177). Injections
of NET-EN may be more painful because, in contrast to
Forecasting Maintains a Steady and Sufficient
Fiow of Injectables
^^orecasts of demand for injectables enable programs to
place accurate and timely orders to manufactufers/donors,
or procurement agents. With demand rising, accurate fore
casting is especially important.The most accurate forecasts
use several types of information.These include expected
increases in use of injectables (for example, as a result of a
communication campaign), past trends in use, numbers of
new and returning clients, and changes in population due to
migration. Forecasting needs to be done at least once a year
and adjusted every six months based on actual use. Stock
levels and trends in use of injectables should be reviewed
every month at service sites and additional orders placed to
maintain supplies (53).Many countries have computerized
logistics management information systems at the central
warehouse to help with forecasting (85,94) (for forecasting
tools, see Table 3, p. 22).
With demand for injectables rising, accurate
^forecasting is especially important. . 1
'
the water-based DMPA, NET-EN is oil-based and a largergauge needle is appropriate. NET-EN can be injected with a
narrower needle, but the injection takes longer to administer
and,asa result, may also be painful (175,176).
At times, switching a client's injectable may be necessary
due to supply shortages. Switching injectables is safe and
does not decrease effectiveness. Switching clients routinely
between injectables is not recommended, however (275).
When clients switch to a different injectable, the schedule for
repeat injections changes and side effects may change. Such
changes led some women in Nepal to stop using injectables,
a country assessment has reported (156).
Cooperation and Conservation Meet
Unexpected Demand
Logistics managers can plan their response to unexpected
demand for injectables.When supplies run low, managers can:
•
Forecasting several years into the future alerts programs to
potential shortfalls and helps governments and donors plan
procurements. For example, the Kenya Ministry of Health
(MOH) projects that the share of injectables in the contra
ceptive method mix will increase from 40% in 2002 to 50% in
2010. In 2003 the MOH's reproductive health advisory board
projected a shortfall of injectables beginning in mid-2004
and recommended that the MOH seek more funds from the
government and donors (158). As a result of the forecasting,
the government for the first time allocated funds in the budget
Order an emergency shipment. USAID-funded programs
can order emergency shipments of DMPA through the USAID
Mission in their country to help prevent stockouts (21).
UNFPA's Global Contraceptive Commodity Program stores
injectables and other contraceptives with their suppliers
to facilitate fast shipment in the case of stockouts and
emergencies such as earthquakes or wars.The normal,
non-emergency lead time for ordering injectables from
UNFPA is 10 weeks (91,197) (seeTable 3, p. 22).
•
Borrow supplies. When delayed shipments of
contraceptives led to stockouts at a health care facility
in Kenya, staff borrowed contraceptives from a nearby
specifically for injectables and covered part of the shortfall.
Also, a donor agreed to provide funding for injectables and
district hospital and other facilities.This was one reason
that this facility was identified as one of 13 high-performing
the MOH ordered injectables from UNFPA (97).
facilities in Kenya (157).
Mobilize suppliers, volunteers,
and shippers.When stockouts of
contraceptives plagued the national
family planning program in Nepal
in 1993, the Ministry of Health and
UNFPA organized 75 graduate
students to pack contraceptives and
other supplies for maternal and child
health. UNFPA supplied DMPA through
its commodity distribution program
(29). A private shipping company
delivered the packages by road, air,
and porter, and within 60 days every
health facility in Nepal's 75 health
districts had reproductive health
supplies (196).
Share clients. If a facility or program
is running out of injectables, it can
encourage clients to go to other
sources for their injections and save
its own supplies for those with no
other source of supply. Public and
private providers can work together to
provide injectables when either has a
stockout. Providers should be able to
An inspector at the central warehouse of the Ministry of Health in El Salvador checks that injectables are stored properly to avoid wastage. DMPA must be stored upright so that any precipitate
collects on the bottom of the vial and can be completely dissolved with gentle shaking. If a vial is
used with sediment on the bottom, the injection may not be effective for three months.
in the storage area, the vial should be thrown away (92).
give clients directions to other sources of injectables.
Injectables should be stored upright so that any sediment
Avoid losses due to passed expiration dates and ruined
stock.The First-to-Expire First-Out (FEFO) metfiod^using
supplies with the earliest expiry date first—helps to
avoid loss through expiration.The shelf-life of progestinonly injectables is three to five years, and of combined
injectables, at least three years (45,98). Injectables should
be stored between 20° and 25°C (68° and 77°F) away from
direct sunlight and protected from freezing. Changes in
temperature can affect the size and solubility of particles
in DMPA and the combined injectable Cyclofem. Usually,
any sediment at the bottom of a vial dissolves with gentle
settles on the bottom of the vial and can be dissolved
again by shaking. Heat can decrease the effectiveness of
NET-EN without changing its odor or appearance. Stock
that has been exposed to high heat, such as fire, should be
thrown away (127).
If injectables are out of stock, providers typically give clients
their second or third choice of contraceptive, or they may give
them oral contraceptives and ask them to return in a month
or more (61). Clients are more likely to stop using a contracep
shaking. If sediment does not dissolve or has collected into
tive that is not the one they wanted, however (132). Faced with
rising demand for injectables, programs and providers need
a solid mass, perhaps because of low temperatures
to look for ways of supplying clients with their first choice.
Training to Meet Demand
As demand for injectables increases, programs need more
health care workers who can provide injectables^ Staffing .
decisions and training content depend on a program's
specific needs. An assessment in advance can help to
determine who most needs training and in what (110,136).
Method Introduction or New Providers May
Require Comprehensive Training
Comprehensive training to provide injectables may be
needed if a program is adding injectables as a new method
or if a program already offers injectables but is training
new health care workers to provide them. Depending on
providers'skill levels and on program needs, comprehensive
training on injectables may include:
■
Characteristics of injectable contraceptives and the
importance of returning on time for the next injection,
•
Giving injections using the universal precautions (see p. 8),
•
Counseling clients, with emphasis on bleeding changes,
■
Screening clients using the Medical Eligibility Criteria
(see the Checklist for Screening Clients Who Wont to Initiate
DMPA (or NET-EN) in the companion issue of INFO Reports),
Give Injections and Dispose of Waste Safely
after a single use. Depending on the design, cither the needle
retracts or the plunger breaks or locks (149). WHO recommends
AD syringes for all immunizations and recommends disposable
syringes—ideally AD syringes —for all other medical injections,
including contraceptive injections (210,223). Purchased in bulk,
AD syringes cost approximately US$0.06 each, about $0.02 apiece
more than conventional disposable syringes (150, 195). USAID
began including the AD syringes with all shipments of DMPA in
2002 (95, 128).
A safe injection is one that does not harm the
recipient, does not expose the provider to any
unavoidable risk, and does not result in waste
that is dangerous to people.
As more providers give injectable contraceptives to more clients,
injection safety remains crucial (208). The spread of infection
from clients to other clients, health care providers, and the
^community can be avoided by:
Srerilizablc needles and syringes should be considered only when
disposable injection equipment is not available and if programs
can ensure that sterilization conforms to WHO guidelines. Sterili
zation of reusable syringes and needles requires heating to 121 °C
(250°F) in high-pressure steam for at least 20 minutes (14, 206).
• Ensuring an adequate continual supply of disposable
injection equipment and sharps containers for safe disposal
of needles and syringes,
• . Following safe injection practices and universal precautions
for infection prevention, and
1 '
•
Establishing a safe waste management procedure.
Safety guidelines for contraceptive injections are the same
guidelines that apply to all medical injections.
WHO delines a safe injection as one that does not harm the
recipient, does not expose the provider to any avoidable risk, and
does not result in waste that is dangerous to people (209). Of the
16 billion injections given for all purposes in developing countries
each year, nearly two in every five are thought to be unsafe (81).
WHO estimates that each year unsafe medical injections cause an
estimated 21 million hepatitis B infections, 2 million hepatitis
C infections, and 260,000 HIV infections (71). Every year these
^nfecrions result in an estimated 1.3 million early deaths, 20 years
of life lost per person, and US$535 million in medical costs (115).
Injections remain an important delivery method for curative and
preventive purposes, so improving injection safety is necessary.
Universal Precautions Prevent Infection Transmission
<
Safe injections require not only the proper equipment but also
that providers understand and follow the universal precautions for
infection control and best practices for injections (160). Developed
in 1987 by the U.S. Centers for Disease Control and Prevention,
universal precautions are a simple set of practices designed to
protect health care workers and their clients from infection in
health care settings. Under the universal precautions principle,
health care workers assume that all blood and body fluids are
infectious, regardless of actual infectiousness (192, 218).
Rules for injections include:
• Prepare each injection in a clean designated area where
contamination from blood or body fluid is unlikely.
• Wash hands with soap and water before and after giving an
injection, if possible. Gloves are not needed unless there is a
chance of direct contact with blood and other body fluids.
• Use a sterile syringe and needle for each injection. Use an AD
syringe, if possible. If only sterilizable equipment is available,
sterilize according to WHO guidelines.
In 2005 contraceptive injections accounted for an estimated 1%
of all injections. No statistics are available on the percentage of
contraceptive injections that are thought to be unsafe.
• Discard used disposable needles.and syringes in sharps
containers immediately after use. Do not recap used needles.
Auto-Disable Syringes Now Preferred
• Safely dispose of sharps waste according to local or regional
environmental regulations (80, 211, 218).
In the past it was common practice to use, sterilize, and reuse
sterilizable injection equipment. More recently, single-use syringes,
if disposed of as intended, have eliminated risk of client-to-client
transmission of infection. The latest development is disposable
auto-disable (AD) syringes. Unlike conventional disposable
syringes, the AD syringe cannot be reused because it inactivates
Proper Waste Disposal Keeps Clients, Staff, and
Communities Safe
Disposable injectable equipment can generate a large amount
of waste. Programs offering injectable contraceptives must have a
procedure in place for collecting, storing, transporting, and
disposing of sharps waste (207).
Used disposable needles and syringes should be placed
in a sharps container immediately after use to prevent
necdlestick injuries and access to used needles. When a
sharps container is three-fourths full, it should be destroyed. >
Overfilling the container can lead to necdlestick injuries.
WHO-approved sharps containers distributed by USAID
arc designed to hold 100 syringes (45). Donors promote
injection safety by “bundling"—that is, shipping matching
quantities of sharps containers with vials of contraceptive
injectables and AD syringes.
Methods for destroying sharps containers and their contents
include burial, burning, and incineration (burning at
high temperature) (128). Unfortunately, there are no
easy nonpolluting methods for destroying used injection
equipment. Programs should choose the method that
is most appropriate for their local conditions, taking
into account cost, safety risks, and local and national
environmental regulations (207, 213, 217).
•
Counteracting myths and correcting misperceptions,
•
Conducting return visits and ensuring continuity of
care (see forthcoming Population Reports,"Developing a
Continuing Client Strategy"), and
•
Managing side effects.
The time needed for training depends on the amount of
content, the initial skill level of trainees, program needs, and
policy requirements.The Pathfinder International DMPA
Training Module (seeTable 3, p. 22) covers characteristics of
DMPA, counseling,giving the injection, conducting return
visits, and managing side effects.The module is designed for
trainees to practice and demonstrate competence in each
skill. It requires about 16 hours to complete (181). In contrast,
in a pilot community distribution program in Uganda (see
p. 12), community providers who had been providing oral
contraceptives and condoms received comprehensive
injectables training that included one week of classroom
sessions and two weeks in hospitals and health centers
(123,183).
Focused Training Meets Specific Needs
Burying sharps waste in a protected pit ar least two meters
deep is a simple and inexpensive method of dispqsal. Some
programs build special pits for sharps waste near the clinic.
Pits must be fenced to prevent community members and
scavengers from entering. Encapsulation—sealing sharps
containers with concrete or other substances before burial—
can ensure that buried waste is not unearthed.
Incineration, at temperatures above 800°C (1472°F),
minimizes die volume of waste and reduces the pollutants
produced. It requires special equipment and fuel, such as
propane or natural gas. Programs with on-site incinerators
should position incinerators in a convenient outdoor
location, away from crops and homes, and far enough away
so that smoke does not blow into the facility. Where an
incinerator is not available on site, some programs transport
waste to a central health facility or use incinerators at other
facilities, such as cement factories (ISOBurning sharps waste in a metal container or a protected
hearth at low temperatures is a commonly used option! Fuel >'
such as kerosene is added to the container, and the waste is
burned until the fire goes out. After burning, the ash and
noncombusrible material are buried in a protected pit at
least one meter deep. This method is relatively inexpensive
and can reduce the weight and volume of waste (/5f).
Burning should be done only when no other options
are available since it produces harmful substances. Some
countries have banned this method of waste disposal.
Illustration: Immediately after giving the injection and without
recapping the needle, a provider deposits the used syringe and
needle in a conveniently located sharps disposal container. Safely
disposing of used injection equipment prevents accidental needle
sticks, which can lead to infection.
To meet demand quickly, programs may consider training
current staff members, such as assistant or auxiliary workers,
to give only routine repeat injections.This would free doctors
and nurses to handle special needs (see box, p. 10). A short
training course for providing repeat injections might focus
on the first three topics listed on page 7: characteristics of
injectables, giving safe injections, and counseling.
Any health care provider who is appropriately
trained can give injections safely.
Focused training also can be used to address a specific
component of service delivery that needs strengthening,
such as counseling. For example, when Vietnam was scaling
up the provision of DMPA in 1999, an assessment of an
earlier pilot project found that client visits typically involved
little counseling and that providers and program managers
believed that a woman's choice about contraceptives
was best made by the provider. As a result of this finding,
providers received focused training in providing balanced
information, listening to clients'concerns, a nd offering
individually tailored guidance.This training improved
counseling and helped women make an informed choice of
DMPA and other contraceptives (224).
Refresher training maintains skills. Regular retraining can
help maintain safe injection practices and maintain good
quality of care generally (218). For example, in a 2005 survey
of 526 nurses and midwives in Uganda, the reported fre
quency of needlestick injuries was lower among those who
had attended safe injection training in their workplace than
among those who had not had workplace training (129).
Depending on program needs, refresher training may be
offered one or two times per year (74). Retraining also may
With Training, a Range
of Providers Can Give
Contraceptive Injections
address clinic staff other than providers, such as waste
handlers (93).
Competency-Based Training Works Best
Training that develops the skills, knowledge, and attitudes
required to meet standards—known as competency-based
training—has proved more effective than conventional
training approaches, in which trainees may have little
Service delivery guidelines in some countries restrict
who can give injections. They limit provision to
doctors and nurses. Studies show, however, that many
types of health care providers can give injections if
opportunity to practice skills (185). With this approach,
training continues until each trainee is competent to provide
injectables.The training uses techniques such as role playing,
discussion, use of job aids, and simulation (93). Vietnam used
they are appropriately trained (36, 66, 183, 200).
Such providers include pharmacists, auxiliary nurses,
midwives, medical assistants, community health
the competency-based approach to training when scaling up
workers, and others who have been specifically trained
DMPA services in 1999 (224).
to provide family planning, as well as those who have
general medical education. Training a wider range of
Supportive Supervision Can Encourage
Good-Quality Services
providers to give injections safely can expand access
to injectables, reduce unsafe unauthorized injections,
and save programs money.
Supportive supervisors are those who meet the needs of
the staff they supervise, thus enabling providers to perform
In some cases, particularly when scaling up pilot
well and meet the needs of their clients (47). By giving
constructive performance feedback, supportive supervisors
can help staff correctly follow injection guidelines, improve
programs, allowing certain groups of providers to give
injectables may require changes in national policy. For
their performance, identify operational barriers, an^i
maintain standards (189).Ongoing supportive Supervision is '
particularly important when programs increase the number
of providers giving injections.
example, in Honduras service delivery guidelines did
not authorize auxiliary nurses to provide DMPA until
1999. Because an auxiliary nurse is often the only
provider at a rural health center, women in rural areas
who wanted injectables could not obtain the method
Program managers and providers together can use the
Standards-Based Management and Recognition (SBM-R)
approach to help improve performance and the quality
of services (24,125) (see Table 3, p. 22). In this approach
supervisors and staff work together to define standards
for service and performance, and they determine how to
easily. When a 1997-98 study demonstrated that
auxiliary nurses could provide these services safely
and cost-effectively, the Ministry of Health changed
the service delivery guidelines (200). As a result,
use of injectables increased 19% after three months
in clinics where auxiliary nurses began offering
meet those standards. For example, if a supervisor sees that
injection safety practices need improvement, SBM-R
can guide the supervisor and provider in (1) setting
injectables, and 35% in clinics where the auxiliary
nurses offered injectables and also promoted the new
performance standards for safe injections that detail what
ito do and howto do it; (2) identifying steps needed to meet
the standards (such as refresher training in safe injection
practices or acquiring more equipment and supplies); (3)
measuring progress; and (4) motivating the providers to
achieve objectives by offering incentives and recognizing
achievements. Supervisors can use the "Checklist for Giving
Intramuscular Contraceptive Injections"to ensure that
providers are following the appropriate steps (see the
companion issue of INFO Reports,“Injectable Contraceptives:
Tools for Providers," p. 2).
services to clients and the community (112).
Formally training those who may be giving
unregulated injections is another way to increase safe
access to injectables. For example, a 2003 study in
»
Egypt found that women frequently seek injections,
both contraceptive and therapeutic, from informal
providers, or “health barbers” (187). Because they
often charge less than the cost of a new needle and
syringe, it is likely that these providers reuse injection
equipment. In this situation, changing guidelines to
allow such providers to provide injections, training
Ongoing supportive supervision is particularly
important when programs increase the number
of providers giving injections.
them appropriately, and supplying them with single
use injection equipment could reduce the potential
for unsafe injections (86).
Checklist for Good-Quality Injectables Services
Family planning program managers can use this checklist to help ensure that
programs are providing good-quality injectables services.
inics have adequate supplies
□
Sufficient single-dose vials are available.
□
Sufficient sterile syringes and needles are available. Use disposable syringes, ideally auto-disable
(AD) syringes, if possible. If only reusable equipment is available, sterilize according to WHO
recommendations (heating to 121 °C (250°F) in high-pressure steam for at least 20 minutes).
□
Sufficient sharps containers are available for disposal of used needles and syringes.
□
Injectables are properly stored, upright and away from direct sunlight at 20-25°C (68-77°F).
□
The oldest stock of injectables is used first.
Tip: Establish a First-to-Expire/First-Out (FEFO) policy (see Pocket Guide to Managing Contraceptive Supplies*).
□
Timely supply orders are submitted.
Tip: Use PipeLine Software to assist with forecasting, pipeline management, and procurement planning?
□
A clean space is designated for preparing and giving injections, with a sharps container nearby.
Providers safely give injections and manage waste properly
□
Providers screen clients for medical eligibility.
Tip: For screening, use the Checklist for Screening Clients Who Want to Initiate DMPA (or NET-EN) in the
companion issue of INFO Reports.
□
Providers counsel clients, with particular erriphasis on side effects and how to manage them:
□
Job descriptions define who:
♦ Oversees logistics, equipment, and supplies
♦ Counsels clients
♦ Provides injections
♦ Manages waste
□
Providers and staff receive ongoing, supportive supervision.
Tip: Use the Standards-Based Management and Recognition (SBM-R) approach.*
□
Pre-service and in-service trainings are offered regularly for all staff involved in giving injections and
managing waste.
Tip: For developing training tools and job aids, use Do No Harm: Injection Safety in the Context of Infection
Prevention and Control: Training Tools and Job Aids. *
□
Guidelines are established for management of injection waste.
Tip: Use Management of Waste from Injection Activities at the District Level: Guidelines for District Health Managers*
□
All staff members follow waste management guidelines.
□
The disposal area (for example, burial pit) is in a convenient location and secure from intruders.
Injectables services are organized efficiently
□
Injectables users receive routine repeat injections without a long wait.
Tip: Set up an “express line'' for repeat injections.
Clients and the community are well informed about injectables
□
Mass media campaigns for family planning mention injectables, if possible.
□
Providers are knowledgeable about injectables and can respond accurately
and helpfully to rumors and misperceptions.
□
Printed materials about injectables are available to clients.
'For more information, see Table 3, p. 22.
I
They gave injections in their homes or at the homes of
their clients and were supervised by program and clinic
staff and district health officers (183).
Providing injectables in the community gives women
the choice of injectables in rural areas of Ethiopia,
Ghana, Papua New Guinea, Thailand, and parts of
other countries where clinics are hard to reach (8, 44,
61,101,124, 739,147). In Bangladesh community
programs serve both urban and rural areas (764).
Community programs offer injectables from mobile
clinics, village clinics, periodic temporary outreach clinics,
or at the homes of clients or community health workers.
Injectables services have been added to community
provision of oral contraceptives and condoms and offered
along with immunizations, other maternal and child health
services, and some curative services (44,183, 786).
In most countries these efforts have consisted ,
of pilot studies. Two exceptions are Bangladesh','
which used elements of the Matlab Project in the
'government family planning program, and Ghana,
which is scaling up the Navrongo Initiative in the
nationwide Community-Based Health Planning
and Services (CHPS) Initiative (138, 764).
1
'
Community provision has dramatically increased use
of injectables. In the Navrongo Initiative, for example,
contraceptive prevalence rose from 3.4% to 8.2%
between 1993 and 1999, when 92% of contraceptive
users were using injectables (44, 138). In this and other
projects, many women chose injectables as their first
modern method of contraception (44, 54, 138, 739/
In some areas of Bangladesh, however, community
provision had less of an effect on overall prevalence
because women switched to injectables from other
modern methods (66).
A study in Uganda compared the quality of the provision
of injectables in the community and in the clinic. The
study—carried out by Family Health International and
Save the Children/USA in collaboration with the Ministry
of Health (MOH) and Nakasongola local government—
enrolled 449 community clients and 328 clinic clients
and followed them up 13 weeks after their first injection
of DMPA. Clinic providers were MOH nurses, and the
community providers were local volunteers, who were
affiliated with a clinic and had been providing free oral
contraceptives and condoms in the community.
The community providers received classroom and clinical
training, and they learned to screen clients with the
help of a checklist (see Checklist for Screening'Clients »
Who Want to Initiate DMPA (or NET-EN), p. 5 in the
companion issue of INFO Reports).
Papua New Guinea. Small community programs in several countries
and large-scale programs in a few have given women in rural areas
the choice of injectables.
Community provision has dramatically
increased use of injectables in some areas.
The study compared several factors that contribute
to quality:
• Screening for medical eligibility: There were no
reported screening mistakes made by community
providers or clinic providers (182).
• Counseling: At follow-up the clients were asked
about side effects and about specific points made
by their providers. Levels of clients' knowledge of
bleeding changes, sexually transmitted infections,
and reasons to return to the clinic were the same
for community and clinic groups, and both needed
improvement. For example, 20% or less of community
and clinic clients knew that no monthly bleeding was a
common side effect of DMPA. One difference reported
by clients was that in initial counseling community
providers mentioned other contraceptive choices less
often than did clinic providers.
• Injection safety: None of the 777 clients reported
infections at the injection site, and no providers
reported needlestick injuries. Overall, 24 of the 449
community clients (5%) reported problems, compared
with 8 of the 328 clinic clients (2%). Most of the
problems were minor, such as temporary numbness
or mild pain at the injection site. Four of the eight
community clients reported severe pain. Three had
received their injection from the same provider, who
was then given more training. In the Matlab Project in
Bangladesh, an assessment reported four abscesses
in over 14,000 DMPA injections (3).
Disposal of waste: In Uganda community providers
were instructed to place used needles and syringes
into sharps containers and carry the boxes to a clinic,
where they would be burned and buried. Also, they
could throw used needles and syringes into pit latrines.
The community providers handled syringes safely, but
disposal of used syringes from both clinic and comr
munity providers needed improvement at some clinics
(182). Disposal has also needed improvement in the
Navrongo and CHPS initiatives in Ghana (1, 225).
Continuation rates: The percentages who had
second injections in Uganda were similar—-88%
among community clients and 85% among clinic
clients. Few other studies have compared continuation
rates in community and clinic programs. In one, a
Mexican study of the combined injectable Cyclofem,
the one-year continuation rate was 37% among the
640 community clients and 22% among 2,817 clinic
clients (60).
In Bangladesh continuation rates were lower in some
areas of the scaled-up government program than in
the Matlab Project. The one-year continuation rate
was 69% in the Matlab Project, in which each provider
was responsible for a population of 1,200 and visited
clients every two weeks. In eight scale-up arbas ,
»
where each provider was responsible for a population
of 6,800 and visited clients every three months or
more, one-year continuation rates in two areas were
35% and 46% (139).
On-time repeat injections: In Uganda almost all
continuing clinic and community clients received their
second injections on time, 94% in both groups. A little
more than half of community clients had their second
injection at the community provider's home, and about
one-third had the injection in their own home. The rest
had the injection either at a clinic or an unrecorded
location (183).
Many women had injections at clinics
or the homes of community providers
rather than in their own homes, most
likely to maintain privacy.
, !.
,
In trials in Bolivia and Guatemala also, many women
had injections at clinics or the homes of community
providers rather than in their own homes, most likely
to maintain privacy (709).
In the Navrongo Initiative some women choose to visit
the community provider on market days, and they
count on her to know if they need an injection or can
wait for the next visit (1).
The benefits of training last only as long as providers
remain on the job. Turnover among community
nurses has been high in the CHPS Initiative in
Ghana. Community nurses work in difficult conditions,
and some are stationed away from their families.
To improve morale, the Ghana Health Service is
increasing incentives for nurses to stay on the job
and encouraging communities to select candidates
and pay for their training. After training, the nurses
return and work in their home areas (1,138, 225).
Community providers in Uganda practice safe injection techniques.
With appropriate training, a range ofhealth care providers can
learn to give injections safely.
The cost of offering injectables and other health
services in clients' homes has been a concern in
Bangladesh. The government stopped household
services in the late 1990s and set up community
clinics to save money and increase efficiency by
offering more services at each client visit (113, 164).
The change in policy did not affect use of injectables
or oral contraceptives in general, but it may have
reduced access to health services for some poor
and uneducated women (5, 113, 164). In a survey,
over 80% of women said they valued home visits
because the community provider gave them helpful
information and their housework was not interrupted. A
new government elected in 2002 resumed, household
services (113).
Today, as pilot projects are scaled-up, community
provision of injectables challenges programs to ensure
quality of care. Hiring and retaining enough providers,
screening for medical eligibility, counseling, and waste
disposal need attention in training and supervision
(1, 66,182, 225). Tomorrow, as more countries test
and improve community provision of injectables,
more women in isolated areas will have another
contraceptive choice.
eeting Rising Demand Efficiently
Faced with limited resources,family planning programs need
to serve more users of injectables without greatly increasing
costs. Programs can increase efficiency by:
•
Organizing work to save time,
•
Getting supplies and equipment at the lowest ayailable
prices,
■
Adding outlets without building clinics,
•
Encouraging providers to decrease unproductive time
while on the job, and
•
Enabling a range of providers to give injections, as noted
(see p. 10).
Also, programs can recover some costs by asking users to pay
for injectables if they can.
Organizing Work Better Can Save Time
Improving the flow of clients through clinics allows programs
to care for more clients without lowering quality, hiring more
providers, or increasing staff hours. For example, in Guatemala
a clinic providing maternal and child health services improved
client flow after a self-assessment by staff and a survey of
clients. Clients used to wait, have a pre-visit discussion, return
to the waiting room, see the provider, return tothejwaitipg
,
room, and then have a post-visit discussion. In the improved
flow clients wait once and receive all services in one visit with
one provider.This change enabled staff to see 33% more clients
and reduced the wait for clients (28). For injectables users
returning for routine repeat injections, clinics can set up an
"express" line to save time for both clients and staff (772), while
giving returning clients the option of more time with a pro
vider if they have questions, problems, or something to discuss.
Recording clients'waiting time and providers'time spent with
clients can help programs identify problems with organization
of work.The COPE® (Client Oriented, Provider Efficient) process
developed by EngenderHealth can help to organize work
more efficiently. COPE tools include software to track the cost
of staff time and supplies (52).The NGO (Non-Governmental
Organization) Service Delivery Program (NSDP) in Bangladesh
uses the CORE (Cost and Revenue Analysis) computer
program developed by Management Sciences for Health to
model the effects on efficiency and cost recovery of changes
in client flow, prices, and staff time (133) (see Table 3, p. 22).
Programs Can Hold Down Costs of Supplies and
Facilities
DMPA and monthly injectables currently cost US$0.78 to
$0.84 per dose from UNFPA. NET-EN costs 30%-50% more
(91,797).The cost of supplies for DMPA, for example, for one
woman for one year (four injections) would be US$3.36 to
$3.60, including four auto-disable syringes costing $0.06
each. By comparison, 12 cycles of oral contraceptives at
US$0.16 to $0.63 per cycle from UNFPA would cost $1.92
to $7.56 (797). The total cost of providing
injectables, of course, includes the time
of the provider to counsel and give the
injection and the overhead cost of the
facility and equipment (see Table 3, p. 22,
for resources to estimate total costs).
To keep costs down programs can buy
supplies in bulk, set up services in existing
buildings, and share facilities with other
health services.
Procure good-quality injectables,
injectable equipment, and other
contraceptives at the lowest available
price. Programs that buy their own
commodities can get low prices by asking
for competitive bids from some of the
A distributor for a social marketing program in Kenya delivers injectables to a pharmacy.
Clients buy the injectable and take it to a health care provider for the injection. The avail
ability ofinjectables in the public and private sector is increasing in Kenya. A projected
shortfall in supplies persuaded the government to allocate funds for injectables and seek
help from donors. Many women are willing to pay for injectables, and sales in the private
sector have increased.
more than two dozen manufacturers of
injectables (83).To ensure the quality of
supplies, programs should ask for bids
only from manufacturers that have been
assessed for quality.WHO will prequalify
injectables and manufacturers by mid-2007
and will provide this information on its
Web site (http://mednet3.who.int/prequal/
default.htm) (104).
POPULATION REPORTS
Programs can also work with the UNFPA, which helps
countries procure injectables and other contraceptives
at low prices. Also,a number of procurement agents
consolidate orders from several clients to qualify for
volume discounts from manufacturers, and they ensure
the quality of the products that they order (38,127).
Adjust procurement to match demand. As users switch
to injectables from other methods, demand for qther
methods may rise more slowly or even decreAse.' lf so,
programs can place larger orders for injectables and
smaller orders for other methods. Monitoring use with
a logistics management system will indicate changes in
Checklist for Improving
0 Access to Injectables
*
To meet the rising demand for injectables, program
managers need to make it easier for women to get to
services—and without a long wait. The items in this
checklist can help to remove barriers and improve
access to injectables.
Women can get to services easily
□
demand and in the method mix and will help programs
avoid overstocking some contraceptives if demand for
them decreases.
□
Set up more outlets for injectables without building
more clinics.Injections have been given in existing
community clinics, mobile clinics.and the homes of clients
□
□
or community providers (8,61,139,183). Facilities for
giving injections need not be elaborate: a private examin
ation area, a waiting area for clients, space to store supplies
and client records, and, if possible, a place for providers to
□
wash hands (204,227).
Share cost of outreach services with other services.
Outreach services can follow the example of clinic-based
integrated family planning and maternal and,child health
Services are offered in rural areas through
community programs
.
services. In Thailand mobile clinics offered STI services. Pap
smears, and other services as well as contraceptives (8). In
rural Ethiopia teams offering DMPA, immunizations, and
antenatal care set up monthly outreach sites in a project
managed by Save the Children/USA (61). Offering multiple
services can save on fixed costs and is likely to be more con
venient for clients who need several types of health care.
□
Services are available to women who cannot
leave their homes or villages.
□
Outreach clinics are set up at least once a month.
□
Community health workers provide injectables or
refer women to accessible clinics.
Injectables are available from:
□
Some Providers Can Increase Productivity
Family planning providers in many programs are
overworked. If they are providing other services, especially
curative services, clients typically form long lines at the
In some programs, however, there may be opportunities
to increase providers'productivity and serve more clients
without increasing costs. Studies in several countries
report that providers in some public or NGO tlinlcs do1 not ‘
concluded that, with small changes in providers'schedules,
the MOH could meet demand for family planning through
the year 2010 without increasing costs or hiring more
providers. If providers increased their work time from six
to seven hours a day and increased the time spent with
clients from about 3 to 4'/2 hours a day, the cost per client
Hospitals
□
Family planning clinics
□
Maternity clinics
□
Clinics providing postabortion care
□
Private doctors and nurse-midwives (Is there a
network of private providers offering injectables?)
□
Pharmacies, including those working with social
marketing programs
clinic, and providers are fully occupied.
work a full day, and they spend less than half their time
with clients. Many spend considerable time performing
administrative duties or waiting for clients (76,88,89,133).
For example,from observations of nurses and doctors in 82
Mexican Ministry of Health (MOH) facilities in 1996,a study
Services in cities and towns are conveniently
located. They are within walking distance or close
to public transportation.
Injectables are available five or more days a
week.
Clinic hours allow women to visit without taking
time off from work
Most clients wait no more than one hour for
service.
Users of injectables receive routine repeat
injections without a long wait—for example, in an
express line.______________________________
Location of service outlets and their hours
are well known to women and their partners
Outlets are well marked. Location and hours are:
□ Publicized at public events set up to provide
information about family planning
□
Included in counseling at clinics providing
maternity and postabortion care
□
Broadcast on radio and television, if possible
□
Publicized regularly in newspapers
and magazines
□
Posted on billboards
gvoi.
’
'
J.
M
Injectables Tomorrow:
Subcutaneous DMPA
and Home Injection
A new lower-dose formulation of DMPA, depo-subQprovera
104 (also called DMPA-SC), is injected under the skin rather
than in the muscle. It contains 104 mg of DMPA rather
than the 150 mg in die intramuscular formulation.
Like the intramuscular formulation, DMPA-SC
is given at 3-month intervals.
Approved first in the United States and
the United Kingdom, subcutaneous
injection of DMPA may be available
in some developing countries by
2008. DMPA-SC is available only
in prefilled, single-use syringes.
In developing countries it will be
available only in prefilled Uniject
devices designed for subcutaneous
injection (102, 103).
DMPA-SC is just as effective as the
formulation injected into the muscle,
and the patterns of bleeding changes and
amount of weight gain arc similar (7, 87).
One-year continuation rates in clinical trials were
high, 68% on average at sites in North and South America
and 80% in Europe and Asia. Despite the lower dose, DMPASC is effective for overweight or obese women (41).
Injections of DMPA-SC are given in rhe upper thigh or
abdomen. DMPA-SC should not be injected intramuscularly,
and the intramuscular formulation should not be injected
subcutaneously. The intramuscular formulation cannot be
diluted to make the lower-dose subcutaneous forjnt^lation.
Given the choice, many women prefer self-injections or
home injection. In trials of DMPA-SC, some women gave
themselves injections and many said they would prefer self in
jection. For example, among 1,787 women participating in trials
of DMPA-SC with standard syringes, 16% gave themselves in
jections. Among rhe approximately 1,600 participants who
answered a questionnaire, most would prefer to give themselves
the injection either at home (50%) or in a doctor’s office (21 %),
while 29% would prefer injections by a provider (42). Even
with intramuscular injections, most women in small studies of
Cyclofem in Brazil and the United States preferred self-injection
in the clinic or at home (//, 184). Self-injection of DMPA-SC
may require approval by drug regulatory agencies and ministries
of health.
Self-injection will save women the time and expense of repeated
visits to a health care provider and could increase continuation
rates. Among 11 1 women who stopped using Cyclofem or
DMPA in a study enrolling 360 women in Kenya, for example,
43% said the reason was related to problems returning to the
clinic on time (165). Women could be given several Uniject
devices at the clinic so that they could have home injections
for a year or more, or they could buy the devices at a pharmacy.
Women or family members will need training to give injections.
Training in Brazil to use Uniject for intramuscular injection
of Cyclofem included several sessions under the supervision of
a nurse. Women learned how to use the Uniject
device, and they practiced giving injections in
oranges. More than 90% of the participants
learned to give themselves injections
correctly (11).
Some women will not want to
give themselves injections. In
Brazil 102 Cyclofem users were
invited to participate in the
study of self-injection. Of these,
14 declined because they did
not want to give themselves
injections, 32 balked at giving
themselves injections even after
training, and 7 gave themselves one
injection but no more, because of
pain. The remaining 49—slightly less
than half—gave themselves two or three
injections (11).
Thus, while self-injection may become an option, it should
not be required of everyone. Those who arc fearful or hesitant
may put off giving themselves an injection and thus increase the
chances of pregnancy. Among people with diabetes or multiple
sclerosis who give themselves daily or weekly therapeutic injec
tions, anxiety reduces adherence to injection schedules (116, 1 17).
Self-service offers possible savings and will need guidelines.
Home injection will decrease cost per client because selfservice clients need less time with health care providers. Still,
community providers will need to check periodically for
problems with side effects, adherence to the injection schedule,
and changes in health that would make switching to another
method advisable. Providers will also need to ensure that
women dispose of used injection equipment safely. A study of
100 diabetic patients in Tunisia reported dial 94% threw used
equipment in the household garbage (39). Family planning
programs may want to develop guidance, including information
on storage of injectable contraceptives and safe disposal of
Uniject for women who choose self-injection and for the
providers who serve them.
Illustration: A new lower-dose formulation of DMPA is injected under
the skin rather than in the muscle. In developing countries it will be
available in prefilled Uniject devices, possibly by 2008. Many women
may choose to give themselves the subcutaneous injection or have
family members give the injection.
Illustration: Rafael Avila/CCP
using combined injectables for a year would decrease from
about US$49 to $37 (76).
Providers can be more productive if more clients come
during times of the day when the clinic is normally not
busy. Appointments can be scheduled during thfse times, u.
generally after 1:00 p.m.,and clients could be charged
less. More research is needed, however, to assess providers'
motivation and the best ways to reward them for seeing
more clients (88). Programs may need to raise salaries or
reward providers for seeing more clients, but the result can
still be a net decrease in cost per client served (89).
Some Injectables Users Are Willing to Pay
Program managers can recover some costs from users of
injectables. Starting to charge clients who have received free
services and supplies, or increasing existing charges, does not
always decrease demand substantially. In general, managers
of public and private nonprofit family planning programs
overestimate the effect of price increases on demand (2,56).
In fact, even doubling the price of contraceptives has reduced
demand by no more than 15%, according to five studies in
Bangladesh, Indonesia, and Nigeria (707). In Indonesia during
the economic crisis in the late 1990s, prices rose faster,than u
iricomes.The price of injectables more than doubled on
average, but demand was unchanged (58,118).
In some countries, however, family planning clients are
sensitive to price changes. In Malawi, for example, increases
and then decreases in prices by an NGO in response to
changes in donor funding led to dramatic decreases and
then increases in numbers of family planning clients (780).
To gauge what people would pay for injectables and other
contraceptives, program managers can conduct a willingnessto-pay survey. Applied to injectables, the survey starts with
two questions: What do you pay for injectables? Would you
be willing to pay X amount (a moderately higher price) for
injectables? The third question suggests a higher price if a
woman is willing to pay X, or less of an increase if she is not
willing to pay X amount. Before increasing prices throughout
the program, managers can raise prices in a few clinics first to
check the accuracy of any predicted changes in demand (2,56).
In rural Ethiopia teams offering DMPA,
immunization, and antenatal care set up
monthly outreach sites.
By definition, social marketing programs charge for their
products. Pricing is not based on costs but rather on ability to
pay. Some social marketing programs set the annual price of
injectables and other contraceptives at 1% or less of median
annual family income—a price that most people can afford.
These programs use attractive packaging for injectables and
other contraceptives to promote them and distinguish them
from public-sector products (69). Sales of injectables in social
marketing programs have risen dramatically. Among country
programs with total annual contraceptive sales of at least
10,000 couple-years of protection, sales of injectables more
than doubled from 8.4 million doses in 2000 to 20.2'million
doses in 2005. By comparison, sales of oral contraceptives
increased by about 50% and total couple-years of protection
provided by these programs increased by 57% (46).
Cross-subsidization is another way to shift costs. Programs
charge more than cost for some products or services and use
the profits to subsidize services that do not cover costs or to
offer free services for the poor. For example, social marketing
programs in Brazil, China, El Salvador, the Philippines,and
other countries have charged more than cost for some
brands of injectables, oral contraceptives, and condoms (9).
Communication Helps Women
When interest in a new product is growing, as with inject
ables, communication by family planning programs can
address people who know about the product but are
hesitating to try it.These are people who think a long time
before trying something new or who are skeptical about
innovations. Many need to see satisfied users among their
peers or be encouraged by opinion leaders before they
try something new (762,227). Each of the three stages
they pass through—being persuaded that the product is
At the same time that programs address this main audience,
they can also address other important audiences —women
who are already using injectables, men, and providers.
Women who are using injectables often have questions or
concerns about side effects.Some men help their partners
choose injectables and use them effectively (227). For ex
ample, a 1995 study in the Philippines found that women
whose husbands supported DMPA use were more than
good, deciding to use it, and then starting to use it—can be
twice as likely to continue the method as women whose
husbands disapproved (143). Providers may need information
addressed by different messages (740).
that addresses their own knowledge and attitudes about
17
about injectables and other contraceptives in television spots
(146). Doctors have been portrayed discussing injectables in
television spots in Egypt and radio spots broadcast in several
sub-Saharan African countries (51,82,134). In Pakistan, where
many people own cassette tape players, a social marketing
program distributed a cassette recording of a simulated
discussion of injectables by a provider and a couple (34).
injectables (6,54). Efforts to introduce injectables in public
family planning programs should include information for
private providers because women may consult them about
side effects (227). Audience research—with focus groups, for
example—helps programs choose messages,sources,and
media that will be effective for the specific audiences they
want to address.
Injectables have been controversial in some countries because
of health concerns. In India, for exam pie, injectables are not
offered in the government family planning program in part
because of opposition from women's groups (63,72,169).
Programs should be ready to respond to groups that publicly ‘
oppose injectables specifically or modern contraceptives in
When interest in a new product is growing, as
with injectables, communication can address
people who know about the product but are
hesitating to try it.
general. Making reliable and balanced information available
to the public and providers has helped programs both avoid
and deal with controversy. Maintaining a good working rela
tionship with the news media and making sure that reporters
are well-informed is an important task for family planning pro
For some people, information in the mass media or on the
Internet may be enough to get them to try a new method.
But for the majority who are hesitating or skeptical, a
medium that offers the opportunity to interact can be helpful
(162). For example, in social marketing projects carried out
by Social Marketing for Change (SOMARC) in Kazakhstan,
grams (161). For example, in Indonesia, when the risk of bone
loss among DMPA users was in the news in 2004 and 2005,
programs contacted journalists so that stories in the mass
media presented information about the benefits of using DMPA
along with the risk of bone loss (105) (For information about
Turkey, and Uganda, radio and television advertising
alleviated concerns about convenience, cost, or availability
of injectables and oral contraceptives.To address concerns
about side effects, however, women needed to interact
with a credible source, such as a doctor or family planning
bone loss, see p. 21).
counselor, and be able to ask questions (18). Interactive
media and forums have included telephone hotlines,
In Various Media Trusted Sources Address
Benefits and Misinformation
Potential users assess the benefits and drawbacks of a
new product before deciding to use it.The important
discussions with providers,and community meetings.
,
characteristics of a new product are its advantages over
current products, its compatibility with a potential user's life
(how familiar it seems), and ease of use. Being
easy to try or to observe is an advantage for
»
Telephone hotlines offer a private connection between
contraceptive users and a trained, credible family planning
counselor. Among callers to a hotline in Turkey were both
women who were using injectables and women who were
a new product (162).
To help potential users assess injectables,
communication programs have pointed
out advantages, side effects, and health
concerns. Also, programs have corrected
misinformation about injectables by
pointing out, for example, that women can
get pregnant after stopping injections (146).
Women may need assurance, if monthly
bleeding stops, that they are not pregnant
and that blood is not building up in their
bodies (18,61,79). For women ready to try
injectables, programs publicize the location
and hours of services (61,183).
Trusted sources have delivered information
about injectables in media or forums that
are appropriate for the audience. In subSaharan Africa aunts are trusted sources
of information about sexuality, and in Cote
d'Ivoire'Auntie Fatou" provided information
18
I’OPULATIC
interested but not using them. DMPA
users typically called because they had
no monthly bleeding and worried that
they might be pregnant. One caller had
a pregnancy test every month to make
sure she was not pregnant. Some women
called the hotline for more information
after their doctors had told them about
irregular or heavy bleeding caused by
DMPA. Health care providers also called
the hotline for information. For example,
a pharmacist called to confirm that
DMPA is given every three months
rather than every month as some local
doctors had said (78).
Discussions with providers. Inviting
women to a clinic to discuss family
planning has given them a chance to
interact directly with providers and
let them know where injectables are
A woman carries a model of a needle and syringe to publicize injectables in a family planning
parade in Peru. Engaging communities and their leaders in communication activities has been
available (50). In one-to-one discussions
in women's homes, village health workers an important part ofefforts to increase access to injectables and other contraceptives.
in Ethiopia provide information about
the benefits of family planning and the
availability of injectables.They refer women to health clinics
later obtained a contraceptive from a clinic. In the areas
for more information and services (61).
where the meetings were held, sales of injectables more than
Coaching can help women talk to providers and get
the information they need. In a study of family planning
counseling in Indonesia, for example, a patient educator
coached women about the importance of asking questions
and helped them prepare questions and practice asking
them. One practice question concerned injectables: "If
women don't menstruate when they use injections, where
does the blood go?" (for the answer, see p. 20). In taped
counseling sessions, coached women asked more questions
than uncoached women and they expressed more concerns
about contraceptive methods. As a result, providers gave
the coached women more information specific to their
situation (96).
To address concerns about side effects of
injectables, some women need to interact
with a credible source, such as a doctor or
family planning counselor.
doubled from the six months before the meetings to the six
months after the meetings (18).
Engaging community leaders has helped the introduction
of injectables and other methods in Ghana and Vietnam
(44,227).The Navrongo Initiative in Ghana, for example,
encouraged support for family planning by enlisting the
help of opinion leaders and using men's and women's social
networks. Councils of elders formed health care action
committees,and village leaders and elders convened regular
community gatherings to discuss health and family planning
with the men.The goal was to show that village leaders
endorse family planning and to encourage couples to discuss
their reproductive health. As noted, the vast majority of
women starting a modern method of contraception in the
Navrongo Initiative chose injectables offered by community
providers (44,138).
Today injectables are becoming more available and
Community meetings are an interactive and public way to
improve knowledge and answer questions about injectables
and other methods.They also provide information for'
»
women who are unable to travel, and for men (18,34). For
example, in the SOMARC project in Uganda midwives set
up one-hour meetings with women interested in family
planning by working with local officials, religious groups,
trade schools, and factories. About 11% of the approxi
mately 17,000 women who attended community meetings
attracting more users.Tomorrow, demand for injectables
will likely grow further as these methods are offered in more
community programs and as subcutaneous injection of
DMPA becomes available. Programs are trying to keep up
with demand by keeping supplies in stock, ensuring that
providers give injections safely,and informing women about
injectables.The result of these efforts will be more satisfied
users of this safe and effective contraceptive method.
Questions &^nswers About
"1 How do injectables work?
g" Will injectables change mood or sex drive?
-8- Injectables work mainly by preventing the development
and release of eggs from the ovaries (ovulation). They also
thicken cervical mucus, which blocks sperm from meeting
the egg. Both progestin-only and combined injectables
are very effective when users return on time for their next
injections.
How are combined injectables similar to com
bined oral contraceptives? How do they, differ?
2
•
Long-term studies of the health risks and benefits are under
way, but few results arc available yet. Still, combined inject
able contraceptives contain the same types of hormones as
combined oral contraceptives (COCs). Therefore researchers
assume that most of the findings about COCs also apply to
combined injectables. A difference is that monthly injectables arc not processed by the liver before entering the
bloodstream, as are medications taken by mouth. As a result,
monthly injectables have less effect on liver function than
COCs, and women can use them with some conditions,
such as gall bladder disease, that would make use of COCs
less safe (2/2). Also, short-term studies have found that
monthly injectables have less effect than COCs do on blood
pressure, blood clotting, and the breakdown of fatty sub
stances (lipid metabolism).
Some women using injectables report mood changes
and less sex drive, but the great majority do not (65, 87,
202). It is difficult to tell whether such changes are due
to injectables or to other causes. There is no evidence that
using injectables changes a woman’s sexual behavior.
Safety
/^Will a woman still be able to become pregnant
VJafter she stops using an injectable?
Yes. Monthly bleeding and release of eggs from the ovaries
(ovulation) return. Women of any age, whether or not they
already have children or want more children, can use any
injectable contraceptive, and it will have no effect on future
fertility.
*yDo injectables cause cancer?
/
Side Efreets
Are the bleeding changes caused by injectablesharmful?
*
In most cases, no. Heavy bleeding, however, which is
uncommon, may contribute to anemia, particularly among
women who are nearly anemic. Also, if there is reason to
suspect that a bleeding pattern has another cause—not the
injectable—then the cause should be investigated.
a woman does not have monthly bleeding
JCwhile using progestin-only injectables, does
this mean that she is pregnant or that blood is
building up in the body?
No. Lack of bleeding most likely does not mean a woman
is pregnant if she was not pregnant when she started
injectables and has been having injections on time.. Blood
does not build up inside a womans body while she uses
progestin-only injectables. Lack of bleeding while using
injectables is similar to lack of bleeding while breastfeeding.
During the menstrual cycle the lining of the womb thickens
and a woman releases an egg (ovulates). If the egg'is riot '
fertilized, the tissue and blood from the thickened lining are
shed as menstrual bleeding. When a woman uses progestinonly injectables or if she fully breastfeeds her baby for six
months, the lining of the womb does not thicken, the woman
usually does not ovulate, and there is no menstrual bleeding.
20
InjeCtableS
Many studies show that DMPA does not cause cancer.
DMPA use helps protect against cancer of the lining of
the uterus (endometrial cancer). Women have a slightly
increased risk of being diagnosed with breast cancer while
using DMPA or shortly after they stop, but this may be due
to earlier detection of existing disease. If a woman has not
developed breast cancer within five years of starting DMPA,
then her risk of breast cancer is the same as the risk for a
similar woman who never used DMPA.
A few studies suggest that there may be a slightly increased
risk of cervical cancer among women who use DMPA for
five years or more if they have persistent infection with
certain strains of human papillomavirus (HPV) (178).
Cervical cancer cannot develop because of DMPA use
alone. It is caused by persistent infection with these strains
of HPV. While HPV infection is common,persistent HPV
infection with one of the cancer-causing strains is not
common. Few additional cases of cervical cancer will occur
because of DMPA use.
Little information is available about NET-EN. It is thought to
be as safe as DMPA and other contraceptive methods contain
ing only a progestin, such as progestin-only pills and implants.
Q Can injectables cause abortion?
C5 No. Injectables do not disrupt an existing pregnancy. They
should not be used to cause abortion. They will not do so.
injectables cause birth defects?
“
No., DMPA does not cause birth defects even if a woman
mistakenly receives an injection when she is pregnant or
even if a woman becomes pregnant while using DMPA ’
(131). There is little evidence about NET-EN, but it is
assumed to be the same as DMPA in this regard.
Combined oral contraceptives do not cause birth defects,
and so it is assumed that combined injectables do not cause
birth defects, either (26, 131, 155).
POPULATION REPOR'
Women With HIV/AlDS
Can Use Injectables
dce ‘ DMPA nffect bone density?
VI DM PA reduces levels of estrogen in the body. Estrogen
helps to regulate the How of minerals to and from die bones.
When estrogen levels are low, more minerals are lost from
bone than are reabsorbed. This leads to a decrease in bone
density (137).
‘ *■
>
v
)
Whether DM PA increases the risk of broken bones requires
more research. A womans lifetime risk of broken bones is
unlikely to be affected because women regain bone density
after stopping DM PA. Among adults who stop using
DMPA, after two to three years their bone density appears
to be similar to that of women who have not used DMPA.
Among adolescents, it is not clear whether the loss in bone
density prevents them from reaching their potential peak
bone mass. Also, more research is needed on the effect of
DMPA use during the reproductive years on the risk of
broken bones during menopause, and the effect of DMPA
use near menopause on a womans ability to regain lost bone
density.
Because of the bone loss issue, drug regulatory agencies
in the United Kingdom and United States advise women
to consult providers after using DMPA for two years to
decide if they want to continue DMPA or to choose another
method (49. 193). An expert working group advising the
World Health Organization, however, concluded yhat the
u
’ decrease in bone density should not limit who uses DMPA,
or for how long, among women ages 18 to 45. The benefits
of using DMPA outweigh the theoretical concerns about
bone fracture for these women and for adolescents younger
than 18 and women over 45. Since there is not enough
information about long-term DMPA use by adolescents
and women over 45, the expert group recommended that
providers and these women reconsider the benefits of
DMPA and their risk of bone fracture over time. These
recommendations also apply to NET-EN (276).
Other Uses
■g
Gin a single injection of a combined injecJ. JL table be used to bring on regular monthly
bleeding in a woman with irregular bleeding?
No. A woman may experience some bleeding (a “withdrawal
bleed”) about a month later as a result of the injection, but
.there is no evidence that giving one injection '6f a'combincd *"
injectable to a woman with irregular bleeding will cause her
monthly bleeding to become regular.
<iin<’Ie injection of a combined
JL aw injectable be used as a pregnancy test?
Giving a woman combined injectables to see if she has
bleeding when she stops taking them is not recommended as
a way to tell if she is pregnant. Combined injectables should
not be given to a woman as a “hormonal pregnancy test”
because they do not produce accurate results.
Injectables are safe and effective for women who have HIV,
including those who have AIDS and those who are taking
antiretroviral (ARV) medications. Effective contraception
helps women avoid the health risks of unintended pregnancy
with HIV infection, including mother-to-child transmission
of HIV (119, 148). Also, although there have been few
studies, there is evidence that some ARV medications harm
a fetus. Women should use efavirenz, for example, only if
they use effective contraception (214).
There have been theoretical concerns that ARV medications
could reduce the effectiveness of hormonal contraceptives
because some medications speed up liver metabolism (141).
One small study of women using efavirenz, nelfinavir, or
nevirapine reported that after an injection of DMPA, levels
of progesterone indicated that no women ovulated (33).
A study of an oral contraceptive, however, reported that
nevirapine had a significant effect on both estrogen and
progestin levels (114). Even if an ARV medication did
decrease the hormone level in rhe blood somewhat, users
are probably still well protected against pregnancy because
DMPA is nearly as effective for three months ata 100
mg dose as at the usual 150 mg dose (203). To date, no
studies have looked at NET-EN or combined injectable
contraceptives.
Because of the concerns about decreased effectiveness, it has
been suggested that women using nevirapine and DMPA
be especially urged to return on time for injections (/Z3).
Women using nevirapine or other ARV medications who
return late but within two weeks of their injection date,
however, should not be denied an injection. No evidence
supports shortening the interval between injections for
women using ARV medications.
The few studies available find that DMPA has little or no
effect on the plasma concentration of ARV medications (33)
or on their effectiveness as measured by rhe plasma concen
tration of lymphocytes (white blood cells) and HIV (32).
Injectable contraceptives offer no protection against
transmission of HIV or other sexually transmitted in
fections. Used consistently and correctly, male or female
condoms help prevent transmission of infection. Condoms
can be used along with injectables and with other family
planning methods. Also, monogamy or at least reducing
the number of sexual partners can lower the risk of HIV
infection.
21
reliable 3: Key Resources for Program Managers and Providers
Availability
Reliable Supplies
Title: Pocket Guide to Managing
Contraceptive Supplies
Organization: U.S. Centers for Disease
Control and Prevention
Description: A quick reference guide for
staff who manage contraceptive supplies
and logistics. Includes logistics formulas
and principles.
: PDF available online *
j To order print.copi.bs,
w
= contact: U.S. tenters for’
: Disease Control and Prevention
■ Division of Reproductive Health.
i MS K-22, 4770 Buford Hwy.. NE
: Atlanta. GA 30341. USA
i E-mail: jtj2@cdc.gov
Title: PipeLine Software Tool
Organization: John Snow, Inc. (JSI)
Description: A tool to help program
managers monitor stock and plan
procurement through forecasting,
maintaining consistent stock levels, and
preventing stockouts.
i Tool available online.’
: To request the PipeLine CD, contact:
: John Snow, Inc./DELIVER Project
i 1616 N. Fort Myer Drive, 11,h Floor
j Arlington, VA 22209, USA
• E-mail; deliver_pubs@jsi.com
Web site: www.jsi.com
Title: Procuring Single-Use Injection Equip
ment and Safety Boxes: A Practical Guide
for Pharmacists. Physicians, Procurement
Staff and Programme Managers
Organization: World Health Organization
(WHO)
Description: A guide to help programs
procure injection equipment and safety
fe>xes and to develop a monitoring system
W ensure quality and reliability.
PDF available online,*
. To order print copies, contact:
: World Health Organization
\ Department of
: Essential Health Technologies
j 20 Avenue Appia
? 1211, Geneva 27, Switzerland
i E-mail: eht@who.int
i Web site: www.who.int/eht
Title: UNFPA Procurement Services
Organization: United Nations Population
Fund (UNFPA)
Description: UNFPA is the largest public
sector procurer of contraceptives. UNFPA
accepts standard orders of US$6,000
or more, and also accepts emergency
procurement orders.
i’ For more informatipn. contact:
• UNFPA
‘ ’
• Procurement Services Section
j Midtermolen 3. P.O. Box 2530
; 2100 Copenhagen, Denmark
\ Web site, www.unfpa.org/
• procurement/index.htm
Safe Injections and Waste Management
Title: Safe Injection and Waste Manage
ment: A Reference for Logistics Advisors
Organization: JSI
Description: A reference guide to help de
sign and support programs for safe injec
tions and waste disposal. Includes assess
ment tools and additional references.
RAsotirno
Resource
r.„
Training and Supervision (Continued)
; PDF available online.*
; To order print copies, contact:
i John Snow. Inc./DELIVER Project
: 1616 N. Fort Myer Drive, 11"’ Floor
i Arlington, VA 22209, USA
J E-mail: deliver_pubs@jsi com
• Web site: www.jsi.com
Title: Management of Waste from Injection
PDF available online *
Activities at the District Level: Guidelines
• To order print copies, contact:
for District Health Managers
World Health Organization Press
Organization: WHO
• 20 Avenue Appia
Description: A guide to help develop an
■ 1211, Geneva 27, Switzerland
action plan to reduce improper disposal of
E-mail: bookorders@who.int
uection waste.
Web site: www.who.int
Ml
iTtle:
ti Do No Harm: Injection Safety in the ;• For more informatipn. contact:
Context of Infection Prevention and Control: j John Snow, Inc./DELIVER Project
Training Tools and Job Aids (forthcoming) i 1616 N. Fort Myer Drive, 111/1 Floor
Organization: JSI and WHO
j Arlington, VA_____
22209,_USA
Description: A tool for implementing nation- • E-mail: deliver_pubs@jsi.com
al injection safely training program strale- j Web site: www.jsi.com
gies. Includes sample handouts and job aids.
Training and Supervision
Title: Comprehensive Family Planning and
Reproductive Health Training Curriculum
Module 6: DMPA Injectable Contraceptive
Organization: Pathfinder International
Description: An adaptable module to train
health care workers to provide injectables.
PDF available online.*
To order print copies, contact:
Pathfinder International
9 Galen Street, Suite 217
Watertown, MA 02472, USA
E-mail: information@palhfind.org
Web site: www.pathfind.org
Title: Standards-Based Management and
Recognition (SBM-R)—A Field Guide,
Facilitator's Handbook, and CD-ROM
Organization: JHPIEGO
Description: A guide for improving perform
ance and the quality of health care services.
For more information, contact:
JHPIEGO
1615 Thames Street
Baltimore, MD 21231, USA
E-mail: orders@jhpiego.net
Web site: www.jhpiego.org
’See Web Table 3 for URL. Additional information at http://populationreports.org/k6/k6tables.shtml
Title: A Guide for Supervising Injections
Organization: WHO
Description: A guide for supervisors
to observe injection practices, provide
feedback about safe and unsafe practices,
and help resolve problems contributing to
unsafe injections.
PDF available online.*
To order print copies, contact: World
Health Organization Department of
Essential Health Technologies
20 Avenue Appia-1211,
Geneva 27. Switzerland
E-mail: eht@who.int
Improving Efficiency
Title: CORE: A Tool for Cost and Revenue i For more information, contact:
Analysis
i Elizabeth Lewis, Management
Organization: Management Sciences for i Sciences for Health. Inc.
Health, Inc. (MSH)
i 748 Memorial Drive
Description: CORE helps managers
j Cambridge. MA 02139, USA
analyze and compare a facility's current
E-mail’core@msh.org
and projected costs and revenues.
= Web site: www.msh.org
Title: COPE: A Process for Improving
Quality in Health Services
Organization: EngenderHealth
Description: The COPE technique helps
supervisors and staff assess the quality of
services, identify problems, and recommend
and implement solutions.
PDF available online."
To order print copies, contact:
i EngenderHealth
; 440 Ninth Avenue
i New York. NY 10001, USA
_• E-mail, mfo@engenderhealth.org
: Web site: www.engenderhealth.org
Title: Maternal and Reproductive Health
Costing Model, Version 1.1 (Millennium
Project Version) ’
Organization: UNFPA
Description: A tool to help program mana
gers estimate the personnel, drug, and sup
ply costs associated with providing injecta
bles and other reproductive health services.
i Excel spreadsheet available online *
; For more information, contact:
? Millennium Project
i One United Nations Plaza
: 21” floor Rm. 2160
: New York, NY 10017. USA
E-mail: Eva Weissman
■ weissman@unfpa.org or Janneke
i Saltner saltner@unfpa.org
Title: International Drug Price Indicator Guide PDF available online ’
Organization: MSH
: To order print copies, contact:
Management Sciences
Description: This guide provides prices
from pharmaceutical suppliers and procure . for Health, Inc.
ment agencies, international development i 748 Memorial Drive
Cambridge. MA 02139, USA
organizations and government donor
Web site: www.msh.org
agencies.
Helping Clients Make an Informed Choice
Title: Decision-Making Tool for Family
PDF available online *
Planning Clients and Providers
: To order print copies, contact:
Organization: WHO and the INFO Project, : Johns Hopkins Bloomberg
Johns Hopkins Bloomberg School of Public School of Public Health Center
Health Center for Communication Programs • for Communication Programs
Description: An evidence-based counsel- • 111 Market Place, Suite 310
ing resource for providers to help clients
Baltimore, MD 21202, USA
make informed choices about family planning. : E-mail: orders@jhuccp.org
Title: Medical Eligibility Criteria for
= PDF available online.*
Contraceptive Use
; To order print copies, contact:
Organization: WHO
i Department of Reproductive
Description: A guide for the safe use of 19 ; Health and Research, WHO
| 1211 Geneva 27, Switzerland
methods for women and men with known
: E-mail: rhrpublications@who.int
medical conditions.
Title: Family Planning: A Global
To order print copies, contact:
Handbook for Providers (forthcoming)
Johns Hopkins Bloomberg
Organization: WHO and the INFO Project i School of Public Health Center
Description: A guide for providing family
for Communication Programs
planning methods, including counseling and i 111 Market Place, Suite 310
managing side effects. Also covers preven- • Baltimore. MD 21202, USA
E-mail: orders@jhuccp.org
lion and identification of sexually transmit
ted infections, including HIV. and numerous . Web site, www.infoforhealth.org/
health topics related to family planning.
pubs/globalhandbook/
Communicating About Injectables
Title: Media/Materials Clearinghouse (M/MC) • For more information, contact:
Organization: Johns Hopkins Bloomberg ........................
; Media/Materials Clearinghouse
School of Public Health Center for
i Johns Hopkins Bloomberg School
i of Public Health Center for
Communication Programs
Description: A resource for health communi : Communication Programs
cation materials from around the world, with
111 Marketplace, Suite 310
over 200 items pertaining to injectables.
: Baltimore. MD 21202, USA
i Web site: www.m-mc.org/
iography
This bibliography includes citations to the
materials most helpful in the preparation of
this report. In the text, reference numbers
for these citations appear in italics.The com
plete bibliography can be found on the
internet at: http://www.populationreports.
org/k6/ The links included in this report are
up-to-date as of publication.
7. ARIAS. R.D. JAIN, J.K., BRUCKER.C, ROSS. D,and RAY, A.Changes
1999. (Available: httpy/wvAv.fhi.org/en/RH/Pubs/booksReports/
93. JOHN SNOW, INC. and WORLD HEALTH ORGANIZATION (WHO).
Do no harm: Injection safety in the context of infection prevention
and control, training tools and job aids. (Forthcoming)
94. JOHN SNOW, INC7DELIVER.The logistics handbook. A practical
programs. Arlington,Virginia, John Snow, Inc/DELIVER, 2000.
99. LANDE, R.E. New era for injectables. Population Reports,
Series K. No. 5. Baltimore, Johns Hopkins School of Public Health,
Population Information Program, Aug. 1995.31 p.
100. LEI, Z.W., WU, S.C., GARC EAU, R.J., JIANG, S„ YANG, 02., WANG,
W.L., and VANDER MEULEN.T.C. Effect of pretreatment counseling
on discontinuation rates in Chinese women given depo-
53(6):357-361 Jun. 1996.
107. MATHENY, G. Family planning programs: Getting the most
11 BAHAMONDES,L.MARCHI. N.M., NAKAGAVA,H.M., DE MELO,
ML. CRISTOFOLETT1MDE. U PELLINI, E.. SCOZZAFAVE, R.H.. and
injectable contraceptive Cyclofem.Contraception 56(5): 301-304.
18.
BERG. R.. KANESATHASAN. N„ and BOLLINGER. L Getting
from awareness to use: Lessons learned from SOMARC III about
marketing hormonal contraceptives.Washington.D.C.,Futures
Group International. Social Marketing for Change (SOMARC), Sep.
1998 (SOMARC Hl Special Study No. 6) 21 p.
BIDDLECOM, A.E.and FAPOHUNDA.B.M. Covert contraceptive
19.
use: Prevalence, motivations, and consequences. New York, Popula-
108. MAULDIN, W.P. and MILLER,V.C.Contraceptive use and
commodity costs in developing countries, 1994-2005. New York,
United Nations Population Fund (UNFPA). 1994.64 p.
109. MCCARRAHER, D. Factors to consider in adding injectables to
lnjectables:Current Developments and Collaboration for Action
Meeting, Baltimore, JHPIEGO, Jan.9,2006.
113. MERCER, A, ASHRAF, A., HUQ, N.L, HASEEN, F„ UDDIN, AM,
and REZA,M.Use of family planning services In the transition to a
static clinic system in Bangladesh: 1998-2002. International Family
Planning Perspectives 31(3): 115-123.Sep. 2005.
121. MORRONI, C., MYER, L, MOSS, M., and HOFFMAN. M.
20.
BIGR1GG, A., EVANS. M..GBOLADE, BA, NEWTON, J„ POLLARD, South African women. Contraception 73(6): 598-601. Jun.2006.
L. SZAREWSKI. A,THOMAS. C.. and WALLING, M. Depo Provera
125.NECOCHEA,E.and BOSSEMEYER,D.Standards-based
management and recognition—A field guide: A practical approach
for improving the performance and quality of health services.
30.CANTO DE CET1NA.T.E., CANTO, P. and ORDONEZ LUNA.M.
BaltimoreJHPIEGO, 2005.84 p. (Available: http://pdf.usald.gov/
pdf_docs/PNADF 143.pdf)
128. NERSESIAN, P„ CESARZ, V.. COCHRAN, A, MBOYANE, J„ and
63(3): 143-146. Mar. 2001.
SCHMID’S, K.Safe injection and waste management: A reference for
31 .CASTLE. S, KONATE, M.K., ULIN. P.R., and MARTIN, S. A qualitative
logistics advisors. Arlington, Virginia, John Snow, IncTDELIVER, 2004
study of clandestine contraceptive use in urban Mali. Studies in
139. PHILLIPS, J.F., HOSSAIN, M.B, HUQUE, A.A,and AKBAR, J. A case
study of contraceptive introduction: Domiciliary depo-medroxy
progesterone acetate services in rural Bangladesh.Segal,SJ..Tsui,
audiotapes: Reaching couples in Pakistan. Journal of Biosocial
A.O,and Rogers,S.M.,eds.ln:Demographicand Programmatic
Consequences of Contraceptive Innovations. New York, Plenum
44. DEBPUU3. C. PHILLIPS. J.F. JACKSON. E.P. NA2ZAR, A.. NGOM.
140. PIOTROW, PT., KINCAID, D.L, RIMON, J.G.D., RINEHART. W., and
SAMSON, K. Health communication: Lessons from family planning
fertility.Studies in Family Planning 33(2): 141-164. Jun.2002.
and reproductive health.Westport,Connecticut, Praeger, 1997.307 p.
45. DELIVER. Contraceptive fact sheets. Arlington, Virginia,
142. POPULATION ACTION INTERNATIONAL Defining reproductive
John Snow. Inc/DEUVER for the U.S. Agency for International
health supplies: A survey of international programs.Washington,
Development. Feb. 2006.22 p. (Available: http7Zpdf.usald.gov/
D.C., Population Action International, Apr. 2001.8 p.
pdf.docsZPNADG030.pdf)
151 PROGRAM FOR APPROPRIATE TECHNOLOGY IN HEALTH
56. FOREIT, J.R. and FOREIT, K.G.The reliability and validity of willing(PATH). Introducing auto-disable syringes and sharps disposal
containers with DMPA.PATH, Jul. 19,2006.10 p. (Available: http://
www.path.org/files/SI .CNVP15904 English.pdf)
58. FRANKENBERG. E, S1K0KI, 8.. and SURIASTIN1, W. Contraceptive
154 RAHMAN. M.B.. JANOWITZ, B ..CHOWDHURY, J.H..and JAMIL.
use in a changing service environment; Evidence from Indonesia
during the economic crisis. Studies in Family Planning 34(2):
103-116Jun. 2003.
62. GLAS1ER. A.F,SMITH, K.B..VAN DER SPUY,Z.M., HO, P.C., and
156. RAO, R. and PANDIT,T. Nepal: Contraceptive security. Issues,
CHENG, L Amenorrhea associated with contraception: An
findings.and recommendations.Arlington,Virginia, John Snow,
international study on acceptability.Contraception 67(1): 1-8.
Inc /DELIVER, Jan. 2004.30 p. (Available: http://portalprd 1 .jsl.com/
Jan. 2003
pls/portal/docs/PAGE/DEL_CONTENT_PGG/DEL_PUBLICATION_
75. HUBACHER. D.. GOCO, N. GONZALEZ. B, and TAYLOR, D. Factors
PG 1/DEL-COUNTRY.RPT. PG1/NEPAL_CONTRACEPTIVEaffecting continuation rates of DMPA. Contraception 60(6):
SECURITY_R2.PDF)
162. ROGERS. E.M. Diffusion of innovations. 4th cd. Free Press, 1995.
76. HUBACHER. D. HOLTMAN, M.. FUENTES, M. PEREZ-PALACIOS,
163t ROSS, J., STOVER, J.. and»ADELAJA, D. Profiles for family
Family planning services provided by the Mexican Ministry of
planning and reproductive health programs: 116 countries. Futures
Group. 2005.182 p. (Available: http://www.constellafutures.com/
138. Sep. 1999.
Documems/Profilesl 16FP2ed.pdf)
80. HUTIN. Y„ HAURI, A., CH! ARELLO, L, CATLIN. M., STILWELL, B..
164. ROUTH, 5., ASHRAF. A, STOECKEL, J. and BARKAT-E-KHUDA.
GHEBREHIWET.T.,and GARNER, J. Best infection control practices
Consequence of the shift from domiciliary distribution to
for intradermal, subcutaneous, and intramuscular needle
site-based family planning services In Bangladesh.Studies In
injections. Bulletin of the World Health Organization 81(7): 491Family Planning 27(2):82-89. Jun. 2001 (Available: http7/www.
500.2003.(Available: http7/www.who.int/bulletin/volumes/8l/7/
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165. RUMINJO, J.K, SEKADDE-KIGONDU, C.8., KARANJA, J.G.,
81. HUTIN, YJ„ HAURI. A.M., and ARMSTRONG, G.L. Use of injections
RIVERA, R, and NASUTiON,M.Comparative acceptability of
combined and progestin-only Injectable contraceptives In Kenya.
al estimates. British Medical Journal 327(7423): 1075. Nov. 8,2003,
Contraception 72:138-145.2005.
83. INTERNATIONAL PLANNED PARENTHOOD FEDERATION (IPPF).
172.SETTY, V. Organizing work better. Population Reports, Series
Directory of hormonal contraceptives. <hnp7/contraceptive.ippf.
0. No. 2. Baltimore, Johns Hopkins Bloomberg School of Public
org/> IPPF. 2006.
Health.The INFO Project.Winter 2004.(Available: http7/www.
88. JANOWITZ. B. Make better use of provider time in reproductive
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173. SI IELTON, J.D. Contraception for women on first-line
Population Council, Aug. 2006. (Available: http7/www.popcouncil
antiretrovirals (ARVs). Baltimore,Johns Hopkins Bloomberg School
of Public Health,The INFO Project. Mar. 25.2005.(Global Health
90JANOWITZ.B..MEASHAM,D.. and WEST, C. Cost of services.
Technical Briefs) (Available: http7/www.maqweb.org/techbriefs/
tb5arv.shtml)
Research Triangle Park, North Carolina. Family Health International,
175. SIMMONS, R.. FAJANS, P, and LU8I5, F. Contraceptive
introduction and the management of choice:The role of Cyclofem
in Indonesia.Contraception 49(5): 509-525. May 1994.
177.SMITJ.,GRAY,A.,MCFADYEN,L„and ZUMA, K. Counting the
costs:Comparing depot medroxyprogesterone acetate and
norethisterone oenanthate utilisation patterns in South Africa.
BMC Health Services Research 1(1):4.200l.
180.SOLO, J.JACOBSTEIN,R.,and MALEMA.D.Malawi case study:
New York City.EngenderHealth, ACQUIRE Project. Sep. 2005.
(ACQUIRE Report) 40 p. (Available. http7/www.acquircproject.
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181 SOLTER, C. Module 6: DMPA injectable contraceptive. In:
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Pathfinder International,Sep. 1999. (Available: http.7/www.
pathfind.org/pf/pubs/module_6.pdf)
183. STANBACK, J, MBONYE, A., LEMELLE, J, BEKHTA, M, SSEKfTO,
Research Triangle Park, North Carolina, Family Health International,
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Technology. 18th ed. New York. Ardent Media, 2004. p. 773-845.
192.U.S.CENTERS FOR DISEASE CONTROL AND PREVENTION
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other bloodborne infections. 1996. (Available: http://www.cdc.
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194. UNITED NATIONS (UN).World contraceptive use 2005.(Wall
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197. UNITED NATIONS POPULATION FUND (UNFPA). UNFPA
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200. VILLANUEVA, Y, MENDOZA, I.. RODRIGUZ, S., and VERNON, R.
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28(1): 1-20. Jul. 1983.
203.WORLD HEALTH ORGANIZATION.A multicentered phase III
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207. WORLD HEALTH ORGANIZATION (WHO). Safe management
of wastes from health-care activities. Geneva, WHO, 1999.242 p.
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210. WORLD HEALTH ORGANIZATION (WHO).Guiding
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212.WORLD HEALTH ORGANIZATION (WHO).Medical eligibility
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mecZindex.htm)
215.WORLD HEALTH ORGANIZATION (WHO). Selected practice
Department of Reproductive Health and Research,-2004.170 p.
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hormonal contraception and bone health.Weekly Epidemiological
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217.WORLD HEALTH ORGANIZATION (WHO). Management
of waste from Injection activities at district level: Guidelines
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http://www.who.int/water_sanitationjiealth/medlcalwaste/
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223.WORLD HEALTH ORGANIZATION (WHO), UNITED NATIONS
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FUND (UNFPA). Safety of injections: WHO-UNICEF-UNFPA joint
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ISSN 0887-0241
23
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ORAL CONTRACEPTIVES —Series A
A-9 Oral Contraceptives—An Update [2000] (F.S)
A-10 Helping Women Use the Pill [20001 (F.S)
INJECTABLES AND IMPLANTS—Series K
K-4 Guide: Guide to Norplant Counseling 119921 (F.S)
K-5 Guide: Guide to Counseling on Injectables [19951 (F.P.S)
K-5 Fact Sheet: DMPA at a Glance |1995] (F.P.S)
K-6 Expanding Services for Injectables [20061
(with supplement. Injectable Contraceptives: Tools for Providers)
ISSUES IN WORLD HEALTH—Series L
L-10 Wall chart: Family Planning After Postabortion Treatment
B-7 New Attention to the IUD [2OO6I
11997| (F.P.S)
BARRIER METHODS—Series H
— L-11 Ending Violence Against Women |1999] (F.P.S)
H-9 Closing the Condom Gap 119991 (F.P.S)
— L-12 Youth and HIV/AIDS: Can We /\void Catastrophe? [20011 (F, P, S)
FAMILY PLANNING PROGRAMS—Series J
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—S-L-13 Birth Spacing: Three to Five Saves Lives [2002] (F.S)
-— L-14 Better Breastfeeding, Healthier Lives [2006]
J-39 Paying for Family Planning |1991 [ (F.S)
(with supplement: Breastfeeding Questions Answered:
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A Guide For Providers)
A Reproductive Health Concern [19951 (F)
[-42 Helping the News Media Cover Family Planning
SPECIAL TOPICS—Series M
M-13 Winning the Food Race 119971 (F.S)
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J-43 Meeting Unmet Need: New Strategies |19961 (F.S)
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J-49 Why Family Planning Matters |1999] (F.S)
M-18 Men's Surveys: New Findings 12004] (F.S)
1-50 Informed Choice in Family Planning: Helping People
M-19 New Contraceptive Choices [20051 (F.S)
Decide 120011 (F.P.S)
J-51 Family Planning Logistics: Strengthening the Supply
MAXIMIZING ACCESS AND QUALITY—Series Q
Chain [20021 (F.S)
Q-1 Improving Client-Provider Interaction [20031 (F.S)
J-52 Performance Improvement [20021 (F.S)
Q-2 Organizing Work Belter [20041 (F.S)
INTRAUTERINE DEVICES—Series B
B-6 IUDs—An Update |1995| (F.P.S)
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ZX JOHNS HOPKINS
BLOOMBERG
INFO Project
Center for Communication
Programs
How family
planning
programs and
providers can
meet clients'
Qnjectable
contraceptives
Key Points
More than twice as many women are using injectable contraceptives today as a decade
ago, and the numbers keep growing. Injectables appeal to the many women who seek a
family planning method that is effective and long-acting and can be used privately.
Family planning services can meet the rising
demand for injectables by:
• Keeping enough supplies on hand.
Anticipating demand for injectables and
placing accurate and timely orders helps
programs maintain adequate supplies and
avoid stockouts. '■
1
«
• Mobilizing a range of providers to offer
injectables. With training, any health care
worker can give contraceptive injections.
’ Taking injectables into the community.
Offering injectables in community programs
increases access and can be as safe as clinic
services.
Series K, Number 6
injectables and Implants
fh USAID
. 'fa5* ■
.tkh
• Organizing services efficiently. Programs can
hold down cost increases by organizing work
more efficiently, purchasing supplies at the
lowest available prices, and encouraging staff
to increase productivity.
° Informing the public. Communication pro
grams can tailor messages to address women
who know about injectables but hesitate to
try them.
As services expand, maintaining good quality
remains an obligation to clients for all family
planning methods.For injectables,attention to
quality includes:
• Giving injections safely. Applying safe injec. tion technique and the universal precautions,
including disposing of used syringes and
needles properly, helps prevent infection.
• Helping clients decide about injectables.
Good counseling helps women decide if an
injectable contraceptive suits their preferences
and their situation. Providers must tell women
that injectables change bleeding patterns.
• Helping clients use injectables successfully.
Women who choose injectables keep using
them longer when they know that bleeding
changes are normal and understand
the importance of returning
for injections on time.
a -
See companion INFO
Reports, "Injectable
Contraceptives: Tools
for Providers"
Injectabies Today and Tomorrow
Surveys find that more women are choosing injectable contraceptives, and
governments, donor agencies, and family planning programs are responding.
Supply Meets Demand With Forecasting and Ingenuity
Successful injectabies services require well-run logistics systems, accurate
forecasting, and the ability to avoid threatened stockouts quickly.
Training to Meet Demand
More health care providers need the skills t'o offer injectbble contraceptives.
Training and supervision can be adapted to suit program needs.
Give Injections and Dispose of Waste Safely
Giving safe injections with sterile equipment and ensuring proper disposal
keeps clients, clinic staff, and communities safe.
With Training, a Range of Providers Can Give Contraceptive
Injections
Allowing pharmacists, auxiliary nurses, and community health workers to
give injections can increase access to injectabies.
Community Programs Can Safely Increase Access to Injectabies
Providing injectabies in the community offers women in isolated areas an
other contraceptive choice.
This report was prepared by Robert Lande
and Catherine Richey, MPH. Ward Rinehart,
Editor. Design by Mark Beisser, Francine Mueller,
Linda Sadler, and Rafael Avila. Production by
John Fiege and Monica Jimenez.
The INFO Project appreciates the assistance of
the following reviewers. Jacob Adetunji, Kim
Best, Richard Blackburn, Marc G. Boulay,Steve
Brooke, Gloria Coe, Marfa del Carmen Cravioto,
Juan Diaz, Maxine Eber. Douglas Huber, Barbara
Janowitz, Sophie Logez, Enriquito R. Lu, Kuhu
Maitra, Kavita Nanda, Fredrick Ndede.Carib
Nelson, Paula Nersesian, Gael O'Sullivan, Joseph
F. Perz, James-Phillips, Roberto Rivera.Ruwaida
Salem, Hilary Schwandt, Stephen Settimi, James
D. Shelton, Jenni Smit, Cathy Solter, J. Joseph
Speidel.Jeff Spieler,Tara M.Sullivan, Jagdish
Upadhyay, Ushma Upadhyay, Marcel Vekemans,
Irina Yacobson, and Vera Zlidar.
Suggested citation: Lande, R.and Richey,C.
"Expanding Services for Injectabies,”Population
Reports, Series K, No.6. Baltimore, INFO Project,
Johns Hopkins Bloomberg School of Public
Health, December 2006.
Available online:
http://www.populationreports.org/k6/
Meeting Rising Demand Efficiently
Programs can increase services without greatly increasing costs by serving
clients efficiently, procuring supplies at low cost, and increasing productivity.
Injectabies Tomorrow: SubcutanepuS DMPA anj! Home Injection
A new formulation of DMPA will enable some programs to offer clients a selfservice option.
Communication Helps Women Try and Use Injectabies
Women and their partners need complete information and often the chance
to talk to a professional about injectabies and other contraceptives.
Questions and Answers About Injectabies
Providers need to know the answers to questions that clients are likely to ask
about the side effects and safety of injectabies.
Women With HIV/AIDS Can Use Injectabies
Injectabies can help women with HIV/AIDS avoid unintended pregnancy.
INFO Project
Center for Communication Programs
Johns Hopkins Bloomberg
School of Public Health
111 Market Place, Suite 310
Baltimore, Maryland 21202 USA
410-659-6300
410-659-6266 (fax)
www.infoforhealth.org
infoproject@jhuccp.org
Jane T. Bertrand, PhD, MBA, Professor and
Director, Center for Communication Programs
Earle Lawrence, Project Director, INFO Project
Stephen Goldstein,Chief, Publications Division
• Table 1: Estimated Worldwide Use of Injectabies, p. 3
• Table 2: Formulations, Injection Schedules, arid Availability of Injectable
Population Reports is designed to provide
an accurate and authoritative overview of
important developments in family planning
and related health issues.The opinions
expressed herein are those of the authors
and do not necessarily reflect the views of
the U.S. Agency for International Development
(USAID) or Johns Hopkins University.
Contraceptives, p. 5
• Table 3: Key Resources for Program Managers and Providers, p. 22
Published with support from USAID, Global, GH/POP/PEC,
under the terms of Grant No. GPH-A-00-02-00003-00.
Bibliography
Note: Italicized reference numbers in the text refer to citations printed on
page 23.These were the most helpful in preparing this report. Other citations
can be found online at http://www.populationreports.org/k6/
Tools for Program Managers
• Checklist: Good-Quality Injectabies Services, p. 11
• Checklist:Improving Access to Injectabies, p. 15
Tools for Providers are in the companion INFOReports.See also Population
Reports, "When Contraceptives Change Monthly Bleeding,"Series J, No. 54,
August 2006.
Coming Soon;"lnjectablesToolkit"Web site.Go to http://www.injectablestoolkit.org
for job aids and information about injectable contraceptives.
Cover Photo: A provider gives a client an
Injection in Bangladesh, where use of inject
abies has doubled over the last decade. As
more women choose injectable contracep
tives, programs will need to offer more good
quality services.
Injectables Today and Tomorrow
private clinics and providers will offer injectables (144,152).
More and more women are using injectable contraceptives
today, and very likely even more will use this method in the
More pharmacists will provide injectables in many countries,
often as a part of social marketing programs (35,36,145).
More programs will offer injectables in community services,
and some women will choose home injection with the new
future as it becomes increasingly available. Women choose
injectables because they are effective, long-lasting, and
private. For family planning programs, meeting increasing
demand while maintaining good quality will be the key to
DMPA formulation for subcutaneous injection (under the skin
rather than in the muscle) (see box, p. 16).
success with injectables.
Between 1995 and 2005 the number of women ,
worldwide using injectable contraceptives more
than doubled. About 12 million married women
used injectables in 1995. In 2005 over 32 million
were using injectables (108,163,194). Injectables
are the fourth most popular method worldwide,
after female sterilization, the intrauterine device
(IUD), and oral contraceptives.In sub-Saharan
Africa, injectables are the most popular method,
chosen by 38% of women using modern methods
(see Table 1). By 2015 worldwide use is projected
to reach nearly 40 million—more than triple the
1995 level (163).
Table 1. Estimated Worldwide Use of Injectables
Among Married Women Ages 15-49, 2006
Region &
Selected Countries
% Currently Using
Any
Modern
Inject
Method
ables
Any
Wlethoi:i
% of Modern
Method
Users Using
Injectables
DEVELOPING AREAS
58
52
3
7
Sub-Saharan Africa
21
15
6
38
Kenya 2003
38
31
14
46
Lesotho 2004
36
35
15
42
Malawi 2004
31
28
18
64
Namibia 2000
44
43
19
44
28
47
Greater access largely explains this rapid growth in
use. Approval of the progestin-only injectable DMPA
(depot medroxyprogesterone acetate) in the United
South Africa 2003
60
60
Near East & North Africa
52
40
2
4
States in 1992 removed a constraint to access and
Egypt 2005
62
57
7
12
a source of controversy in many countries over pro
viding a drug that was not approved for contracep
tion in the United States. Also, approval in the United
Asia
States enabled the U.S. Agency for International
Development (USAID) to supply DMPA to develop
ing countries. As of 2006 DMPA was registered in
179 countries, an increase from 106 countries in
1995 (83,99). Several countries, including Ghana,
Vietnam, and Zambia are introducing or scaling up
DMPA services as part of a package of reproductive
or primary health care services (138,224,226).
In the next 10 years more family planning pro
grams will offer injectables, and they will offer
clients more choices of injectables. Most can be
expected to offer a progestin-only injectable—
DMPA injected every three months or NET-EN
(norethisterone enanthate) injected every two
months. Many will offer a combined injectable,
probably either medroxyprogesterone acetate (MPA)
combined with the estrogen estradiol cypionate
(E2C) or NET-EN combined with the estrogen
estradiol valerate (E2V). Both are injected monthly.
Other combined injectables are available in some
countries and regions (see Table 2, p. 5).
Women will be able to have injections in more
convenient locations (see Checklist, p. 15). More
63
59
3
5
Bangladesh 2004
53
47
10
21
Cambodia 2005
40
27
8
29
Indonesia 2002-03
60
57
28
49
Nepal 2006
Latin America
& Caribbean
48
44
10
23
71
62
4
6
Haiti 2005-06
30
24
11
47
El Salvador 2002-03’
67
61
18
30
22
Nicaragua 2001
67
66
14
DEVELOPED AREAS
68
57
1
1
Europe
74
64
0
0
Eastern Europe &
Central Asia
63
42
0
1
North America
75
71
3
4
Other developed11
59
64
0
0
WORLD
59
53
3
6
‘Data for women 15-44
‘Includes Australia. Israel, Japan, and New Zealand
Methodology and data sources: Data for the number of married women ages
15-49 for each country were obtained from population projections for 2005 by
the World Bank (201) Percentages are weighted by population size—that is,
they reflect differences in population among the countries. Usage rates come
from the most recent data from the Demographic and Health Surveys and
Reproductive Health Surveys and, for countries without these surveys, data
from the United Nations, 2005 (194), the U.S. Census Bureau's International
Database (191), and other nationally representative surveys, including the U.S.
National Surveys of Family Growth (122).
How to Use This Report
factors, including access to injectables, norms related to
“This report can help family planning program managers develop
strategies to:
contraceptive use, government policies, women's tolerance
for side effects, and communication about injectables.
• .Meet the increasing demand for injectables with good-quality
• Address women who:
- Would like to use injectables but lack access.
- Hesitate to use injectables because they need more information
about side effects or safety.
Providers can use the companion issue of INFO Reports, “Injectable
Contraceptives: Tools for Providers," to review the important ele
ments of good-quality services. 'I he tables and checklists in the
INTO Report are aids for counseling women, giving safe injections,
and helping women be satisfied users of injectables.
Demand Accelerates and Suppliers Respond
Since 1995 the percentage of married women who rely on
injectables has increased in 40 of 44 developing countries
with multiple surveys (see Web Table 1'). Use increased
particularly in Indonesia among married women ages 15-49
from 15% in 1994 to 28% in 2002, after the method was
^rigorously promoted and more widely distributed. Nearly half
of all married Indonesian women using contraception now
Governments, donors, and manufacturers respond. Where
demand is increasing rapidly,governments have responded
by placing larger procurement orders for injectables (see p.6).
Major donor agencies have steadily increased shipments
of progestin-only injectables to developing countries (see
Web Figure2). Between 2003 and 2005 shipments by the
United Nations Population Fund (UNFPA), USAID,and the
International Planned Parenthood Federation (IPPF) more
than doubled, rising from 23 to 48 million doses per year.
These donors contribute almost 60% of the total donated
contraceptives worldwide. UNFPA, currently the largest
supplier of injectables, shipped 27 million doses in 2005,
a 35% increase over 2004.Shipments by USAID doubled
between 2000 and 2005, rising from 9.3 million to 18.6
million doses, and they are expected to increase to 20
million in 2006 (21,159). Sales of injectables by social
marketing programs more than doubled between 2000
and 2005 (see p. 17). One manufacturer of DMPA projects
annual demand for 150 million doses (enough for 37.5
million users) by 2010 (103).
rely on injectables. Use also has increased sharply in Haiti,
Malawi,and Namibia.Between 2005 and 2015 the largest
increases in number of users are expected in Indonesia
(almost 2 million additional users), Nigeria (almost 1 million
more),and Pakistan (over 200,000 more) (763).
Effectiveness, Convenience, and Side Effects
Influence Use
Many women have chosen injectables as their first modern
method, and others have switched to injectables from oral
Popular in some countries but little used in others.
Overall,awareness and use of injectables are increasing, but
levels of use vary widely within regions. In sub-Saharan Africa, ,
contraceptives or other methods (44,139).Women are choos
ing injectables because they offer a variety of advantages:
Asia, and Latin America and the Caribbean, over 40% of married
•
contraceptive users rely on injectables in some countries,
while 5%-7% use them in other countries (see Web Table 2').
Variations within regions can be attributed to a variety of
Highly effective. Used correctly, injectables are more
effective than female sterilization. If women return on
time for injections, in the first year on average 3 among
every 1,000 women using progestin-only injectables
will become pregnant, and 5 among
every 10,000 women using combined
injectables (190). As injectables are
commonly used in the United States, 3 in
every 100 women become pregnant in
the first year of use.This pregnancy rate
is higher than that for IUDs, implants, and
male and female sterilization but lower
than that for oral contraceptives.
• Long-acting. Users need to remember
only to have an injection every two
Workers package DMPA in the warehouse ofProSalud, a nonprofit organization in Bolivia.
Manufacturers, donors, and family planning programs in many countries are increasing the
supply ofinjectables to meet demand.
Web Tables are available for download and printing at http://www.populationreports.org/k6/k6tables.shtml
The Web Figure is available fordownload and printing at http://www.populationreports.org/k6/k6figures.shtml
or three months for progestin-only
injectables or once a month for com
bined injectables. Users do not have to
remember to do something every day
or when about to have sex (20,54).
• Reversible. Fertility returns after a
woman stops using an injectable.
|l^Sk| Table 2. Formulations, Injection Schedules, and Availability of Injectable Contraceptives
. N »mes
1
|
Formulation
Injection Type and
Schedule
1
Registration/
Availability in 2006
iogestin-Only injectabies
Depo-Provera®.
Megestron®, Contracep®,
Depo-Prodasone®
depo-subQ provera 104s
(DMPA-SC)
Depot medroxyprogesterone
acetate (DMPA) 150 mg
One intramuscular
(IM) injection every 3
months
Registered in 179 countries
DMPA 104 mg
One subcutaneous
injection every 3
months
Approved in United States and
United Kingdom; approval
expected soon in other European
countries; expected to be
available in some developing
countries by 2008
Noristerat®. Norigest®,
Doryxas®
Norethisterone enanthate
(NET-EN) 200 mg
One IM injection
every 2 months
Registered in 91 countries
Registered in 12 countries2
Combined Injectabies (progestin + estrogen)1
Cyclofem®, Ciclofeminina®,
Lunelle®
Medroxyprogesterone aceta/e 25
mg + Estradiol cypionate 5 mg
(MPA/E2C)
One IM injection
every month
Mesigyna®, Norigynon®
NET-EN 50 mg + Estradiol
valerate 5 mg (NET-EN/E2V)
One IM injection
every month
Registered in 33 countries
Dihydroxyprogesterone
(algestone) acetophenide 150
mg + Estradiol enanthate 10 mg
One IM injection
every month
Registered in 14 Latin American
countries and Spain
Anafertirf, YectameS®
Dihydroxyprogesterone
(algestone) acetophenide 75 mg
+ Estradiol enanthate 5 mg
One IM injection
every month
Registered in 7 Latin American
countries
Chinese Injectable No. 1®
17 a-hydroxyprogesterone
caproate 250 mg + Estradiol
valerate 5 mg
One IM injection every
month, except 2 injec
tions in first month
Registered in China
Mh Deladroxate®, PerlutaP,
TopaseP, Patectro®,
Deproxone®, Nomagest®
Sources: IPPF 2005 (83), Lande 1995 (99), Liggeri 2006 (103), WHO 1990 (204), WHO 1993 (205)
' Also called monthly injectabies.
’The U.S. Food and Drug Administration has approved Lunelle, but it is currently not available in the United States.
Women stopping DMPA to become pregnant, however,
take several months longer to conceive on average than
women who used other methods (130,171).
Private. Women can use injectabies without anyone else
knowing (20,109,126,138,186)—particularly if a partner
or in-laws object to contraception (19,31).
Progestin-only injectabies offer additional advantages for
some women:
•
They can be used during breastfeeding starting six weeks
bleeding changes, no monthly bleeding, and weight gain
(13,70,135,168). In a large multinational World Health
Organization (WHO) trial,on average half of women stopped
using DMPA and NET-EN within 12 months (202). In the United
States more women stop using injectabies within 12 months
than stop oral contraceptives or the copper IUD (190).
Good counseling can be the difference between
successful and unsuccessful efforts to expand
access to injectabies.
after giving birth (212).
•
Monthly bleeding stops after a time for many users. Some
women see this as an advantage of the method (62).
•
Weight gain, common with use of injectabies, is welcome
Good counseling, especially about changes in monthly bleed
ing and other side effects, helps women decide whether
injectable contraception will suit them and it helps women
Side effects deter many, but counseling helps. At the
continue using injectabies (30,59,75,100,227). Good
counseling can be the difference between successful and
unsuccessful efforts to expand access to injectables (77,
78,224). Introducing injectabies or any new method is an
same time, many women do not choose injectabies or they
stop using them mainly because of side effects—particularly
opportunity to improve counseling and quality of care for all
available methods (224).
for some women (4,78,109,166).
: Contraception. 1997 Dec;56(6):353-9.
Related Articles, Links
Introductory study of the once-a-month, injectable contraceptive
Cyclofem in Brazil, Chile, Colombia, and Peru.
Hall P, Bahamondes L, Diaz J, Petta C.
Special Programme of Research, Development and Research Training in Human
Reproduction, World Health Organization, Geneva, Switzerland.
An introductory trial with the injectable contraceptive Cyclofem was carried out
in Brazil, Chile, Colombia, and Peru, with participation by 3,183 women. Women
were followed-up for up to 2 years of use and the data were evaluated by life table
analysis. A total of 29,676 women-months were accumulated for up to 2 years.
No pregnancies were observed in the 2 years. The discontinuation rates for
amenorrhea in the first year ranged from 3.4 in Brazil to 8.1 in Colombia, and for
menstrual disturbances from 5.1 in Chile to 9.2 in Brazil. The discontinuation
rates for other medical reasons ranged from 7.8 in Brazil to 26.3 in Colombia, and
for personal reasons from 17.2 in Chile to 23.5 in Brazil. Continuation rates
ranged from 42.3 in Colombia to 52 in Chile. In the second year of observation
the rates of discontinuatiop were lower than those observed in the first year, with
the exception of personal reasons in Brazil, which were the same as those
observed in the first year. Continuation rates ranged from 19.4 in Brazil to 36.8 in
Chile. The comparison of reasons for discontinuation in selected clinics showed
that the rate for amenorrhea in one clinic in Chile was more than three times that
in others and in Peru was seven times more in one clinic than in another.
Regarding menstrual disturbances, in Peru one clinic presented a rate three times
higher than the others. The main reasons for discontinuation due to other medical
reasons were headache and weight gain. In conclusion, Cyclofem presented a high
contraceptive efficacy and an acceptable rate of continuation and discontinuation
for up to 2 years in the four countries.
PIP: The performance of the monthly injectable contraceptive, Cyclofem, was
evaluated in an introductory trial involving 3183 women recruited from family
planning centers in Brazil, Chile, Colombia, and Peru. A total of 29,676 womenmonths of use were accumulated during up to 2 years of follow-up. No
pregnancies occurred during the study period. Discontinuation rates per 100
women in the first year ranged from 3.4 in Brazil to 8.1 in Colombia for
amenorrhea and from 5.1 in Chile to 9.2 in Brazil for menstrual disturbances. The
discontinuation rate for other medical reasons (primarily headache, weight gain,
and acne) ranged from 7.8 in Brazil to 26.3 in Colombia and for personal reasons
from 17.2 in Chile to 23.5 in Brazil. First-year continuation rates ranged from
42.3 in Colombia to 52.0 in Chile. In the second year of use, continuation rates
ranged from 19.4 in Brazil to 36.8 in Chile. Upon receiving these results, national
regulatory authorities in the 4 participating countries approved Cyclofem
registration. Acceptance of injectable contraception, which currently entails
administration of the method by a service provider and travel to a clinic, could be
improved in developing countries by training in self-administration.
: Contraception. 1994 Apr;49(4):387-98.
Related Articles,
Links
Once-a-month injectable contraceptives: efficacy and reasons for
discontinuation.
Koetsawang S.
Siriraj Family Planning Health Research Centre, Department of Obstetrics and
Gynaecology, Mahidol University, Bangkok, Thailand.
Reports of the phase III clinical trials on four combined progestogen-estrogen
once-a-month injectable contraceptives, Deladroxate, Cyclofem, Mesigyna and
Chinese Injectable No. 1, are reviewed focussing on efficacy and reasons for
discontinuation. Deladroxate, currently used in many Latin American countries
has proved to be highly effective and well accepted. However, this combination
was withdrawn by the original manufacturer because the progestogen component
of this drug induced a high number of breast cancers in dogs and very curious
pituitary hyperplasia in rats. Cyclofem and Mesigyna were found to be highly
effective and highly acceptable drugs. Side-effects were minimal and were of
minor importance. The Chinese Injectable No. 1 had unacceptably high failure
rates with a monthly injection schedule. After doubling the dose in the first month
of use, the efficacy was satisfactory. It was found that all monthly injectable
contraceptives provided better cycle control than the every 3 months depotmedroxyprogesterone acetate, although abnormal bleeding was still the main
drug-related complaint and reason for discontinuation. Missed appointment is
another reason for discontinuation which might reflect the problem of frequent
injection schedule, thus indicating the need for proper selection of the users and
good counselling.
PIP: This literature review examines the efficacy and reasons for discontinuation
of 4 combined progestogen-estrogen, once-a-month injectable contraceptives:
Deladroxate, Cyclofem, Mesigyna, and Chinese injectable No. 1. Deladroxate is
used mainly in Latin America, while the Chinese injectable No. 1 is largely
limited to China. Among 18 studies, no pregnancies occurred in the 3017 women
using Deladroxate (32,857 woman-months). It was well accepted, but the
manufacturer withdrew it from the market after studies showed that the
progestogen (dihydroxyprogesterone acetophenide) caused dogs to develop breast
cancer and rats to develop; an odd pituitary hyperplasia. Of the 4 once-a-month •
injectables, Cyclofem and Mesigyna provide the most promise. They are very
effective at preventing pregnancy (0-0.23/100 women-years of use and 0.080.48/100 women-years of use, respectively). Acceptance of Cyclofem and
Mesigyna was high. Side effects were limited and had minimal importance. An
advantage of Cyclofem' arid Mesigyha is their much better cycle control than the
once-every-3 months injectable Depo-Provera. The failure rate of the Chinese
Injectable No. 1 on the once-a-month injection schedule was too high (10.35/100
women-years of use). When researchers doubled the dose in the 1 st month of use,
however, efficacy was satisfactory (0.8/100 women-years of use). The main drugrelated complaint and reason for discontinuation of all once-a-month injectables
was abnormal bleeding. Another key reason for discontinuation was missed
appointment, suggesting that a frequent injection schedule poses a problem. Good
planning and health workers properly selecting users and providing them good
counseling may overcome this problem. Frequent visits would increase the staff
work load.
CONTENTS
•
•
Editor's Summary
Credits
Chapters
1.
Combined Oral
Contraceptives
Progestin-Only Pills
Progestin-Only
Injectables
4. Combined
Injectables
5. Norplant Implants
6. Copper-Bearing
IUDs
7. Female Sterilization
8. Vasectomy
9. Lactational
Amenorrhea
Method
10. Natural Family
Planning
11. Barrier Methods
2.
3.
•
•
How to Be
Reasonably Sure
the Woman Is Not
Pregnant
Importance of
Selected Procedures
for Providing
Family Planning
Methods
Combined Injectable Contraceptives
The name of combined injectable contraceptives, or CICs, is
given to a group of hormonal contraceptives administered by
intramuscular injection. The term "combined" indicates that
these injectables contain both a progestin and an estrogen. At
present there are three main types of CICs on the market:
Progestin
Natural
Estrogen
Brand
Name
Depomedroxyprogesterone
acetate (DMPA)
25 mg
Estradiol
cypionate
5 mg
Norethisterone enanthate
(NEt EN) 50 ftig
Estradiol valerate Mesigyna
5 mg
Dihydroxy-progesterone
acetophenide 150 mg
Estradiol
enanthate
10 mg
Cyclofem
Deladroxate
The first two are new products becoming more widely used
throughout the world; the third is mostly used in some Latin
American countries. The three formulations provide very
effective pregnancy protection for a 30-day period. Therefore
they are also referred to as "monthly injectables."
CICs have some similarities with progestin-only injectables:
•
•
WHO Medical
Eligibility Criteria
Bibliography
•
•
•
•
POPLINE
Other Issues
To Order
CCP Home Page
Published by the Population
Information Program, Center
for Communication Programs,
The Johns Hopkins School of
Public Health, 111 Market
Place, Suite 310, Baltimore,
Mary land 21202-4012, USA
Volume XXIV, Number
2
October 1996
the two new CICs contain precisely the same progestin as the
two most widely used progestin-only injectables (DepoProvera and Noristerat)", however, the progestin dose
received over time is much lower with the new CICs.
Although a basic difference from the progestin-only
injectables is the presence of estrogen in the CICs, the
estrogen was incorporated mostly to improve the control ofthe menstrual cycle.
Both CICs and combined oral contraceptives (COCs) are
combined hormonal contraceptives. Besides the different
route of administration, from a safety point of view the most
important difference is the presence of a "natural" estrogen in
the CICs versus a "synthetic" estrogen in the COCs. It is now
recognized that natural estrogens have very favorable effects
on lipid metabolism and cardiovascular function. The use of
natural estrogens in postmenopausal women has actually
shown a protective effect against cardiovascular disease,
including both cerebrovascular and cardiac problems.
Estradiol has direct effects on the arterial wall and on various
stages of atherosclerotic plaque formation, resulting in an
increase of tissue blood flow and in an anti-atherosclerotic
effect! No significant changes in these effects have been
found attributable to the addition of a progestin.
Based on the above evidence, CICs might actually be
considered safer than COCs. However, due to the recent
introduction of the two new CICs, no long-term safety
information on CIC use is available yet. Therefore, the
medical criteria for CIC use are mostly derived from the
information existing on COC use.
Q.l. When is the best time to start CICs?
In general?
Recommendation: CICs can be started any time you can be reasonably
sure the woman is not pregnant (see
)•
If given within the first 7 days of the menstrual cycle, it becomes effective
immediately. However, if CICs are started after the first 7 days of a cycle
or the woman is not menstruating, a back-up method is recommended to
be used for 7 days. Some providers recommend a back-up method be used
for 7 days if Cyclofem or Mesigyna are begun after the fifth day of the
cycle.
Hypothetically, all CICs are effective when begun within the first 7 days
of the menstrual cycle.
Rationale: Deladroxate is effective immediately when given within the
' first 7 days of the menstrual cycle and possibly later. Most clinical trials
of Cyclofem and Mesigyna (two newer, lower-dose formulations of CICs)
have used the first 5 days of the cycle as the period for initiation.
1 However, a recent study has demonstrated high contraceptive efficacy for
; a CIC similar to Cyclofem and Mesigyna when initiated between days 7
and 10 of the menstrual cycle.
| Some experts believe that the lower-dose CICs are effective at least as
promptly as COCs. These CICs have slightly less estrogen effect and
I more progestin effect than COCs, and it is presumed that their effect on
■ cervical mucus is at least as prompt as.the effect of COCs (46, 152).
Postpartum for breastfeeding women?
Recommendation: Because they contain estrogen, CICs should not be
considered the first option for breastfeeding women. The WHO considers
the risks from using estrogen-containing methods during breastfeeding
■ before 6 weeks postpartum to generally outweigh the benefits (Category
| 3), unless other methods are not available or acceptable.
Rationale: There are no data on the effects of combined injectables used
• during lactation. The following rationale is based on what is known about
combined oral contraceptives.
: Even low-dose (30 micrograms) COCs decrease breastmilk production; it
I may be that estrogen-containing injectables, although they have a lower
, estrogen dose than COCs, will have a similar effect, but this has not been
! studied (310,311).
Postpartum for nonbreastfeeding women?
Recommendation1: CICs can be started from the second to the third week
I postpartum or at the first postpartum menstruation.
i Rationale: Blood coagulation and fibrinolysis are essentially normalized
by 3 weeks postpartum (and are close to normal at 2 weeks postpartum).
i CICs have minor effects on blood coagulation (51,98).
Postabortion?
Recommendation: CICs can be initiated any time within the first-week
I after an abortion.
i Rationale: CICs may be initiated any time after a first- or second' trimester abortion or postseptic abortion (310).
Q.2. When can the next injection be provided?
Recommendation: The best time to provide the next injection is on the
same date each month (or a 4-week schedule may be practical for some.
i programs). This should be emphasized when training personnel and
! counseling clients.
The grace period of combined injectable contraceptives is officially 3
dayp. If a client copies in after the grace period (27 to 33 days after the •
previous injection), advise her that delays in obtaining injections increase
the risk of pregnancy. Offering re-injection for women who come in after
the grace period is reasonable for women who state that, once beyond the
i grace period, they have been abstaining or consistently using a back-up
I method and/or the provider can be reasonably sure that the woman is not
pregnant.
Rationale: Clinical trials have studied the efficacy of CICs given 27 to 33
days after the previous injection and found the efficacy to be very high.
Some studies have found that the risk of ovulation is low up to 60 days
after the previous Cyclofem or Mesigyna injection (1, 18, 235).
Recommendation: There is a risk of in ulero exposure to the injectable if
she is pregnant when she receives the next injection. However, there is no
evidence that fetal exposure to CICs will be harmful.
Rationale: Although the estrogens and progestins in CICs have no known
teratogenic effects, avoiding the risk of fetal exposure is preferable on ,
general principles (28, 251).
Recommendation: It is acceptable to give the injection if you can be
reasonably sure she is not pregnant (see
). Some programs will advise women to use a
i back-up method for the rest of the cycle.
Q.3. If a woman complains of heavier menses and/or
prolonged bleeding, is there a medical basis
for discontinuing CICs?
Recommendation: Not usually. Heavy bleeding (greater than normal
menstrual bleeding) is common in the first 3 months of use and usually
does not require discontinuation.
i Rationale: Approximately 20% of CIC users experience frequent or
prolonged menstrual bleeding within the first 3 months. However, these
; variations from normal bleeding patterns tend to decrease with time (30‘0).
Recommendation: If bleeding has stopped and the woman wants to
i continue using CICs, reassure her first. The woman should be reassured
by informing her that these effects usually pose no threat to health and
; tend to improve over time.
| Rationale: Compared with women not using any contraceptive method,
' CIC users experience a significantly increased incidence of frequent,
irregular, and prolonged bleeding (300).
Recommendation: Ifa woman is experiencing more days of bleeding
i than she was prior to starting CICs, the first approach should be
counseling to provide information and reassurance.
If the bleeding is intolerable to the woman but she wishes to continue
CICs, then administration of supplementary short-term estrogen (or
COCs) or prostaglandin inhibitors may be tried.
Rationale: Little research has been done on the management of heavy
bleeding in CIC users. Prolonged or heavy bleeding in users of COCs or
progestin-onjy injectables may be managed by stabilizing the
endometrium with increased doses of estrogen or by ibuprofen (or related
nonsteriodal anti-inflammatory drugs), which blocks prostaglandin
synthesis and thus decreases uterine bleeding (261, 303).
Recommendation: Some women may not be able to tolerate heavy or
prolonged bleeding and will discontinue CICs and need another method.
Evaluate and address anemia if appropriate.
Do not perform uterine evacuation unless another medical condition is
suspected. (Vacuum aspiration is always the preferred method of uterine
evacuation.)
Q.4. Who can safely initiate and resupply CICs?
Recommendation: CICs (including immediate postpartum and
postabortion injections) can be safely administered by appropriately
trained service providers (e.g., nurses, midwives, pharmacists, CBD
workers, and others), provided that infection-prevention measures can be
assured.
Rationale: Nurses, midwives, and other community health workers can be
appropriately trained to initiate and resupply injectables (303).
Recommendation: Under certain circumstances, clients may be provided
with the supplies for self-administration or administration by another
individual, provided that appropriate storage and infection-prevention
procedures can be assured and that the woman knows where she can
receive supportive services, should she have any problems.
Q.5. What is the recommendation for the once-a-month
injectable contraceptive with 10 mg of estradiol enanthate
and 150 mg of dihydroxyprogesterone acetophenide?
Recommendation: Use of the older injectable (10 mg of estradiol
enanthjste and 1 SO^mg of dihydroxyprogesterone acetophenide) is not encouraged due to the availability of newer, lower-dose injectables
(Mesigyna and Cyclofem). The newer CICs have theoretical advantages
(lower estrogen dose) and more clinical trial data demonstrating their
safety and efficacy.
However, some women may prefer the more reliable menstrual periods
produced by the CIC with 10 mg of estradiol enanthate and 150 mg of
dihydroxyprogesterone acetophenide (this "menstrual signal" can serve as
a reminder for reinjection) or may otherwise have a personal preference.
The older CIC may be made available since it may be an appropriate
choice for some women.
Rationale: Both the older and newer CICs have very high efficacy.
However, there is a theoretical concern of using 10 mg of estrogen
monthly, because of the possible negative effects on blood coagulation.
Newer CICs, such as Cyclofem and Mesigyna, have half the estrogen
dosage of the older CICs. The lower-dose CICs have, at least
theoretically, less risk.
In the first year of use, the CICs with 10 mg of estradiol enanthate and
150 mg of dihydroxyprogesterone acetophen ide cause menstrual
irregularities in an average 22.4% of users, with a range of 7.5% to
24.4%* However, 30% of users of Cyclofem and Mesigyna experienced'
menstrual irregularities within the first year. The incidence of menstrual
irregularities decreased with duration of use (152, 300).
Previous | Next
I
111 Market Place, Suite 310, Baltimore, MD 21202, USA
Phone: (410) 659.6300/Fax: (410) 659.6266/E-mail: Poprepts@ihuccp.org
IE L S E V 1 E R
I: Contraception. 2005 Aug;72(2): 13R-45.KUSt^jt£iWg^a Links
Comparative acceptability of combined and progestinonly injectable contraceptives in Kenya.
Rum in jo JK. Sekadde-Kigondu CB, Karan ja JG, Rivera R, Nasution M,
Nutlev T.
Department of Obstetrics and Gynecology, University of Nairobi, Nairobi, Kenya.
OBJECTIVE: We compared 12-month continuation rates, menstrual bleeding
patterns and other aspects of acceptability between users of Cyclofem and users of
Depo-Provera. METHODS: The life-table method was used to calculate quarterly
continuation rates. In all, 360 Kenyan women were randomly assigned to one of
the two contraceptives. User-satisfaction questionnaires were administered at 6
and 12 months or at discontinuation, whichever occurred first. RESULTS: The 1year continuation rate was 75.4% for Depo-Provera users versus 56.5% for
Cyclofem users (p<.001). Main reasons for discontinuation included difficulty
making clinic visits (45.1% for Cyclofem vs. 40% for Depo-Provera), menstrual
changes (14.1% vs. 12.5%) and nonmenstrual problems (15.5% vs. 12.5%). Nope
of the Depo-Provera users and'8.5% of the Cyclofem users claimed frequency of
visits as the main reason for discontinuation. In all, 70.6% of the Depo-Provera
users were amenorrheic after 12 months, as were 20.8% of the Cyclofem users.
CONCLUSIONS: The 1-year continuation rate was higher for Depo-Provera than
for Cyclofem. There was no important difference in discontinuation rates because
of menstrual problems; the difference mainly reflected the frequency of visits
required.
[E"L S fe v t HR |
1: Contraception. 2004 Feb;69(2): 115-9.WiMM33t«arwai=|
Links
Menstrual pattern and lipid profiles during use of
medroxyprogesterone acetate and estradiol cypionate
and NET-EN (200 mg) as contraceptive injections.
Canto de Cetina TE, Luna MO, Gctina Canto J A, Bassol S.
Dr. Hideyo Noguchi Biomedical Research Centre, University of Yucatan,
Yucatan, Mexico, Mexico. tcetina@tunku.uady.mx
The objectives of this study were to compare effects of medroxyprogesterone
acetate 25 mg + estradiol cypionate 5 mg (Cyclofem) and norethisterone
enanthate (NET-EN) upon the menstrual pattern and determine changes in
lipoprotein parameters after 12 months of use. One-hundred females were
included and 87 (45 with Cyclofem and 42 with NET-EN) women completing 12
months were evaluated. Menstrual changes were the leading complaint among
users. At the end of 12 months, 20/45 (44.4%) and 18/41 (43.9%) Cyclofem and
NET-EN users, respectively, had normal menstrual pattern. Irregular and
infrequent bleeding were the two most important changes that occurred. The
discontinuation rate at 12 months due to menstrual disturbances did not show any
significant differences between the two preparations, but showed lower incidence
compared to other studies. Total cholesterol, high-density, low-density and very
low-density lipoprotein cholesterol and triglyceride levels decreased at 12 months
in both groups and these changes were statistically significant.
1: Contraception. 2003 Sep;68(3)j 159-76.
Links
Comparative study of the effects of two once-a-month
injectabie contraceptives (Cyclofem and Mesigyna) and
one oral contraceptive (Ortho-Novum 1/35) on
coagulation and fibrinolysis.
United Nations Development Programme/United Nations Population
Fund/World Health Organization/World Bank Special Programme of
Research, Development and Research Training in Human Reproduction,
Task Force on Long-acting Systemic Agents for Fertility Regulaion.
A randomized controlled multicenter study was undertaken to monitor the effects
on hemostasis of two once-a-month injectable contraceptive preparations,
Mesigyna (50 mg norethisterone enanthate and 5 mg estradiol valerate) and
Cyclofem (25 mg medroxyprogesterone acetate and 5 mg estradiol cypionate) in
comparison with a well-known oral contraceptive (OC) Ortho-Novum 1/35
(norethisterone 1 mg and ethinyl estradiol 35 microg). A total of 378 volunteers
from four centers (Bangkok, Hangzhou, Santiago and Singapore) were monitored.
Blood sampling took place in one pretreatment cycle, the third and ninth injection
intervals and one posttreatment cycle. In each of the three treatment groups, a rise
in hemoglobin, and increases in platelet count and in prothrombin time were
observed. With treatment there was a significant increase in activated partial
thromboplastin time among Mesigyna users, no changfc among Cyclofem users
and a significant decrease among OC users. OC use led to increases in plasma
levels of fibrinogen, factor VII, factor X, plasminogen, protein C and decreases in
plasma levels of t-PAI and antithrombin. Use of combined injectables induced no
change (Cyclofem) or decreases (Mesigyna) in plasma levels of fibrinogen, factor
VII, factor X and antithrombin. Use of both combined injectables led to decreases
in protein C, slight decreases in plasminogen and increases in plasminogen and
fibrinogen. Overall, the injectable preparations may be more beneficial than the
oral preparation in not Enhancing a hypercoagulable state because of the reduced
synthesis of fibrinogen, factors VII and X; however, decreases in antithrombin
and protein C, which are potent coagulation inhibitors, may raise some concern.
Whether these changes can lead to modifications in the risk of arterial or venous
disease can only be ascertained by conducting epidemiological studies.
1: Contracept Technol Update, 1998 Jan;19(l):3-4.
Links
New year, new option: Cyclo-Provera awaits word.
[No authors listed]
PIP: This article discusses the potential availability of Cyclo-Provera, a monthly
injectable similar to Depo-Provera that is being considered for approval by the US
Food and Drug Administration (FDA). A new drug application was filed by its
marketing company, Pharmacia and Upjohn of Kalamazoo, Michigan, in
September 1997. The company wants mutual recognition by the FDA in US and
European markets. The Jones Institute for Reproductive Medicine at the Eastern
Virginia Medical School in Norfolk recently completed a company-sponsored
clinical trial of the drug. This Institute is 1 of 44 sites conducting nationwide
clinical trials among a total sample bf 1200 women over 5 years. Cyclo-Provera is
comprised of depomedroxyprogesterone acetate (DMPA), which is the same
ingredient in Depo-Provera. Cyclo-Provera has a lower dose of DMPA (25 mg)
combined with 5 mg of estradiol cypionate. The ingredients are expected to
provide improved monthly menstrual cycle control. Cyclo-Provera is marketed
outside the US under the name Cyclofem. Cyclofem is mainly used in China and
Latin America. Germany produces a similar drug. The World Health Organization
(WHO) has conducted multinational studies on both drugs. WHO recommends
Cyclofem for most women who desire effective, reversible contraception and who
are not at risk for most cardiovascular complications. The estrogen in Cyclofem is
less potent and has a shorter life span than the estrogen in combined
contraceptives. WHO guidelines suggest that Cyclofem has advantages that
outweigh disadvantages for smokers under 35 years old, light smokers older than
35, women with mild hypertension (160/100), women with current or medically
treated gall bladder disease, or women with mild cirrhosis. Cyclofem is not
recommended for heavy smokers over 35 years old, women with a history of .
hypertension, and women with severe cirrhosis.
1: Contracept Technol Update. 1998 Jan;19(l):3-4.
Links
New year, new option: Cyclo-Provera awaits word.
[No authors listed]
PIP: This article discusses the potential availability of Cyclo-Provera, a monthly
injectable similar to Depo-Provera that is being considered for approval by the US
Food and Drug Administration (FDA). A new drug application was filed by its
marketing company, Pharmacia and Upjohn of Kalamazoo, Michigan, in
September 1997. The company wants mutual recognition by the FDA in US and
European markets. The Jones Institute for Reproductive Medicine at the Eastern
Virginia Medical School in Norfolk recently completed a company-sponsored
clinical trial of the drug. This Institute is 1 of 44 sites conducting nationwide
clinical trials among a total sample of 1200 women over 5 years. Cyclo-Provera is
comprised of depomedroxyprogesterone acetate (DMPA), which is the same
ingredient in Depo-Provera. Cyclo-Provera has a lower dose of DMPA (25 mg)
combined with 5 mg of estradiol cypionate. The ingredients are expected to
provide improved monthly menstrual cycle control. Cyclo-Provera is marketed
outside the US under the name Cyclofem. Cyclofem is mainly used in China and
Latin America. Germany produces a similar drug. The World Health Organization
(WHO) has conducted multinational studies on both drugs. WHO recommends
Cyclofem for most women who desire effective, reversible contraception and who
are not at risk for most cardiovascular complications. The estrogen in Cyclofem is
less potent and has a shorter life span than the estrogen in combined
contraceptives. WHO guidelines suggest that Cyclofem has advantages that
outweigh disadvantages for smokers under 35 years old, light smokers older than
35, women with mild hypertension (160/100), women with current or medically
treated gall bladder disease, or women with mild cirrhosis. Cyclofem is not
recommended for heavy smokers over 35 years old, women with a history of
hypertension, and women with severe cirrhosis
I Is
S I: V [ i: R|
1: Contraception. 1997 Dec.;56(6)- 3 53-9
Links
Introductory study of the once-a-month, injectable
contraceptive Cyclofem in Brazil, Chile, Colombia, and
Peru.
Hall P, Bahamondes L, Diaz J, Petta C.
Special Programme of Research, Development and Research Training in Human
Reproduction, World Health Organization, Geneva, Switzerland.
An introductory trial with the injectable contraceptive Cyclofem was carried out
in Brazil, Chile, Colombia, and Peru, with participation by 3,183 women. Women
were followed-up for up to 2 years of use and the data were evaluated by life table
analysis. A total of 29,676 women-months were accumulated for up to 2 years.
No pregnancies were observed. in the 2 years. The discontinuation rates for
amenorrhea in the first year ranged from 3.4 in Brazil to 8.1 in Colombia, and for
menstrual disturbances from 5.1 in Chile to 9.2 in Brazil. The discontinuation
rates for other medical reasons ranged from 7.8 in Brazil to 26.3 in Colombia, and
for personal reasons from 17.2 in Chile to 23.5 in Brazil. Continuation rates
ranged from 42.3 in Colombia to 52 in Chile. In the second year of observation
the rates of discontinuation were lower than those observed in the first year, with
the exception of personal reasons in Brazil, which were the same as those
observed in the first year. Continuation rates ranged from 19.4 in Brazil to 36.8 in
Chile. The comparison of reasons for discontinuation in selected clinics showed
that the rate for amenorrhea in one clinic in Chile was more than three times that
in others and in Peru was seven times more in one clinic than in another.
Regarding menstrual disturbances, in Peru one clinic presented a rate three times
higher than the others. The main reasons for discontinuation due to other medical
reasons were headache and weight gain. In conclusion, Cyclofem presented a high
contraceptive efficacy and an acceptable rale of continuation and discontinuation
for up to 2 years in the four countries.
PIP: The performance of the monthly injectable contraceptive, Cyclofem, was
evaluated in an introductory trial involving 3183 women recruited from family
planning centers in Brazil( Chile, Colombia, and Peru. A total of 29,676 women.months of use were accumulated during up to 2 years of follow-up. No
pregnancies occurred during the study period. Discontinuation rates per 100
women in the first year ranged from 3.4 in Brazil to 8.1 in Colombia for
amenorrhea and from 5.1 in Chile to 9.2 in Brazil for menstrual disturbances. The
discontinuation rate for other medical reasons (primarily headache, weight gain,
and acne) ranged from 7.8 in Brazil to 26.3 in Colombia and for personal reasons
from 17.2 in Chile to 23.5 in Brazil. First-year continuation rates ranged from
42.3 in Colombia to 52.0 in Chile. In the second year of use, continuation rates
ranged from 19.4 in Brazil to 36.8 in Chile. Upon receiving these results, national
regulatory authorities in the 4 participating countries approved Cyclofem
registration. Acceptance of injectable contraception, which currently entails
administration of the method by a service provider and travel to a clinic, could be
improved in developing countries by training in self-administration.
Population
Reports
HIGHLIGHTS
Page
DMPA approved in US................. 3
New monthly injectables
introduced.................................. 4
Donors increase shipments.......... 7
Injectables offer benefits.............. 7
Bleeding changes common.......... 9
WHO publishes cancer studies... 14
The user's perspective................... 16
Good counseling crucial.............. 18
Innovative communication uses
mass media................................. 20
Reliable supplies require
planning.................... .................22
Age and parity restrictions
unnecessary................................24
Infection prevention demands
attention..................................... 25
CONTENTS
Research and Regulatory Approval 3
Use of Injectables.......................... 5
Effectiveness and Reversibility.... 7
Side Effects and Complications... 9
More Evidence in the Cancer
Debate......................................... 14
Noncontraceptive Health
Benefits............................ ........... 16
Counseling Issues.......................... 18
Communicating with the Public ... 19
Maximizing Access and Quality... 21
Bibliography ................................... 28
Published with this issue:
' DMPA at a Glance" fact sheet
“Counseling Guide"
Published by the Population Informa
tion Program, Center for Communica
tion Programs, The Johns Hopkins
School of Hygiene and Public Health,
111 Market Place, Suite 310, Baltimore,
Maryland 21202-4012, USA.
Volume XXIII, Number 2
Series K, Number 5
New Era for Injectables
In the next few years millions of couples
throughout the world will be offered
the choice of injectable contraceptives.
Reassuring research findings, approval
of the 3-month injectable in the US,
and the introduction of new monthly
injectables promise wider access.
Whether expanding services or offering
injectables for the first time, programs
have a new opportunity and challenge
to provide good care that responds to
their clients' needs.
About 12 million couples throughout the world now use
injectable contraceptives. Progestin-only injectables are the
most widely used: DMPA (depot medroxyprogesterone
acetate), known by the brand name Depo-Provera, provides
three months of protection, and NET EN (norethindrone
enanthate), known as Noristerat, two months. One-month
injectables combine estrogen with progestin. The new
•monthly injoctables Cyclofem and Mesigyna are well-tested
alternatives to older monthlies.
Although the first injectables were developed soon after oral
contraceptives, limited availability has constrained use in all
but a few countries, such as Indonesia and Thailand. More
than 100 countries have approved DMPA since the early
1960s, but political controversy and scientific uncertainty
have held back injectables in some programs.
Now, research by the World Health Organization (WHO)
and US regulatory approval of DMPA may mark the start of a
new era for injectables. The WHO research reduced fears
Injectables and Implants
August 1995
about DMPA causing cancer. Approval of DMPA by the
United States Food and Drug Administration in 1992 made
this injectable available in the US and allows the United
States Agency for International Development (USAID) to of
fer DMPA to developing-country family planning programs.
The User's Perspective
Throughout the world many women value injectables be
cause they are highly effective, long-acting, reversible, and
convenient, and they can be used privately. Also, breastfeed
ing women who want to use a hormonal contraceptive can
use progestin-only DMPA or NET EN.
Women experience a variety of side effects with injectables,
however. Disruption of menstrual bleeding is common, and
some women find it troublesome. Counseling helps women
understand that the frequent or irregular bleeding and
amenorrhea are not dangerous, and many continue to use
injectables despite these bleeding changes. Cyclofem and
Mesigyna disrupt menstrual bleeding less than DMPA and
NET EN. Also, some women using injectables report weight
gain, headaches, and dizziness.
Introducing or Expanding Services
Experience with injectables for more than 20 years suggests
that the most successful programs:
• Provide accurate and balanced information and dispel
unwarranted fears about injectables through mass-media
communication for the public, testimony from satisfied
users, client education, and counseling.
• Counsel to ensure informed choice and use. With informa
tion and encouragement from providers, women make
their own choices among family planning methods. They
also learn what to expect and how to use their method.
Having chosen injectables, women need to know when
they can get injections and to expect bleeding changes.
• Expand provision of injectables through pilot projects.
Seminars can inform providers and policymakers. Pilot
studies can gauge clients' responses and identify key com
munication and counseling issues.
• Ensure reliable supply. Order injectables six months to a
year in advance, making accurate forecasts ofclemand. to
avoid logistical problems, offer only one progestin-only in
jectable and, if there is a demand, one monthly injectable.
• Avoid unnecessary barriers to use of injectables, such as
age and parity requirements or restricting the first injection
to the first seven days of the menstrual cycle.
• Use needles and syringes safely. Used disposable equip
ment should be destroyed. Reusable equipment should be
sterilized or high-level disinfected.
• Consider community-based distribution or social market
ing of injectables. These approaches increase availability
but require good training and attention to quality.
This report was prepared by Robert E.
Lande. Ward Rinehart, Editor. Stephen
M. Goldstein, Managing Editor. Design
by Linda D. Sadler. Production by Merridy Gottlieb.
The assistance of the following review
ers is appreciated: Gretchen Bachman,
Sriani Basnayake, Martha Carlough,
Philip Corfman, Kathryn Curtis, Cather
ine d'Arcangues, Elizabeth DuVerlie,
Hanni Levi Ellis, Henry L. Gabelnick,
Lauren Goodsmith, Ronald H. Gray,
David Griffin, Peter E. Hall, Carolyn
Hart, Robert A. Hatcher, Cathrine Hoyo,
Douglas Huber, Carlos Huezo, Andrew
M. Kaunitz, Suporn Koetsawang, Debra
Kristensen, U.C. Shyam Lama, Laurie S.
Liskin, Firman Lubis, James McCarthy,
Edwin B. McDaniel, Erin McNeil, Alice
Payne Merritt, Elizabeth Oliveras, Her
bert Peterson, James F. Phillips, Phyllis
Tilson Piotrow, Malcom Potts, Walter
Proper, Jose G. Rimon II, Roberto
Rivera, Judith P. Rooks, Katrina Schuur,
Pramilia Senanayake, Lois Schaefer,
James Shelton, Jill Sherman, David B.
Thomas, Margaret N. Thuo, and Regan
Warner-Rowe.
Suggested citation: Lande, R.E. New era fpr in
jectables. Population Reports, Series K, No. 5.’
Baltimore, Johns Hopkins School of Public Health,
Population Information Program, August 1995.
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, Associate Director for Scien
tific Information and Dissemination
Anne W. Compton, Associate Director for
POPLINE computerized bibliographic services
Jose G. Rimon II, Deputy Director, Center for
Communication Programs and Project Direc
tor, Population Communication Services, de
veloping family planning communication
strategies, projects, (raining, and materials
Population Reports (USPS 063-1 SO) is published
four times a year (July, August, October, De
cember) at 111 Market Place, Suite 310, Balti
more, Maryland 21202, USA, by the Popu
lation Information Program of.lhe Johns Hopkins
School of Public Health. Second-class postage
paid at Baltimore, Maryland. Postmaster to send
address changes to Population Reports, Popu
lation Information Program, The Johns Hopkins
School of Public Health, 111 Market Place,
Suite 310, 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.
Published with support
from the US Agency for
International Development
POPULATION REPORTS
Research and
Regulatory Approval
Three events signal a new era for injectable contraceptives:
• A multinational epidemiological study by the World
Health Organization (WHO) produced largely reassuring
findings about the 3-month injectable depot me
droxyprogesterone acetate (DMPA) and cancer. Previous
controversy about DMPA had arisen from animal studies.
• The United States Food and Drug Administra
tion (US FDA) approved DMPA as a contra
ceptive in 1992, 25 years after the manufac
turer, the Upjohn Company, first applied. As
a result, the United States Agency for Interna
tional Development (USAID) has begun pro
viding DMPA to developing countries; and
• Two new monthly injectables, Cyclofem and
Mesigyna6', are being introduced after thor
ough clinical studies by WHO (see pp. 4-5).
Together, these events may clear away some of
the constraints that have limited widespread use
of this 30-year-old method to a few countries.
Development of
Injectables
Research on injectable contraceptives be
gan shortly after the development of oral con
traceptives. Karl Junkmann and colleagues
at the German pharmaceutical firm Schering
AG synthesized the first injectable progestins
in 1953 (64, 149) and in 1957 developed norethindrone enanthate (NET EN, or Noristerafy,
the first injectable contraceptive, which is
injected every two months (150). The US
pharmaceutical firm the Upjohn Company syn
thesized medroxyprogesterone acetate (Provera®)
in the late 19S0s (1 7). Upjohn conducted the first
clinical trials of Provera in its depot, or in
jectable, form—Depo-Provera®—in 1963
(313, 321). Researchers developed the first
monthly injectables and conducted clinical
trials in the 1960s. The combination of pro
gestin and estrogen that became Cyclofem
was first tested in 1968, and the combination
that became Mesigyna was first tested in
1974 (223).
Q
US Regulatory History
of DMPA
DMPA has always been the most widely used injectable, but
the long wait for approval in the US has made it controver
sial. Upjohn applied for US FDA approval in '1967. At the
time progestin-only methods seemed promising because the
estrogen in combined oral contraceptives (OCs) caused
nausea and vomiting in some women. Researchers sus
pected as well that estrogen caused blood clots (thromboem
bolic disease) in some users of combined OCs. These
suspicions were later confirmed. Also, progestin-only con
POPULATION REPORTS
traceptive injections fulfilled many of the goals of re
searchers and family planning providers who wanted to be
able to offer a method that was effective, reversible, did not
interfere with lactation or require action at the time of sexual
relations, and could be easily delivered by rural health care
providers.
Nevertheless, the US FDA denied approval of DMPA in
1978, saying that it lacked sufficient evidence demonstrating
safety, particularly with regard to breast and cervical cancer
(35). A 3-member expert review panel, convened in 1983 at
Upjohn's request, upheld the US FDA decision (322).
DMPA Research
Tests of DMPA in beagle dogs and monkeys in
the early 1970s raised questions about cancer
that delayed US regulatory approval and held
back use in many countries. Beagles developed
breast tumors and some monkeys developed
endometrial tumors in tests then required by the
US FDA of any new hormonal contraceptive
(148). These studies were influential because at
the time there was little information on the
long-term effects of DMPA use among women
(322). Many experts questioned the relevance
to humans of the beagle and monkey stud
ies, however (3, 10, 136, 313, 330, 346).
The WHO Collaborative Study of Neo
plasia and Steroid Contraceptives exam
ined the risk of cancer among users of
hormonal contraceptives and reached
the following conclusions, published largein 1991, about DMPA and cancer:
■ Breast cancer: No increased risk overall, but the
study found that DMPA users had an increased
risk for several years after starting DMPA-^. perhaps due to accelerated growth of exist
ing tumors. Some of the apparent increase
in risk may be explained by detection bias
(see p. 14).
• Cervical cancer: No increased risk of
invasive cancer.
• Endometrial cancer: Protective ef
fect.
• Ovarian cancer: No increased risk.
• Liver cancer: No increased risk.
The findings about breast and en
dometrial cancer were the most crucial
because they answered the
long-standing questions raised
by animal studies.
The WHO study provided
epidemiologic evidence that humans differ from these ani
mals in their response to hormones. The US FDA no longer
requires testing contraceptive hormones for carcinogenicity
in beagles (148).
The WHO study led the US FDA to change its position in
1992 and approve DMPA. US FDA approval removed a
source of controversy in the history of DMPA: use in devel
oping countries of a drug that was not approved for contra
ceptive use in the US.
The US had been one of the few countries to withhold
approval of DMPA. Over 90 countries had approved DMPA
before the US (see Figure 1).
Following US approval, India,
the Philippines, and several
other countries also approved
DMPA. By comparision, NET
EN is registered in over 60
countries. Registration does
not necessarily mean, how
ever, that a product is readily
available.
Monthly Injectables
Monthly injectables have been
most widely used in China and
Latin America. Chinese Inject
able Number 1 consists of hy
droxyprogesterone caproate
and estradiol valerate and has
been used by about 1 million
women (271). In Latin America
at least one million women use
dihydroxyprogesterone aceto-
-
on Schedule, and Avail ability of Inject.ible Contraceptives
Formulation
Developer
Brand Name/Manufacturer
Injection Schedule
Progestin only:
150 mg depot
medroxyprogesterone
acetate (DMPA)
The Upjohn
Company
Depo-Provera/Upjohn
Megestron/Organon
Every 3 months,
12 weeks, or
90 days
Registered in over 100
countries; available in
both public and private
sectors.
Progestin only:
200 mg norethindrone
(norethisterone)
enanthate (NET EN)
Schering AG
Noristerat*/Schering AG
Every 2 monthsb
Registered in over 60
countries; available In
both public and private
sectors.
Progestin + estrogen:
25 mg DMPA + 5 mg
estradiol cypionate
Upjohn,
WHO
Cyc/ofem/Aplicacidnes
Farmaceuticas (Mexico),
Upjohn (US)
Cyclo Ceston/Py Tunggal,
PT Triyasa Nagamas Farma
(Indonesia)
Every month
Registered in Guatemala,
Indonesia, Mexico, Peru,
and Thailand
Progestin + estrogen:
50 mg NET EN +
5 mg estradiol valerate
WHO
^rie^/gyna/Scheripg AG
Every month
. Registered in Argentina,
Brazil, and Mexico
Progestin + estrogen:
150 mg dihydroxyprogesterone
acetophenide + 10
mg estradiol enanthate
Squibb
Pharmaceutical
Company
Perlutan, Topasel, Agurin,
Horprotal, Uno-Ciclo/
Every month
Available in pharmacies
in many Latin American
countries and Spain;
generally not available in
public family planning
programs.
Ooryxus/Richter Gedeon Ltd.
Half-dose: 75 mg
di hydroxy progesterone
acetophenide + 5 mg
estradiol enanthate
Progestin + estrogen:
250 mg 17a-hydroxyprogesterone caproate
+ 5 mg estradiol
valerate
Various manufacturers
in Latin America
Anafertin, Tecfames/Various
Availability
,
Every month
manufacturers in Latin
America
Chinese
researchers;
Squibb
Pharmaceutical
Company
Chinese Injectable No. 1
Every month; 2
injections in
first month
*Called Norigesi in Pakistan
'’Alternative schedule: every 2 months for 6 months and then every 3 months
Sources: Warner-Rowe (318), WHO 1990(333), WHO 1993 (331)
China
Population Reports
POPULATION REPORTS
phenide and estradiol enanthate, which
was originally developed by Squibb Phar
maceutical Company in the 1960s and
marketed under the brand name Deladroxate. Within a few years Squibb with
drew Deladroxate, but the same formuulation, manufactured by others, is now mar
keted in Latin America and Spain-under a
variety of other brand names (see Table 1). It
has not been thoroughly studied (223, 331).
Two new monthly injectables, Cyclofem
and Mesigyna, have completed multina
tional clinical trials conducted by WHO.
They are being introduced in a number of
countries.
• Cyclofem, previously known as Cycloprovera, combines DMPA and the es
trogen estradiol cypionate. The Upjohn
Company developed Cycloprovera and
turned it over to WHO in 1984.
• Mesigyna, developed by WHO, com
bines NET EN and the estrogen estradiol
valerate.
Introductory trials of Cyclofem have been A Thai woman receives an injection of DMPA from a provider who traveled to her
conducted in Chile, Indonesia, Jamaica, village in a mobile clinic. The McCormick Family Planning Program began the mobile
Mexico, Thailand, and Tunisia, and the clinic in 1969 to reach women in rural areas of northern Thailand. In 1970 it was
new injectable has been registered in Gua one of the first programs to offer DMPA, which became its most popular method.
temala, Indonesia, Mexico, Peru, and
Thailand. The Concept Foundation, a private nonprofit or voluntary female sterilization, 25% on IUDs, 12% on oral
ganization set up by the Program for Appropriate Technql- contraceptives, 9% on vasectomy, and 6% on condoms. In
bgy in Health (PATH) and given rights to Cyclofem by WHO,
most countries levels of use of injectables are too low to
has licensed manufacturers in Indonesia and Mexico to detect any trends over time (83, 195).
produce Cyclofem and has identified distributors in other
countries, primarily in Latin America. The Upjohn Company Regulatory delay in the US and the controversy surrounding
injectables have limited availability and thus use around the
has obtained rights to Cyclofem in the US and in several
other developed and developing countries. Upjohn plans to world. Many clinics do not offer injectables, or they often
run short of supplies (4, 19, 134,144, 262, 281, 297, 366).
submit an application for Cyclofem to the US FDA by August
In Bangladesh, for example, even though injectables are
1996(318).
widely available, 58% of providers and program managers
Schering AG is handling registration, distribution, and mar surveyed in 1992 said that lack of supply had forced them to
keting of Mesigyna. Schering AG plans to begin marketing turn away would-be users; 11 % of women said that they had
Mesigyna in Latin America. Mesigyna is manufactured in
stopped using injectables or had switched to another
Mexico and has been registered in Argentina and Brazil as method because they could not get an injection (4). In 1994,
well as Mexico (74).
5% of married women of reproductive age in Bangladesh
were
using injectables (218).
With new opportunities to offer injectables, policymakers,
program managers, and providers need to reacquaint them
Knowledge of injectables is not as widespread as knowledge
selves with these contraceptives: their effectiveness and
of some other methods. For example, in 31 of 53 countries
reversibility, side effects, and noncontraceptive benefits,
covered by Demographic and Health Surveys or similar
why women use injectables, and how users respond to side
surveys, one-quarter or more of married women of reproduc
effects. This knowledge can help program staff make deci
tive age did not know about injectables (268) (see Table 2).
sions concerning communication and service delivery issues
(By comparison, in 16 countries one-quarter or more did not
posed by injectables (see "Lessons Learned" .pn back pf
khow about OCs.) Women who know of injectables often
"DMPA at a Glance").
do not know where to obtain them.
(Jse of Injectables
Except in a handful of countries, few women use injectable
contraceptives compared with other methods. Statistics from
donor agencies, however, suggest that use is increasing.
About 12 million women in developing countries use inject
able contraceptives, 1.5% of married women of reproduc
tive age and about 3% of married contraceptive users. By
comparison, 36% of married contraceptive users rely on
POPULATION REPORTS
A few countries offer a contrast to the world pattern. In the
countries with the greatest use of injectables—Indonesia, at
15% of married women of reproductive age and Thailand,
at 12%—injectables have been widely available for more
than 15 years. Thailand registered DMPA in 1970 and began
to offer it in the national family planning program in 1975,
becoming one of the first countries to do so (20, 34). Be
tween 1987 and 1991 use in Thailand increased from 9% to
12% of married women of reproductive age. Indonesia
registered DMPA in 1976, and it is manufactured locally
(187). Between 1987 and 1994 use increased from 10% to
|
Table 2
|| Knowledge
*1 and Current
S Use of
H Injectable
Contraceptives
■ Among Married
■ Women of
S Reproductive
I Age,
I Findings,
I 1984 -1994
AFRICA
33
4
1
91
Burkina Faso 1993.............
63
Burundi 1987.....................
65
Cameroon 1991.................
63
Ghana 1988........................
77
Kenya1993..........................
Liberia 198b......................
68
Madagascar 1992..............
62
Malawi 1992.......................
92
Mali 1987...........................
30
Mauritius1991...................
100
Namibia 19^2..}........ ......... ( b90
Niger 1992.........................
58
Nigeria 1990.......................
42
70
Senegal 1992-93...............
South Africa 1987-89.........
NA
Black................................
NA
NA
White...............................
Sudan 1989-90..................
71
NA
Swaziland 1988.................
Tanzania 1991-92.............
72
Togo 1988...........................
82
79
Uganda 1988-89...............
87
Zambia 1992......................
99
Zimbabwe 1994................
ASIA & PACIFIC
Bangladesh 1993-94.........
100
NA
China 1988.........................
96
India 1992-93....................
Indonesia 1994...................
96
Nepal 1991.........................
93
77
Pakistan 1990-91..............
97 Philippines 1993................
99
Sri Lanka 1987.,.................
Thailand 1991. -........ ......... '•
NA
NA
Vietnam 1994.....................
LATIN AMERICA & CARIBBEAN
Belize 1991.........................
NA
Bolivia 1989.......................
69
Brazil 1986.........................
100
Northeast 1991...............
100
Colombia 1990..................
100
Costa Rica 1986................
NA
Dominican Rep. 1991........
100
Ecuador 1989....................
92
El Salvador 1988................
NA
Guatemala 1987................
72
Haiti 1989..........................
NA
Jamaica 1993......................
NA
Mexico 1987.......................
93
Panama 1984......................
NA
Paraguay 1990....................
98
Peru 1991-92....................
95
Trinidad & Tobago 1987 ....
99
NEAR EAST & NORTH AFRICA
Egypt 1992...... ...................
100
Jordan 1990.... i.................. '•
99
Morocco 1992...................
99
Tunisia 1988......................
99
Turkey 1993........................
99
Yemen 1991-92.................
53
58
40
4
93
43
48
68
18
94
85
39
34
34
NA
NA
NA
46
75
40
61
41
38
87
C.
<1
]
0
o
27
5
7
i
49
26
2
4
5
56
49
79
6
3
3
9
42
0
2
8
1
1
23
27
3
0
0
o
o
3
18
100
0
o
26
Q
40
29
0
3150
25
<20
41
55
0
24
o
o
0
o
7
97
NA
19
91
65
62
54
85
NA
NA
36
71
36
52
24
9
25
41
69
65
0
15
2
1
0
29
8
11
<4
12
<1
18
<1
86
44
58
85
92
90
57
72
81
46
61
NA
87
86
89
82
80
42
13
57
54
55
58
52
42
44
19
9
58
46
53
35
33
46
4
1
1
<1
2
1
o
0
1
1
?
6
3
j
5
2
1
10
8
2
<2
45
27
36
41
35
6
<1
o
o
<2
d
o
2
82
51
63
60
39
32
.
7
<1
1
'
2
5
20
10
2
6
2
•
17
POPULATION REPORTS
15% of married women of reproductive age. Injectables are
well liked in these countries, where women value the con
venience of injectables and are not discouraged by irregular
menstrual bleeding or amenorrhea (see pp. 9-12).
Among developed countries the highest prevalence of inject
ables use is in South Africa (see Table 2) and New Zealand.
In 1993-94, 4% of visits to the Family Planning Association
of New Zealand were for initial or repeat injections of DMPA
(206). Surveys in other developed countries do not mention
injectables or else include them among "other" methods (228,
289, 319). In the US the latest national survey was done
before DMPA was approved (247). The Planned Parenthood
Federation of America supplied DMPA to about 141,000 wom
en in 1994, about 7% of their family planning clients (363).
Shipments by Donors Increase
Donor agencies report increasing orders for injectables in
the 1990s. The United Nations Population Fund (UNFPA),
the largest supplier of injectables, provided about 12 million
doses in 1992 and 20 million doses in 1994, including
shipments for the World Bank. DMPA makes up three-quar
ters of UNFPA shipments of injectables, and NET EN, onequarter (118). Thus in 1994 UNFPA shipped! enough
injectables for about 4.6 million woman-years of use. Deliv
eries of DMPA by the International Planned Parenthood
Federation (IPPF) increased from 336,000 doses in 1991 to
735,000 in 1994. Deliveries of NET EN increased from
305,000 in 1991 to 438,000 in 1994 (145).
USAID plans to deliver at least 2.6 million doses of DMPA
in 1995—enough for 650,000 women for one year. The
agency delivered 1 million doses in 1994 between August,
when shipments began, and December. The largest ship
ments for 1995 are planned for Nepal (311,200 doses),
Mozambique (248,000), Peru (215,600), Tanzania
(206,400), and Nigeria (200,000) (45).
Effectiveness and
Reversibility
Injectable contraceptives combine almost complete effec
tiveness with reliable reversibility. Most clinical trials report
less than 1 pregnancy per 100 women in the first yqar of use
.(39,41, 271,277, 336, 338, .340, 342). Thus inject’ables are
comparable in effectiveness to Norplant® implants, the
TCu-380A IUD, and voluntary sterilization.
Women who have used DMPA or NET EN and stop to have
a baby may have to wait several months longer on average
for pregnancy than former IUD or OC users. Thus rumors
persist that some women who use injectables become ster
ile. In fact, after two years pregnancy rates among former
DMPA, IUD, and OC users are the same. Providers may need
to reassure clients and the public that injectables do not
cause infertility but to note that women should expect a wait
of some months after stopping injectables to become preg
nant. Service policies based on a fear of infertility—in particu
lar, age and parity restrictions—can be dropped (see p. 24).
Effectiveness
Injectables work mainly by preventing ovulation. They sup
press the surge in hormones from the pituitary gland that is
POPULATION REPORTS
necessary for ovulation (70).
They also thicken cervical
mucus, making it a barrier
to sperm (357).
DMPA has been tested in a
variety of doses and injec
tion schedules. The 150 mg
dose every three months (or
12 weeks or 90 days) is the
most widely used regimen.
The first-year failure rate in
the US for the 150 mg dose
is 0.3% compared with
0.4% for voluntary female
sterilization, 0.4% for Nor
plant implants, 0.8% for the
TCu-380A IUD, and 3.0%
for oral contraceptives (370).
The 200 mg dose of NET EN
is mostly used on a 2-month
schedule. Some programs
use a 2-month schedule for
the first six months and then
give injections every three
months (107,193, 200, 209,
342). In a WHO trial the oneyear pregnancy rates for the
two schedules were not sig
nificantly different: 0.4 per
100 women on the 2-month
schedule and 0.6 on the 2and then 3-month schedule.
IPPF and WHO recom
mend the 2-month sched
ule, however (333, 365).
Injection
Technique
Important
Careful injection technique
ensures that the full dose is
absorbed at the right rate and
thus is fully effective.
• With DMPA, providers need
to shake vials to dissolve any
sediment at the bottom, but
they should not shake so
vigorously that the liquid be
comes frothy and difficult to
draw into the syringe.
• With NET EN, wanning vials
to body temperature thins the
viscous solution and makes it
easier to draw completely into
the syringe (333).
• With all injectables, the in
jection should be given in
muscle because absorption
may be too slow if the
provider injects into fat (85).
In contrast, massaging the in
jection site accelerates absorp
tion and thus also should be
avoided (333).
Monthly injectables also are highly effective (157, 166, 271,
331, 336). In a WHO trial there were two pregnancies
among 1,152 Mesigyna users (0.2 per 100 women) and none
among 1,168 Cyclofem users after one year (336). Women
using Deladroxate, the precursor of many monthly inject
ables currently available through pharmacies in Latin Amer
ica, had no pregnancies in 10 studies conducted in the
1960s and 1970s and covering more than 1,500 womanyears of rise (166).
The effectiveness of injectables depends ori the timing of the
first injection, adherence to the injection schedule, and the
injection technique (see box, this page). In a Thai study the
timing of the first injection made a significant difference in
the accidental pregnancy rate. The 3-month pregnancy rate
was 0.16 per 100 women receiving their first injection in the
first eight days of the menstrual cycle but 0.62 per 100
women receiving their first injection after the eighth day
(102). Thus the first injection is usually given during the first
seven days of the menstrual cycle but can be given at other
times (see Table 3).
The dosages and injection schedules ensure that users can
come a little late for the next injection without risking
pregnancy. As a guideline for programs, DMPA users can
come at least two weeks late; NET EN users, at least one
week late; and users of monthly injectables, up to three days
late. If users come any later, the provider must be reasonably
sure that they are not pregnant before giving the next injec
tion. Clients also may return early (see Table 3).
■
Return to Fertility
Most former users of injectables can expect to
become pregnant within a year after their last
injection if they do not use another contracep
tive. The largest study of return to fertility among
users of DMPA, conducted in Thailand, found
that women conceived nine months on average
after the last injection, or 5.5 months aftjer dis
continuing, which the researchers assumed to
be 15 weeks after the last injection (236). Other
studies report similar findings (24, 277). By com
parison, OC users in the Thai study conceived
on average three months after discontinuing,
and IUD users, 4.5 months after discontinuing
(233, 235, 236) (see Figure 2). An Indian study
found that 69 former NET EN users on the 2- and
then 3-month schedule conceived on average
11 months after the last injection, or 8 months
Table 3. Progestin-Only Injectables: When to Give the injection
Question
Recommendation
When can the first injection
be given!
Any time the provider can be reasonably sure that a woman is not pregnant’—for example, during
any of the 7 days that begin with the onset of menses (days 1 through 7 of the menstrual cycle).
Use of backup methods: For a woman having menstrual cycles, no backup method is needed if
she is in the first 7 days of her menstrual cycle and is still menstruating. If she is in the first 7 days
of her cycle but is not menstruating, some programs may recommend use of a backup method
for 1 week. If injections are started after day 7 of a regular cycle, a backup method (or abstinence)
for up to 1 wedk niay be recomKiended.
Postpartum: When can the
first injection be given!
For breastfeeding women: If she does not rely on the Lactational Amenorrhea Method (LAM) or
another nonhormonal method, ideally wait until 6 weeks postpartum. If the woman relies on
LAM, she can start DMPA or NET EN when her menses return, or when she is no longer fully or
nearly fully breastfeeding, or at 6 months postpartum, whichever comes first.
For women who are not breastfeeding: The first DMPA or NET EN injection can be given
immediately postpartum or whenever the provider can be reasonably sure that the woman is not
pregnant.3
After spontaneous or in
duced abortion: When can
the first injection be given?
Within the next 7 days, because fertility returns almost immediately.
Where should the injection
be given!
Into the muscle of the arm or the buttock. The choice is best left to the client.
Grace period: How late or
early can users come for
subsequent injections?
DMPA: Up to 2 weeks late and possibly up to 4 weeks late depending on the population. Up to
4 weeks early although not ideal.
NET ENb: Up to 1 week late and possibly up to 2 weeks late depending on the population. Up
to 2 weeks early although not ideal.
Monthly injectables: Up to 3 days late and up to 3 days early.
If a woman returns after the grace period, she can receive the injection if the provider is reasonably
sure that she is noqpregnant.3 If she may be pregnant, she should use a barrier method until it is
clear whether dr not she is pregfiant.
Cumulative effect? Does a
woman have to stop using
injectables at any point to
give her body a rest?
No. There is no cumulative effect of injectables, and extended amenorrhea is not a medical
problem. It may be an advantage in areas where anemia is common. Counseling can reassure
the user who is worried about amenorrhea.
*A provider can be reasonably sure that a woman is not pregnant if she has no symptoms or signs ofpregnancy and she:
• is within the first 7 days poslabortion; or
• has been correctly and consistently using a reliable contraceptive; or
• is fully breastfeeding, amenorrheic, and less than 6 months postpartum.
• is within the first 7 days after normal menses; or
If available, a pregnancy test may be helpful, but it is not required.
• is within 4 weeks postpartum (for nonlactating women); or
Source: Technical Guidance Working Group 1994 (299)
Population Reports
h2-month schedule.
POPULATION REPORTS
after they would have received their next injection. By
comparison, 110 former IUD users in the study conceived
on average about 3.5 months after discontinuing (21). With
monthly injectables, studies of ovarian function indicate that
most former users first ovulate three to four months after the
last injection, or two to three months after the next injection
would have been given (26, 27, 339).
A Colombian pos
ter by Profamilia
offers 1-month
and 3-month in
jectables along
with other family
planning meth
ods. Injectables
add to the choice
of methods a very
effective hormo
nal contraceptive
that is private and
requires no daily
pill-taking
Women have to wait to conceive partly because injectables
remain in the bloodstream for several months after the next
injection would have been given. DMPA, for example, is
detectable in the bloodstream for eight months on average
after one injection (277).
There is no evidence that injectables cause infertility. In the
Thai study 91 % of former DMPA users had conceived within
two years after discontinuing compared with 93% of former
IUD users and 95% of former OC users. These differences
are not statistically significant (236). By comparison, among
US couples stopping contraception of all type?, about 9,0%
have conceived in 18 months, and about 10% of couples are
infertile (351, 367). Amenorrhea may persist for several
months after women discontinue injectables. Providers
should warn women of this and reassure them that their
regular cycles will return eventually.
Long-term users of injectables need not fear any cumulative
impairment of fertility. There is no difference in the time to
return of fertility between long-term and short-term users of
DMPA (24, 87, 92, 235, 236, 277).
Despite this evidence, to avoid any possible blame for
subsequent infertility, some programs have required women
to have been pregnant at least once before allowing them to
use DMPA. Such a policy restricts use unnecessarily. The
McCormick Family Planning Program in Thailand followed
this policy at first but removed it because of demand from
women without children; indeed, some women lied about a
previous pregnancy to be able to use DMPA. Following up
these women after they stopped using DMPA, the program
found no difference between their fertility and that of DMPA
users who had had previous pregnancies (199).
5/cte Effects and
Complications
Disruption of regular menstrual bleeding and amenorrhea
are the most common side effects of injectables and the main
reasons that women stop using them. Also, most women
report weight gain. Far fewer women report a variety of other
side effects, for example, headaches, dizziness, abdominal
discomfort, acne, and moodiness. These side effects are
bothersome for some women, but they are generally not
dangerous. Some of these less common side effects are
plausible reactions to hormones, while others occur at rates
typical of the general population and cannot be clearly
attributed to injectables.
Because bleeding changes and weight gain are so common,
during counseling all women who choose injectables
should be told of these likely changes. Program managers
need to decide what other side effects to mention based in
part on the side effects most often reported by clients. Th,ese
decisions should be made with the goal of helping clients to
make a fully informed choice and to use the method effec
tively and confidently (see pp.18-19).
POPULATION REPORTS
Researchers have investigated whether use of injectables
might increase the risk of certain serious conditions. In
general, studies of the cardiovascular system, carbohydrate
metabolism, liver function, and lactation have been reassur
ing (see Table 4). Some recommended restrictions on use of
DMPA and NET EN, however, are based on their effect on
cholesterol metabolism (see p. 12). Conflicting findings on
bone density and the outcome of pregnancy are being de
bated (see pp. 1 3-14).
■
Bleeding Changes
The most reliable information on bleeding patterns among
women using injectables and other hormonal contracep
tives comes from WHO-coordinated multicenter clinical
trials in which women keep menstrual diaries. These records
"document the diversity of bleeding patterns as well as the
averages (see Table 5 for definitions) (30, 31,331). Data on
menstrual bleeding among women not using hormonal con
traceptives, used for comparison, were collected from 2,700
US women between 1935 and 1962 by Alan Treloar and
colleagues (308, 331).
Only about 10% of DMPA users have normal cycles in the
first year of use. DMPA users can expect to have irregular
bleeding in the first six months and then infrequent bleeding
or amenorrhea in the next six months and beyond. By
comparison, in a WHO trial of six OCs, 59% to 87% of
women had normal bleeding patterns after one year (349).
NET EN has somewhat less effect on bleeding patterns than
DMPA. In a comparative trial bleeding episodes in the first
six months were significantly shorter among NET EN users
than among DMPA users. Bleeding patterns after six months
were similar, however. Amenorrhea lasting more than 90
days was significantly less common among NET EN users (342).
With monthly injectables, about half of women have regular
bleeding during the first year of use (see Table 5). Users tend
40 have irregular or prolonged bleeding in the first three
months and then increasingly regular patterns by the end of
the first year (272, 331). In particular, the first bleeding
interval may be shorter than usual (157). With monthly
9
Table 4. Investigating Injectables: Study Findings
______ Monthly Injectables________
DMPA and NET EN___________
Ref. Nos.
Findings
Ref. Nos.
Findings
Blood pressure.......... ..........
Most studies find no effect.
75, 122, 129,
No significant effects
108, 271,
Blood coagulation.................
Most studies find no effect.
77,122,123,
124,201, 208,
209, 309
6,75,77,78,
122, 158,200,
334
No significant effects
86,94,208,
331
Most studies find no
significant effects on
total, LDL, or HDL
cholesterol.
86,94,108,
331
7, 47, 76, 105,
122,184
No significant effects
86,94, 108,
331
7,47,276,280
126, 165,197,
329
52, 56. 72, 197,
329
No significant effects
Not studied. (With
combined oral
contraceptives, the
estrogen component
decreases the quantity
and quality of breast
milk <329).)
108
Most studies find higher
levels of low-density
lipoprotein (LDL) cholesterol
and lower levels of highdensity lipoprotein (HDD
cholesterol. 9
Carbohydrate metabolism.... Do not induce diabetes in
normal women but may
significantly increase glucose
and insulin levels.
Liver function...................... Most studies find |io effect.^
Lactation............................... Increase or no effect on milk
volume
No effect or possibly
beneficial effect on quality of
breast milkc
Lengthening or no effect on
duration of lactation*
No effect on nursing infants
Cholesterol..........................
J Three studies find no changes in LDL or HDL cholesterol (93. 122, 300).
hOne study of DMPA reported a possible enhancing effect through induction of
liver enzymes (79).
*•'Measured by fat concentration, calories, minerals, protein, lactose, and immu
noglobulin.
One review concluded that DMPA and Norplant implants had Utile effect on
a? 143 779
347,354, 356
61, 126, 143,
152, 168, 237,
279, 347, 348
wO/nen whose b'e.i .We i'-cl,p.ir.'u.1. " t.
ri.
/he duration of
breastfeeding among women who practiced full breastfeeding (175).
eNursing infants ingest a small amount of hormone if their mothers use inject
ables—up to 10 mg of DMPA or 2 mg of NET EN per day (56). Studies have
examined children's weight, height, movement, skills, and general health from
‘ 1/" 1 '
Population Reports
injectables, most women have bleeding 10 to 15 days after
the first injection and then every 30 days after that. Thus
women have regular bleeding 10 to 15 days after each
injection (336).
Bleeding patterns may differ among ethnic groups. Southeast
Asian women using DMPA, for example, report mord days
of bleeding and spotting than women in the Caribbean,
Europe, South Asia, or North Africa. North African women
report amenorrhea more often than European women. The
full reasons for these differences are not known. Some of the
variation may be due to regional differences in the nutri
tional status of users, sensitivity to menstrual changes and
thus reporting, and accuracy of menstrual diaries (32).
Individual differences may also affect bleeding patterns. For
example, among DMPA users in a WHO trial, heavy women
tended to have more amenorrhea and less bleeding than
lighter women. Among women using NET £N, however,
there was no relationship between weight and amenorrhea
(341). Bleeding patterns of individuals cannot be predicted.
Discontinuation of use because of menstrual bleeding
changes or amenorrhea in WHO trials reflected their differ:ng effects on bleeding patterns. After one year 15% of
DMPA users had discontinued use because of bleeding
changes, and about another 12%, because of amenorrhea.
NET EN users discontinued for bleeding problems at about
the same rate as DMPA users, but only 7% discontinued
because of amenorrhea. About 7% of users of monthly
10
injectables discontinued for bleeding problems, and only
about 2% discontinued because of amenorrhea (89, 157,
331, .338, 340, 342). Frequent bleeding or a worsening
pattern—a change from a regular pattern to amenorrhea or
infrequent bleeding, for example—was especially likely to
lead to discontinuation (103,337).
Discontinuation rates vary widely among regions. In a oneyear study of DMPA, for example, Thai women had a median
of 4.7 months without bleeding or spotting, but none discon
tinued because of amenorrhea. Egyptian women, in con
trast, had a median of 5.0 months without bleeding or
spotting, and 27% discontinued because of amenorrhea (338).
Counseling may have influenced these discontinuation rates.
The reasons that women give for stopping a method, how
ever, may not always be the real reasons. Some may want to
stop for a personal reason, but, afraid the provider will not
accept it, they give medical reasons instead. Others may
have been troubled by a number of side effects but tell
providers only about the one that made the most difference.
For example, in a clinical trial of DMPA, almost two-thirds
of women who discontinued citing other medical or non
medical reasons or who were lost to follow-up after several
injections had severely disrupted bleeding patterns (.339).
Clinical implications. Since bleeding patterns vary among
injectables, programs may offer clients a choice, tn Namibia,
for example, providers recommend NET EN over DMPA for.
younger clients partly because, providers say, it causes less
POPULATION REPORTS
Tab e5. M enstrual P itterns Among Users of Injectable Contraiceptives,
% Experiencing Bleeding Patterns
Type of
Injectable or
Untreated
DMPA
Mesigyna......
Untreated13...
Irregular
Bleeding
Frequent
Bleeding
Prolonged
Bleeding
Total Variations
from Regular
Patterrf
23.9
37.0
38.6
15.7
25.8
24.8
27.8
46.0
35.7
27.7
17.9
10.5
8.3
6.6
43.4
27.7
17.3
16.5
91.0
93.1
93.6
91.7
43.0
63.2
61.3
70.0
0.1
0.2
1.1
2.3
0.1
3.4
5.4
3.7
39.6
23.5
25.4
13.6
22.3
3,3
2.8
6.5
20.8
13.3
9.4
10.1
57.0
36.8
38.7
30.0
1,000
860
766
713
47.2 ■
62.8
63.3
68.4
0.2
06
0.1
2.2
2.0
5.0
34.6
25.2
24.8
14.6
29.6
5.5
4.9
6.2
16.2
11.1
12.6
12.7
52.8
37.2
36.7
31.6
3,893
3,893
3,893
3,893
90.3
90.8
90.1
85.1
1.3
3.4
4.5
0.2
2.6
9.7
2.9
4.8
0.3
2.3
9.2
5.4
2.8
2.6
0.1
9.9
3.1
8.6
0.3
4.3
14.9
A bleeding episode is defined as asquiring the use of a pad or other
Regular
Pattern!}
509
406
311
241
4.o
6.9
6.4
8.3
10-12
1,001
885
802
730
0-3
4-6
7-9
10-12
0-3
4-6
Months
0-3
7-9
10-12
Cyclofem......
Infrequent
Bleeding
Number of
Diaries
0-3
4-6
10-12
Amenorrhea
' 10.6 ‘
1.3
1.6
Note; Patterns arc defined for 90-day observation periods:
Regular patterns—Three episodes of bleeding or spotting each lasting about five days.
Amenorrhea—No bleeding
Infrequent bleeding--Fewer than two bleeding or spotting episode
Frequent bleeding—More than four bleeding or spotting episodes
Irregular bleeding—A pattern in vvhich the difference between the longest and shortest
bleeding-free Intervals is more than 17 days
Prolonged bleeding—At least one.• bleeding or spotting episode lasting 10 days or more
(30, 31, 331)
menstrual disruption (186). In introductory trials of Cy
clofem in Indonesia, Jamaica, and Thailand, 36% to 45% of
women had switched from DMPA mainly because of bleed
ing problems (110). Offering several injectables may pose
logistical problems, however (see p. 22). Counseling can
help women deal with menstrual bleeding changes or
amenorrhea (see p. 18 and Counseling Guide).
Some women using progestin-only injectables cannot ac
cept frequent bleeding despite counseling. They have no
choice but to continue for several months, until the inject
able wears off. Providers have used several approaches to
decrease bleeding.
protectio n. A spotting episode doos not require proteciion. No compatable data for NET EN are available.
J Some subjects appear in more that »one category.
‘‘From Tretoar el al. 1967(300)
Source. WHO 1993 (331)
Peculation Reoorts
after one year rates of discontinuation for bleeding were the
same for both groups (60).
Anti-inflammatory drugs (except aspirin) also have helped to
control bleeding. Ibuprofen and other nonsteroidal anti
inflammatory drugs block the synthesis of prostaglandins,
which induce bleeding (299).
Giving the next injection of DMPA or NET EN early can
temporarily reduce bleeding among women who want to
continue despite bleeding problems. Injections generally
should not be given sooner than four weeks after the pre
vious injection, however (299).
Women with heavy or prolonged bleeding—twice as much
If estrogens are not contraindicated, providers have given or twice as long as usual for them—require special care.
one to three weeks of combined oral contraceptives 8r of ‘Such bleeding is unusual and rarely requires treatment.” A
estrogen, which temporarily reduce or stop most episodes of survey of 35 researchers in 20 countries found that 1% to 2%
bleeding. For example, in a WHO study among women with of users have heavy bleeding (88). Only 6 of 1,200 women
bleeding lasting seven days or more during the first six participating in a WHO multicenter trial required treatment
for heavy bleeding, and in the first 10 years of the McCor
months of DMPA use, 93% of women given ethinyl estradiol
mick Family Planning Program in Thailand, only two of
stopped bleeding while under treatment compared with
about three-quarters of women given a placebo, a significant more than 70,000 DMPA users had very heavy bleeding that
was
considered a medical complication (20, 346). Never
difference (60). Women also have used OCs for a few months
theless, programs must ensure that women using injectables
to get over initial irregular bleeding caused by DMPA.
can be treated for heavy bleeding.
Over the long term, however, estrogen may be no more
helpful than counseling. After treatment in the WHO study,
women given ethinyl estradiol had fewer bleeding days but
more varied patterns than women given the placebo, and
POPULATION REPORTS
Before treating heavy bleeding, providers should consider
other causes of bleeding, such as pregnancy, cancer, or
sexually transmitted disease, and should check for anemia.
If estrogen is not contraindicated, providers may give
high or low blood pressure, or low blood sugar cobld cause
dizziness. Lack of exercise or pregnancy could cause weight
gain. In some instances providers can encourage women
concerned about weight gain to diet and exercise more.
If other causes are unlikely, these side effects often can be
handled through counseling. Clients may need reassurance
that these side effects are not dangerous and are not symp
toms of more serious problems. If, after counseling, a client
insists that side effects are unacceptable, providers should
recommend that she choose another method and help her to
do so without expressing criticism or disapproval (259).
To provide support and reassurance, providers emphasize
that clients should return for help whenever they have prob
lems or questions. If possible, clients who receive injections
at a clinic should return there for help because those provid
ers are trained to handle side effects of injectables. Inexperi
enced providers at other clinics may respond inappro
priately—for example, treating bleeding by dilation and
curettage (23).
Because of the effect of progestin-only injectables on cho
lesterol levels, a group of experts assembled by WHO rec
ommends that women with severe vascular diseases (such
as severe hypertension, a history of stroke, or ischemic heart
disease) or with diabetes involving vascular complications
should not use these injectables unless other methods are
not available, or, in a provider's careful clinical judgment,
other methods would not be acceptable. Women who de
velop these conditions while using progestin-only inject
ables or who develop recurrent severe headaches with focal
neurologic symptoms should see a doctor or nurse and
switch to a nonhormonal contraceptive method because
there is some concern that such headaches sometimes pro
gress to stroke (332) (see p. 24).
Bone Density
DMPA may have both an enhancing and depleting effect on
bone. Estrogen maintains bone density by slowing bone
resorption (36). In premenopausal women medroxypro
gesterone acetate (MPA) suppresses estrogen production,
which increases loss of bone density (58, 287). Irj contrast,
in postmenopausal women, whose natural estrogen levels
are already low, MPA slows loss of bone density (367).
Three studies have examined osteoporosis (reduction in the
quantity of bone) among DMPA users. A Thai study reported
no difference in bone density between 75 women who had
been using DMPA for at least three years and 147 women
who had not used DMPA (316). A 6-month Swedish study
found no change in bone density among 9 DMPA users
(215). A study in New Zealand, however, found a difference
of about 7% in the density of the lumbar spine and femoral
neck between women 25 to 51 years old who had been
using DMPA for at least five years, on one hand, and other
premenopausal women, on the other (58). The longer dura
tion of DMPA use in the New Zealand study may explain the
different results. A 7% bone loss would not increase the risk
of fracture immediately but might increase the risk of a
fracture at some lime in a woman's life by 10% to 15% (207).
The loss appeared to reverse, however, when women
stopped using DMPA (57). In general, genetic inheritance
and family history have the most influence on bone devel
opment, explaining 10% to 50% of the variation in bone
POPULATION REPORTS
‘
’
»mass among premenopausal women. Exercise, diet, and
smoking also affect bone density (287).
The New Zealand study has been criticized. It was retrospec
tive and thus could not measure bone densities of the
women before they started DMPA (296). Also, the study did
not control for smoking (369). Two prospective studies are
underway in the US (34, 38). There are no published studies
of the effects of NET EN on bone density.
Clinical implications. Findings on bone density to date do
not warrant denying DMPA to any group of women. Provid
ers may give special consideration to women under age 16,
however. Loss of bone mass at this age may increase the risk
of osteoporosis after menopause Pregnancy at this age,
however, also can affect bone mass (287). Thus the benefits
of an effective, reversible method such as DMPA to sexually
active young women probably outweigh the risks (332).
H
Fetal and Child Development
A fetus could be exposed to contraceptive hormones in the
rare cases that injectables fail to prevent pregnancy, if, a
woman receives an injection while’pregnant, or if a woman
becomes pregnant after discontinuing the method but hor
mones are still in her bloodstream.
The great majority of studies assessing fetal exposure to oral
contraceptives or other progestins or estrogens at contracep
tive doses find no effects on development of the heart, limbs,
spinal chord, brain, or genitalia (40, 49,59, 155, 265, 276,
282, 326, 328). Clinical findings with DMPA have been
mixed but largely reassuring. Early clinical studies of DMPA
in Bangladesh, Sri Lanka, and Thailand found no evidence
of developmental defects after fetal exposure (25,169, 240,
276). A Thai cohort study, however, involving about 4,000
women not using contraception, 3,300 OC users, and 1,200
DMPA users, reported that children of DMPA users were
more likely to have extra or missing fingers (polydactyly and
syndactyly) and chromosomal defects. The researchers
doubt that DMPA caused the defects because (1) limb de
fects and chromosomal defects generally have different
causes; (2) other studies have not found such defects among
DMPA users; and (3) 9 of the 15 children with defects were
conceived more than nine months after the last injection,
.when DMPA would no longer be in.the bloodstream; only 4
were definitely exposed to DMPA (234).
Another Thai study, which reported on more than 1,400
pregnancies of women who had used DMPA, found a link
between DMPA exposure during gestation and the outcome
of pregnancy. The study reported that exposure to DMPA
within one month before or after conception almost doubled
the risk of low birthweight and, perhaps partly as a result,
more than doubled the risk of neonatal death. Risks declined
with increasing time between exposure to DMPA and con
ception in the study, a dose-response relationship that
strengthens the link to DMPA (100, 101,232). If there is an
increased risk, however, the resulting attributable risk would
be very low because accidental pregnancies among DMPA
users are rare. The mechanism of the effect is unknown.
Followed to age 17, children exposed to DMPA during
pregnancy have grown and developed normally (237).
The studies of pregnancy outcome have been criticized
because of the difficulty of controlling other related factors
and of estimating gestational age because of DMPA-induced
amenorrhea. Both difficulties could bias the finding of a
dose-response relationship in the Thai study (106). Further,
the study compared unplanned pregnancies among DMPA
users with planned pregnancies. Unplanned pregnancies
have a higher risk of poor outcome than planned pregnan
cies (120).
There is little information on possible fetal effects of NET EN.
Small clinical studies have found no abnormalities in babies
who had been exposed to NET.EN during gestation or whose
mothers had used NET EN before becoming pr.egnaqt (87,>
122). No cases of fetal anomalies have been reported to
Schering AC (15). There have been no studies of the effect
of monthly injectables on fetal development.
Clinical implications. Providers need to be reasonably sure
that women are not pregnant when they are given inject
ables. This can be done by giving the injection in the first
seven days after menstruation starts or by asking questions
to determine whether a woman has been exposed to the risk
of pregnancy since her last menstrual period (see Table 3). If
a woman mistakenly receives an injection while pregnant or
becomes pregnant while using an injectable, providers can
reassure her that contraceptive hormones have no harmful
effect on the fetus in the vast majority of cases.
Evidence in
the Cancer Debate
In the 1980s several epidemiologic studies assessed the risk
of cancer among women using injectables. AS'noted (see p. 3),1
the largest and most carefully controlled of these studies was
the WHO Collaborative Study of Neoplasia and Steroid
Contraceptives, conducted from 1979 to 1988 in 10 coun
tries. It examined the risk of cancer of the breast, cervix,
endometrium, ovary, and liver among users of various hor
monal contraceptives. The study investigated DMPA in
Kenya, Mexico, and Thailand and reported generally reas
suring findings (see Table 6). Little information is available
on NET EN or monthly injectables. Inferences about monthly
injectables cannot be made from findings on oral contracep
tives because they use different hormones, and the daily
levels of hormones in the bloodstream differ (283).
■
Breast Cancer
After skin cancer, breast cancer is the most common cancer
among women worldwide. In 1985, the last year for which
global estimates are available, there were an estimated
719,000 cases of breast cancer worldwide compared with
437,000 cases of cervical cancer, which has the next highest
incidence (239) (see Table 6).
, !
,
DMPA. The WHO study found no overall increased risk of
breast cancer among women using DMPA. A similar finding
was reported by a well-controlled study in New Zealand.
Both studies, however, found that young women faced an
increased risk, as did women in the first few years after they
started to use DMPA (243, 301). An analysis of combined
data from the two studies found that the increased risk was
mainly among women in the first five years after they started
DMPA (relative risk of 2.0, statistically significant). Most of
these recent users were young women. If women had not
developed breast cancer within five years after starting
DMPA, they faced no increased risk (284). The few earlier
studies of DMPA and breast cancer, smaller and less reliable
than the WHO and New Zealand studies, reported conflict
ing results (104, 180, 183).
The pattern of increased risk in recent users but not in users
in the distant past suggests that DMPA may speed up the
growth of existing tumors rather than turn normal cells into
cancerous cells (243, 284, 301). If DMPA initiated breast
cancer, women exposed to the largest amounts of DMPA—
that is, women who used DMPA the longest—would havethe highest risk of breast cancer. Among all users, however,
duration of use makes little difference to risk.
Better detection of breast cancer among DMPA users may
explain part of the apparently increased risk. If contraceptive
users age 20 to 34 detected breast cancer one year earlier
than nonusers, their relative risk would be 1.2 (284). The
relative size of the tumors in users and nonusers suggests
little or no detection bias, however; the tumors in DMPA
users were as large as or larger than the tumors in nonusers
(301). Another possible explanation involves benign breast
disease, which can mask breast cancer: DMPA suppresses
benign breast disease and thus could reveal cancerous tu
mors that remain hidden in women not using DMPA (98).
DMPA users and users of combined OCs may face similar
risks of breast cancer. Most studies find no overall increase in
risk of breast cancer among OC users, but young users or
recent users may be at slightly increased risk (192, 314).
Pregnancy has a similar effect on the risk of breast cancer.
Several studies report that aftera full-term pregnancy women
have a greater risk of breast cancer than women with no
children (44, 141, 178, 325). After 15 years, however,
women with one child may have less risk of breast cancer
than women with no children (141, 1 78). This pattern, too,
suggests that higher than usual levels of reproductive hor
mones accelerate the development of existing tumors.
If DMPA does increase the risk of breast cancer, the addi
tional cases attributable to DMPA would be slight. Most
users are young women whose risk of breast cancer is low;
only about 15% of breast cancers occur in women under age
40 (69). According to the WHO study, in Chiang Mai,
Thailand, an estimated additional 1 or 2 women per 100,000
might be diagnosed with breast cancer each year because
they used DMPA. This estimate applies to women 20 to 35
years of age, whose relative risk of breast cancer in the study
was 1.4 if they used DMPA. The incidence of breast cancer
among women in this age group who had never used DMPA
would be 3.2 per 100,000 per year, according to the study,
while, for women who had ever used DMPA, it would be 4.5
per 100,000 per year—a difference of 1.3 cases per 100,000
per year (301). The findings concerning breast cancer do not
justify restrictions on the availability of DMPA.
Monthly injectables. The only study of breast cancer among
users of monthly injectables found a relative risk of 0.8 (a
slight protective effect), not statistically significant. The re
port used data collected by the WHO study in Chile and
Mexico and involved 267 women with breast cancer and
1,520 women in the control group (13).
□
Cervical Cancer
DMPA. The WHO study found no increased risk of invasive
cervical cancer (see Table 6). There were no trends in risk of
invasive cancer by duration of use or time since first or last
POPULATION REPORTS
Table 6. Risk of Various Cancers and Use of DMPA
WHO Collaborative Study of Neoplasia and Steroid Contraceptives, 1979-190d
Relative Risk for Women
No. of Cases Who
No. of Controls Who Used
Who Ever Used DMPA
Used DMPA/AU Cases
DMPA/All Controls
(95% Confidence Intervals)6
Site of Cancel
Ref.
No.
Breast
WHO Stiidv_____________
WHO + New Zealand d......
301
1 09/Rf>9 (1 3%)
1 497/11 R90 (1 7%1
1 7 (O 9A-1 971
284
219/J,708 (12%)
.1,725/13,905 (12%)
1.1(0.97-1.4)
Worldwide
Incidence
Among Women,
1985c
719,000
Cervix
Invasive................................
30.3
338/2,009 (17%)
1,415/9,583 (15%)
1.1(0.96-1.29)
437,000
In situ......................................... 304
168/757 (22%)'
1,375/8,942 (15%)
1.25 (1.02-1.52)'
Endometrium.........................
302
3/122(2%)
84/939(9%)
0.2(0.1-0.81
140,000
Ovary...................................... 291
22/224 (10%)
229/1,781 (13%)
1.1 (0.6-1.8)
162,000
Liver
101,000
Kenya...................................
269
4/22(18%)
12/142(9%)
1.64 (0.4-6.6)
Thailand...............................
269
4/49 (8%)
65/388 (17%)
0.33(0.1-1.0)
'■’who study data for breast and invasive cervical
relative risks reported here, relative risk of cervical
rWomen with symptoms only. Relative risk stalisli.
cancer come from Kenya. Mexico, and Thailand, for carcinoma in situ is significantly increased, while risk rally significant al pe.OS.
cervical carcinoma in situ and ovarian cancer, from of endometrial cancer is significantly decreased (pro 1Results lor Kenya and Thailand are presented
Mexico and Thailand; for endometrial cancer, from
tective effect). All others are not significant.
separately because risk of liver cancer among DMPA
Thailand.
'Source. Parkin et al. 1993 (239)
hRelative risk is statistically significant if range of 95% Pooled data from WHO and New Zealand studies
confidence interval does not include 1.0. Among
(243)
Population Reports
use. Researchers controlled for the sexual behavior of the
women and their husbands and for a history of sexually
transmitted diseases, among other variables (303).
The study reported a slightly increased risk of cervical cancer
in situ (cancer confined to the epithelium, the surface layer
of the cervix)—1.25 among women with symptoms (statisti
cally significant). To avoid screening bias—more detection
of cancer in situ without symptoms among DMPA users
because they were seeing providers more regularly than
nonusers—the researchers emphasize the findings for
women who had symptoms at diagnosis. The researchers
conclude from these findings—increased risk of in situ but
not invasive cancer—that the in situ lesions induced by
DMPA may be reversible or that they do not lead to invasive
cancer (304). Other studies of cervical cancer among DMPA
users have found no significant increased risk of cervical
dysplasia (precancerous lesions) (221, 222), cancer in situ,
or invasive cancer (227).
Monthly injectables. The only published study devoted ex
clusively to monthly injectables concluded that users may
have a slightly increased risk of cervical cancer (relative risk
of 1.3). The report, which analyzed data collected in the
WHO study, involved women in Chile and Mexico who had
used a monthly injectable containing dihydroxypro
gesterone acetophenide and an estrogen, usually estradiol
enanthate (300).
)
Endometrial Cancer
Women who use DMPA reduce their risk of endometrial
cancer, according to the WHO study. Thai women using
DMPA had a relative risk of 0.2 compared with nonusers (see
Table 6). The protective effect lasted for more than 12 years
after first use and 8 years after last use. Since only three
women with endometrial cancer had used DMPA, the study
could not tell whether risk declined with duration of use.
POPULATION REPORTS
The protective effect of DMPA may be even stronger than the
WHO study suggests. All three DMPA users who had en
dometrial cancer had also taken estrogen to regulate bleed
ing. Estrogen increases risk of endometrial cancer (317).
Epithelial Ovarian Cancer
The WHO study found no association between use of DMPA
and epithelial ovarian cancer (291), which accounts for more
than 90% of ovarian cancers (67). The overall relative risk
among DMPA users was 1.1, not statistically significant. The
study found no pattern of risk related to duration of use, time
since first or last use, or age at first use (291).
The failure to find a protective effect is surprising. Like OCs,
DMPA prevents ovulation, which reduces the risk of ovarian
cancer. Thus the injectable should offer similar protection
against ovarian cancer. Women who have ever used OCs have
about two-thirds the risk of ovarian cancer of non users, and use
for five years or more cuts the risk of ovarian cancer in half (290).
■
Liver Cancer
The two studies of liver cancer and injectable contracep
tives, the VVHO study and a South African study, report no
increased risk. The WHO study reported results for Kenya
and Thailand, the only countries where DMPA use is high
enough to assess the risk of liver cancer. The relative risk of
liver cancer among Kenyan DMPA users was 1.6, and
among Thai users, 0.3. The researchers have more confi
dence in the Thai data because most of the cases of liver
cancer were confirmed histologically in Thailand, but only
about one-third were confirmed histologically in Kenya
(269). The South African study found that users of progestinonly injectables had a relative risk of liver cancer of 0.4, not
statistically significant but, like the Thai data, suggesting a
protective effect (159).
15
The User’s Perspective on
you don't have such worries. The field worker keeps
track ofwhen I'm supposed to take my shots and comes
and gives them to me herself. And since it's a woman
who's giving me the shots, my family doesn't object.
Women’s attitudes toward progestin-only injcctables largely
reflect their feelings about the privacy and convenience of in
jections and menstrual bleeding disruptions. These feelings
in tum reflect not only the attributes and physiological ef
fects of the method but also women's knowledge and under
standing of the method, personal needs, contraceptive
experience, partners’ attitudes, and cultural norms. Family
planning providers can better counsel and advise clients if
they are aware of these differing attitudes and physiological
responses. Similarly, communication programs must under
stand people’s attitudes and reactions in order to devise
effective messages.
The New User
Women choose injectables because:
• They want a highly effective, reversible contraceptive.
• They want a long-acting method but not one that(lasts for
years. They do not want to take a pill every day.
• They have faith in the effectiveness of injectable medica
tion because of the well-known efficacy of injectable anti
biotics and the success of campaigns with injected
penicillin, such as yaws eradication.
• They may like amenorrhea, especially if they usually have
heavy menstrual flows and cramping.
• They want a contraceptive that can be used privately,
a method that can be obtained quickly at the clinic and
requires no supplies around the house.
• They want a method that does not require action at the
time of sexual relations.
• They want a reliable and safe method that can be used
during breastfeeding.
• They have talked with friends or relatives who are using
injcctables satisfactorily (14,20,23,46, 54,62, 95, 146,
160, 162, 198,217,350).
In interviews women in places as different as Bangladesh
and the US mention many of these advantages (14, 62):
Bangladesh
...with pills you have to have a dose every day, and
there's a chance of your forgetting. With injectables.
^oncontraceptive
Health Benefits
Injectables have several health benefits in addition to pre
venting unintended pregnancy. They help to prevent en
dometrial and possibly ovarian cancer (see p. 15). They also
may help women with anemia and sickle-cell disease. Also,
like other contraceptive methods that prevent ovulation,
such as combined oral contraceptives and, to a lesser extent,
Norplant implants, injectables protect women against ec
topic pregnancy, which can kill from sudden and severe
internal bleeding if a fallopian tube ruptures. A few studies
One of my husband's relatives once said to me, 'inject
ables are good, t've been using them for three years.
Come with me and you'll be able to get an injection,
too. There won't be any trouble.' So I talked to my
husband and after he agreed, I began using injectables.
Many others have followed me. Even my sister-in-law
uses injectables now.
I started using injectables after I had two children in
quick succession.
United States
«
I got pregnant when I was 13 and had my baby when I
was 14. I did not use any birth control when I got
pregnant. Depo is much easier than taking the Pill every
day. I'm not good at remembering to take pills.
I decided to use the Depo shot beca use it was very easy.
You just come back every three months. I didn't decide
to take the Pill because I am on medication for seizures.
I thought I would forget to take the pills.
I was a poor pill taker. I thought barrier methods were
inconvenient and messy.
The Continuing User
Users’ attitudes toward injectables are reflected in discon
tinuation rates. The most common reason for stopping Inject
ables is side effects. In a WHO trial of DMPA, for example,
half of users discontinued after one year, about one-third
stopped because of side effects—for example, menstrual dis
ruption, headaches, dizziness, or weight gain—and the rest
stopped for personal reasons or were lost to follow-up (342).
Women’s attitudes toward side effects, particularly men
strual disruption, are varied and complex (III, 115, 278,
324,327). Irregular bleeding is inconvenient for many
‘women who do not have sexual relations while menstruating
(327). Muslim women often discontinue injectables because
their religion forbids them to pray, fast, read from
suggest other benefits of injectables, such as prevention of
pelvic inflammatory disease (PID).
IB
Reduced Anemia
A contraceptive that increases hemoglobin levels is espe
cially valuable in developing countries, where 20% to 40%
of women suffer from iron-deficiency anemia (343). Several
studies find that blood hemoglobin levels in DMPA or NET
EN users increase (65,121,122,201), although other studies
find no change (1, 129). Progestin-only injectables may
increase hemoglobin levels by reducing menstrual blood
loss and by accelerating the formation of red blood cells and
lengthening their survival (65, 121). Two studies of monthly
injectables have found no change in hemoglobin levels (86,
POPULATION REPORTS.
Injectables
the Koran, or have sexual relations during vaginal
bleeding. Amenorrhea may make some women think
that they are pregnant or that a dnig powerful enough
to take away monthly bleeding is unhealthy in other
ways. Many people have the false idea that, if a
woman does not menstruate, poisonous blood collects
in her body (327).
Such attitudes are not universal. Many users in
Jamaica, Indonesia, and Thailand, for example, accept
menstrual disruption (115). For many users the bene
fits of effective contraception clearly outweigh the dis
advantages of side effects. A Bangladeshi woman
commented:
We are very poor. So we won't be able to survive if
we have too many children. That's why I use Oepo,
even though it does give me a little trouble (62).
For some women amenorrhea and weight gain are
advantages of injectables. A US woman using DMPA
commented:
I became amenorrhelc after one month of use. I love
that. I haven't had periods for five years and it has
been great. I worried the first month that I might be
pregnant. I talked with my doctor about it and was
reassured. Before Depo I had dysmenorrhea [painful
menstruation) and now it has disappeared —no
bloating, cramps, or weight gain (275).
Women in Egypt, Nepal, the Philippines, Sierra Leone,
and Thailand have reported that they like weight gain
experienced with progestin-only injectables (11, 117,
241,270,298).
Survey of Service Providers
Service providers in 10 countries responded to a Population"
Reports questionnaire asking about their perception of inject
ables, their clients’ perceptions, difficulties and benefits of pro
viding injectable services, medical eligibility requirements for
the use of injectables, and lessons learned. Their answers have
been used extensively in this report, particularly in “The
User’s Perspective."
Bangladesh:
Sabera Rahman, Mohammadpur Fertility
Services and Training Centre
Roberto Santiso Galvez, Asociacion Pro
Bienestar de la Familia de Guatemala
(APROFAM)
Hong Kong: Margaret Kwan, Family Planning Association
of Hong Kong
Kenya:
C.N. Kamau and Margaret N. Thuo, Family
Planning Association of Kenya
Madagascar: Manitra Andnamasinoro, Fianakaviana Sambatra
Philippines: Jovencia B. Quintong, Family Planning Service,
Department of Health
Sierra Leone: Willie E. Taylor, Planned Parenthood Associa
tion of Sierra Leone
Sri Lanka:
Sriani Basnayake, Family Planning Association
of Sri Lanka
Sudan:
Ahmed M. Youssif, Sudan Family Planning
Association
Thailand:
Sombhong Pattawichaipom, Planned Parent
hood Association of Thailand
Guatemala:
Interviews with users of injectables in Bangladesh were con
ducted by Achintya Das Gupta, Yasmin Khan, Marufa Khanam, Khadija Bilkis, Rashida Sultana, and Tawfique N.
Hamid, all staff members of the Bangladesh office of Johns
Hopkins Population Communication Services.
Counseling can help women who choose injectables to
adapt to the side effects (see p. 18). Counseling may be
so important to clients, in fact, that they are willing to
pay for it. In the 1970s the McCormick Family Plan
ning Program, which pioneered use of DMPA in Thailand,
offered the injectable for a small fee, while the public family
planning program in the same area offered free services.
108), while a one-year study of the monthly Mesigyna found
a significant increase after the third injection (208).
Fewer Sickle-Cell Crises
Program staff observed that many DMPA users preferred to
pay the small fee because of the good counseling that they
received with each injection in the McCormick program (20).
and sickle-cell disease, women using DMPA in a 2-year trial
had significantly fewer crises than women given a placebo.
Hematological tests found significant increases in total he
moglobin and red cell counts among DMPA users and sig
nificant decreases in the level of irreversibly sickled cells (65).
Sickle-cell disease is caused by a defect in the structure of
hemoglobin that leads to deformation of red blood cells into
a sickle shape when deprived of oxygen. These cells block
blood flow, causing painful sickle-cell crises. Sickle-cell dis
ease is most common among blacks and causes at least 80,000
deaths worldwide every year (231).
Progestin-only injectables may help women with reproduc
tive tract infections, epilepsy, or endometriosis. Evidence is
slight, however, and further studies are needed.
Testosterone, progesterone, and progestins such as DMPA
prevent sickle-cell crises, probably by stabilizing the mem
brane of red blood cells (139). In the only study of DMPA
Progestin-only injectables may help to prevent pelvic in
flammatory disease. A WHO multinational study of 319
women with PID and 638 matched controls found that the
POPULATION REPORTS
Possible Additional Benefits
risk of acute PID among DMPA or NET EN users was half that
among nonusers, although the difference in risk was not
significant because of the small sample (99). Injectables may
protect against PID by thickening cervical mucus, prevent
ing STD organisms from passing through the cervix.
Progestins have decreased the frequency of seizures in
women with epilepsy (194, 359). Several studies have re
ported that the frequency of seizures in women decreases
when progesterone levels are high during the menstrual
cycle and increases when estrogen levels are high. In one
study of 14 women who added oral and injected medroxyprogeterone acetate to their antiepileptic drugs for an
average of 12 months, the frequency of seizures among 11
women who developed amenorrhea declined by 30%, from
eight seizures per month before the addition to five after, a
significant change (194)
Endometriosis causes painful menstruation and prolonged
bleeding. Oral medroxyprogesterone at 20 to 30 mg a day is
used to treat endometriosis (214). Clinical observation sug
gests that DMPA at the contraceptive dose decreases symp
toms as well (154).
(Counseling Issues
Good counseling helps clients choose and use contracep
tives. What do clients need to know to make an informed
choice of injectables and to use them successfully? Programs
answer this question in counseling guidelines appropriate for
their clients. The counseling guide accompanying this issue of
Population Reports is designed to help programs set coun
selingguidelines for injectables, to train providers, and as a
reference on the job.
Counseling for injectables and other contraceptive methods
is crucial. Women are more likely to continue a method
when they have received good counseling and Ijnow what
to expect. Also, if informed about other methods, clients are
more likely to switch to another method rather than slop
using contraception if they are unhappy with their first
choice (9, 256). Of course, counseling cannot be the only
way that people obtain information about injectables and
other family planning methods. A wide range of channels,
from community meetings to broadcast media, supports and
enhances face-to-face communication between providers
and the public (see p. 19). .
In a clinic an overview of family planning methods may be
presented during education sessions for groups of clients. In
individual counseling, providers can make sure that clients
understand the information given to the group, help the
client choose a method, and provide information that helps
clients use the method—for example, the date of the next
injection and likely side effects. In fact, many women come
to the clinic knowing what method they want. If they obtain
that method, they tend to use it longer than women given
methods that they did not want (238).
Injectables pose a number of difficult counseling issues,
some of which are posed by other contraceptives as well.
Providers may need help in deciding what to say about':
• The range of side effects of injectables,
• Bleeding changes,
• Breast cancer,
• Delay in return of fertility, and
• Returning late or early for injections.
18
■
Counseling About Side Effects
Program managers may consider a number of factors, some
of which conflict, in deciding what providers should tell
clients about side effects or should be prepared to discuss
with clients. For example:
• Time. Providers may have just a few minutes to talk with
each client and dispense a method. A few extra minutes
in initial counseling, however, could save more time later
when women return because of unexpected side effects.
• Clients' reactions to unexpected side effects. People
often tolerate side effects that they expect but may dis
continue a method if they are surprised by a side effect.
Unless clients are told, they have no way to know whether
the side effect is minor or serious, or whether it will get
worse and threaten their health or instead eventually will
diminish or disappear.
• Clients' reaction to a long list of side effects. Some
providers fear that mentioning side effects may discour
age clients from using a method (188). Descriptions of
serious but rare side effects may be especially frightening
to clients. Also, providers should avoid giving clients
more information than they can absorb in a short coun
seling session. Studies in developed countries, however,
find that patients, including OC users, generally want
detailed information about sideeffects, whi le doctors and
pharmacists prefer to discuss only serious side effects and
the most common minor effects (196, 226). Providers
might ask clients if they want to know all the side effects
of a drug or procedure or just the ones that are most
common (250).
• Clients' understanding of risk. How can providers make
the concept of probability understandable? Describing a
slight risk of a serious side effect may be especially
difficult. How risks are presented can influence a client's
choice. In a study of treatment for lung cancer, for
example, both doctors and patients preferred a treatment
described as having a 90% survival rate after one year to
an identical treatment described as having a 10% mor
tality rate after one year (203). Thus, family planning
providers may point out that, while 5% of users experi
ence a side effect, 95% do not.
• Cultural or religious customs. These may limit discussion
between client and provider. For example, in some cul
tures clients may not expect to ask questions or to have
long discussions with providers, who have higher social
status than they do (281). Women may not want to discuss
intimate matters with male providers (292). Where pos
sible, managers may arrange for female providers to
counsel female clients.
• Clients' concerns. Providers should be able to reassure
clients if they raise concerns about reports in the mass
media or rumors from friends or relatives. During educa
tion sessions in the McCormick Family Planning Program,
for example, providers asked groups of 5 to 15 clients
about the rumors that they had heard about DMPA and
then provided accurate information (199).
E
Bleeding Changes
Women considering injectables must know that injectables
probably will affect their menstrual patterns and in what
ways. Women who have been counseled in advance about
bleeding changes tend to continue using injectables despite
POPULATION REPORTS
the changes (33, 41,88, 1 15, 281,331). In a WHO study of
bleeding disturbance and discontinuation among women
using a variety of hormonal methods, OC users, who gener
ally did not receive counseling about bleeding, tended to z
discontinue for mild bleeding changes. In contrast, DMPA
users, who had been counseled, continued to hjtve injec
tions despite major disruption of their menstrual cycles (33).
In a study of monthly injectables, women who received no
counseling were twice as likely to discontinue as women
who were counseled (115). Women may need extra help to
get through the first months of frequent or irregular bleeding
(14, 212). Also important is reassurance that amenorrhea is
not harmful: Lack of menstrual bleeding does not mean that
women are pregnant or that blood is building up in their
bodies (see Counseling Guide). Providers can reassure cli
ents that bleeding returns to normal after stopping progestinonly injectables but may take six months or more to do so.
■
Breast Cancer
A nurse in Thailand counsels new family planning clients about
DMPA. Counseling helps women to understand that the common
Telling potential users of injectables about bleeding changes side effects of menstrual changes and weight gain are not harmful.
is clearly necessary, but what to say about other matters is
often unclear. The findings of breast cancer studies present To ensure informed choice, providers should tell clients that
a particular problem. According to the WHO-New Zealand they may return late or early for an injection and still be
combined analysis, women face an increased risk of breast protected against pregnancy. Without this information, cli
cancer for five years from the time that they start using ents may assume that they have no choice but to return on a
DMPA, but very few women will be diagnosed with breast
specific day. If they miss an appointment, they may assume that
cancer because they use DMPA (see p. 14). Someiprograms ‘they cannot get another injection, and they may discontinue use
may decide that the risk of breast cancer is so small that it is (167). Providers may tell women, however, that if they have not
not necessary to mention it. Others may decide that clients returned by the end of the grace period and it is not reasonably
have a right to know. The WHO and New Zealand re certain that they are not pregnant, they may need a pregnancy
searchers suggest telling clients that DMPA may speed up the test or to wait for their next menstrual period before they can
growth of tumors that already exist (284).
get another injection. They should use condoms or another
barrier method until then. In areas with reliable telephone
■
service, some providers do not tell users about the grace
period unless users call to say that they cannot come on the
Return to Fertility
scheduled day.
No woman should use DMPA or NET EN without knowing
that she may have to wait to become pregnant after stopping.
Providers should not tell clients that the grace period is
Providers may simply say that pregnancy may be delayed for shorter than it actually is. Once users find out the truth, they
several months. If women want to know how long they may may distrust providers. Studies are needed to assess the effect
have to wait, providers have several options for describing of information about the grace period on clients' adherence
the typical delay:
to the injection schedule.
• Time from last injection: Half of DMPA users become
pregnant in the first nine months after the last injection, Clients who are often late can be given appointments earlier
than usual—for example, after 2 months and three weeks for
and half wait longer.
DMPA rather than the full 3-month interval. Providers should
• Time from when the next injection would have been
try to determine why clients are late—for example, they may
given—six months, on average, for DMPA.
• Compared with other methods: DMPA users may have fear getting an injection or they may have trouble getting to
to wait two to three months longer on average than former Mlhe clinic—and help them to overcome any problems (116).
OC users.
In any case, providers need to make clear that time to
conception cannot be predicted for any woman.
■
Returning Late or Early
Programs in Guatemala, Indonesia, Jamaica, Kenya, and
other countries report that the vast majority of clients return
on time for their injections (48, 127, 188). Many programs
help clients return on time by giving them an appointment
card. In Indonesia, for example, providers write the date of the
next injection on a family planning identification card that
the client keeps, and providers are encouraged to remind clients
twice during counseling of the specific day to return (188).
POPULATION REPORTS
with the Public
Injectable contraceptives have great potential, but they also
have been controversial. People need to know what is true
or scientifically proven about injectables and what is incor
rect or unproven. Also, they need to know the advantages
and disadvantages of injectables and be able to compare
them with those of other methods. By creating an accurate
impression of injectables at the start, programs can avoid the
more difficult task of correcting a wrong impression later.
19
The wider availability of injectables is an opportunity to
reach more people with more information through a variety
of media. With a few exceptions, most programs have lim
ited experience communicating about injectables. Typi
cally, programs have gone no further than to produce
informational print materials for clients and providers—for
example, posters, brochures, or flip-cfiarts*—tl>at describe
injectables along with the other contraceptive methods. As
access to injectables increases, so does the need for com
plete and readily accessible information about injectables.
Effective communication efforts start with research. Needs
assessments or situation analyses identify audiences, their
interests and concerns, and how they can be reached. A
particular issue with injectables is women's responses to
menstrual disruption—responses that differ from country to
country and even within countries (see p. 10).
Research methods include surveys, interviews, focus-group
discussions, observation of providers, and evaluation of
communication channels and facilities. For example,
Demographic and Health Surveys and other national sur
veys can help programs identify audiences. Such surveys
may report a high percentage of women intending to use
family planning, and many of these women may say that
they plan to use injectables. In Kenya, for example, 58% of
currently married women not using contraception said that
they intend to use family planning at some time, and 44%
said that they intend to use family planning in the next year.
Among women intending to use family planning at some
time, 41% said they planned to use injectables (156).
Well-planned communication programs can help these
women carry out their intentions. Messages may need to
address public attitudes towards family planning in general,
public knowledge of injectables, and the history of contro
versy about DMPA.
Public attitudes toward family planning. What charac
teristics of injectables can communication programs empha
size! The convenience of injectables is one of their most
attractive characteristics. Surveys in places as different as
Egypt and the Philippines find that "easy to use" is a major
asset for any contraceptive (140, 161). Research on inject
ables confirms this finding. For example, in focus-group
discussions conducted by the Social Marketing for Change
(SOMARC) project in Nepal, women suggested the brand
name for DMPA of "Easy 3-month injection" (.307).
The reversibility of injectables also can be an appealing
feature. In Nepal surveys find that people associate contra
ception with sterilization, and many are unaware of the
possibility of birth spacing. In the 1991 Fertility, Family
Planning and Health Survey, 14% of women said that they
would like to space children, but only 1% were using
contraception. Thus the Contraceptive Retail Sales project,
which sells DMPA, plans to emphasize reversibility in its
social marketing promotion of the injectable (117, 307).
In Zimbabwe programs have informed the public about.
injectables while encouraging men to share responsibility
for family planning. In the mid-1980s research found that
men often made the decisions about family planning and
family size and that men wanted more information about
family planning. Therefore, in programs conducted from
1987 to 1994 by the Zimbabwe National Family Planning
Council with assistance from Johns Hopkins Population
Communication Services, weekly radio dramas addressed
men; posters and newspaper and magazine articles informed
the public about long-acting methods; costumed performers
portraying injectables and other contraceptives clowned on
the football field during a tournament; and providers offered
family planning counseling at community events. Surveys
before and after a campaign in 1993-94 found significant
increases in the percentage of men who approved of inject
ables, from 55% to 67%, and in the percentage of women
who said their partners approve of injectables, from 46% to
60% (160,174).
Of course, some women use injectables because they do not
want their husbands to know that they are using contracep
tion. Communication programs generally do not publicly
emphasize this attribute of injectables. Rather, they encour
age partners to talk and reach agreement about family plan
ning. Women use injectables longer when they have the
support of their husbands (267). Using injectables secretly is
best discussed informally by providers in one-to-one coun
seling. While encouraging couples to discuss family plan
ning, programs should lake care not to alienate women who
cannot talk with their partners about family planning.
This Indonesian poster explains that the injectable Cyclofem is
given monthly, does not interfere with work, and affects menstrual
bleeding only in the first month. Informative posters such as this
one can reach many women and tell them about family planning
methods even before they meet a provider. Indonesia was one of
five countries that participated in introductory trials of Cyclofem.
20
Public knowledge. The broadcast media, widespread distri
bution of brochures and posters, and promotion of profes
sional providers have helped to increase knowledge and use
of injectables. Most of these programs cover injectables
along with other available methods. In Tanzania, for exam
ple, a multimedia campaign conducted from 1991 to 1994
by the Ministry of Health produced posters, radio spots, and
POPULATION REPORTS
method-specific leaflets describing injeclables and other
long-term methods. A national introduction and introduc
tions in several regions attracted press and public attention.
After the campaign a survey in three regions found that the
percentage of men and women ages 15 to 44 who men
tioned injectabies without prompting had risen from 18% to
49%. and use of injectabies had risen from 1% to 3% (142)
Overall, in 1991-92, 0.4% of married women in Tanzania
used injectabies (224). In Pakistan an estimated 20 million
people saw the 13-part television drama, Nijaal (Deliver
ance), one episode of which showed a couple considering
their contraceptive options and choosing an injectable (119,
147). In Indonesia the Blue Circle campaign promotes the
family planning services of private doctors and midwives
who provide injectabies and other methods (295). The cam
paign distributed a leaflet on injectabies for clients that asks,
"Mothers, do you know enough about the injectable contra
ceptives?"
j
A full-fledged communication program may not always be
necessary. The McCormick Family Planning Program in
Thailand depended mainly on word of mouth. In its first four
years the program attracted 60,000 clients, two-thirds of
whom chose DMPA. Women in the program area had a
strong desire for family planning and trusted the McCormick
Christian Hospital, which ran the program (20).
Communication programs also can help to make sure injec
tions are safe. Programs can portray providers using safe
injection technique and encourage women to insist that their
injections are safe (see p. 25).
The history of controversy about DMPA. Communication
programs need to address providers and the public, who may
ask how a drug that was once suspected of being dangerous
can now be thought safe. Programs can point out that the
fears were based on studies in animals and that more reliable
epidemiological studies in women have now been com
pleted.
Information about the latest research on DMPA can be
presented in special seminars, as has been donp injEcuador,
Peru, and the Philippines, to educate policymakers and
providers. In Ecuador and Peru injectabies are well known,
but many providers consider them dangerous. Seminars in
both countries have paved the way for limited introduction
or expansion of services (51,84, 255). In the Philippines the
Department of Health produced an information kit for
providers that stresses the extensive research underlying US
FDA approval of DMPA. The kit also cites support for family
planning by the Philippines president and health secretary,
the popularity of DMPA in the Philippines, and the country's
ability to produce DMPA (248). New service guidelines
emphasize the importance of client education (125). The
social marketing program in the Philippines placed an ad
vertisement in the Manila Bulletin entitled "Facts about
Depo-Prnvera." It cites studies of DMPA in the Philippines,
describes use of the method in developed countries and
approval in the US, emphasizes that DMPA is reversible, and
refutes the rumor that it is an aborlifacient (53). Also, the
program has trained family planning providers to be inter
viewed on television and radio and to counter misinforma
tion and false rumors about DMPA (18).
In India, however, such efforts have failed to riassbre so‘me
groups opposed to DMPA. The Upjohn Company worked
with the Indian Council of Medical Research (ICMR), which
has endorsed DMPA. Upjohn also invited policymakers from
POPULATION REPORTS
Thailand to discussions with Indian scientists and policy
makers (91). Some women's groups are unconvinced that
DMPA is safe, however, and their challenges have delayed
the introduction of DMPA into the national family planning
program.
Working with groups opposed to DMPA, government agen
cies can address some of their concerns. US FDA officials,
for example, have met with representatives of the National
Women's Health Network to discuss establishing a national
registry of DMPA users that would track side effects (244).
fyfaximizing Access
and Quality
J he potential increase in the availability of injectabies offers
family planning programs the opportunity to set up accessi
ble, good-quality services. Some programs have offered
injectabies for many years and now are strengthening serv
ices. Others—for example, in Turkey and the US—are offer
ing injectabies for the first time. If a program decides to offer
injectabies or expand services, it needs to ensure that the
choice of an injectable—and of every other program
method—is continuously and widely available, provided
safely, and offered without unnecessary restrictions on who
can provide it or use it.
Program managers face a number of issues specific to inject
abies. These include:
• Setting up services;
• Ensuring reliable supplies;
• Establishing appropriate eligibility criteria;
• Establishing appropriate screening and counseling;
• Switching clients from one injectable to another;
• Preventing infection by properly handling used injection
equipment;
• Training providers, especially in counseling and safe
injection technique; and
*• Offering injectabies outside the clinic through commu
nity-based or social marketing programs.
Setting Up Services
Introducing a new contraceptive and expanding services are
formidable tasks. Programs need to train providers, deliver
supplies to clinics and other outlets, and start communica
tion campaigns. Training and communication each can take
18 months or more to set up. Getting injeclables and other
contraceptives to clinics can take six monthsto a year or more
from the time that they are ordered. Realislic estimates of the
time required to prepare each component are essential for a
well-coordinated introduction (311).
Many programs conduct pilot studies or operations research
to gauge potential users' response to injectabies. In Ecuador
operations research is assessing users' attitudes toward DMPA
compared with other methods, the characteristics of users,
and the effectiveness and cost-effectiveness of clinic and
community-based distribution (254). In Peru operations re
search is studying community-based distribution.of DMP/k
and users' responses to menstrual disruption. In one part of
the study, mystery clients—program staff posing as DMPA
users—visited 26 community health workers and evaluated
their knowledge of DMPA and their counseling skills. They
21
The Shelf-Life of Injectables
Confusion arises over a difference in the labeled shelf-life
of DMPA: DMPA made by Upjohn’s Belgian subsidiary is
labeled with a shelf-life of five years; DMPA made by Upjohn
in the US is currently labeled for three years of shelf-life.
The US and Belgian products are identical, however. When
the US FDA first approved DMPA in 1992, the'stability of
DMPA manufactured in the US had been tested for just two
years. Upjohn since then has continued to test DMPA, and
the US FDA is gradually extending the labeled shelf-life of
the US product every six months. It will reach five years
in April 1997 (55). The labeled shelf-life of NET EN and
Mesigyna is five years. The labeled shelf-life of Cyclofem is
being extended to four years in Indonesia and to three years
in Mexico (173).
'
AU injectables should be stored at room temperature, away
from excessive heat and moisture. DMPA may be stored at
temperatures from 15“ to 30“C (60° to 86“F) (223, 312).
found that about three-quarters offered a choice of methods
including DMPA, but only about one-quarter gave users
enough information about side effects (181, 255). WHO
conducted introductory trials of Cyclofem in national family
planning programs in Indonesia, Jamaica, Mexico, Thailand,
and Tunisia. Such trials, a transition between clinical trials
and full-scale introduction, allow program managers to as
sess the effectiveness and popularity of a rrew’-method and3
its impact on overall service delivery (110,288). Other initia
tives need not wait for the results of such pilot studies. Work on
postpartum programs or social marketing programs can start
at the same lime.
Pilot programs are especially important where injectables
are little known or have been controversial. In Turkey, for
example, where few women have used injectables, the
Ministry of Health introduced DMPA in a one-year pilot
study in 15 urban clinics to assess clients' reactions (352).
Communication programs await the completion of the pilot
study In the Philippines injectables were available in the
private sector bul were controversial because of religious
opposition and lack of approval of DMPA in the US. After
the US FDA approved DMPA, the Philippines Department
of Health began to offer DMPA in 1994 through government
clinics in six provinces and four cities, where about 15% of
the population lives (51). Introductory programs generally
offer only one type of injectable.
The private sector is helping to introduce injectables in some
government family planning programs. In Ecuador, for ex
ample, the Centro MSdico de Orientacidri’y Planificacibn"
Familiar (CEMOPLAF), a private nonprofit family planning
organization, is conducting the introductory study (255).
The social marketing project in the Philippines added DMPA
to its line of contraceptives, sold under the brand name
Couples' Choice, and is sharing the lessons of its experience
with the Department of Health (210).
3
Ensuring Reliable Supplies
Programs can ensure a reliable supply of injectables, nee
dles, and syringes by:
• Offering only one or two types of injectable,
22
• Accurately projecting numbers of users,
• Ordering well in advance,
• Training providers in logistics (ordering and managing
supplies),
• Shortening the pipeline—the stops on the route from the
manufacturer to the provider; and
• Ordering needles and syringes packed with injectables.
Logistics need to be taken into account in program planning
and coordinated with events that can affect demand such as
communication campaigns and provider training.
Offering only one or two types of injectable. Offering
several injectables increases choice but creates logistical
problems. The decision about which injectables to offer rests
on several factors:
• Source of supply. Most programs obtain injectables from
donor agencies. USAID provides only DMPA, while
UNFPA and IPPF supply DMPA and NET EN. Donors
supporting the same program may supply different inject
ables; consultation can ensure that programs offer only
the appropriate number of injectables. The policy of the
Department of Health in the Philippines is to refuse
donors' offers of injectables and other products if they
would be a burden to the logistics system (113).
• Preference of clients. Users may have preferences based
on duration of contraceptive protection or extent of
bleeding changes. For example, the Thai National Family
Planning Program found that NET EN was less popular
than DMPA and thus decided not to offer it (167).
• Training providers. Providers must be able to counsel
clients about each injectable that they offer.
• Efficiency of the logistics system. To offer several inject
ables, programs must be able to supply clinics with
amounts that reflect clients' preferences. This requires
keeping track of the different types of injectables.
• Cost. The cost of commodities alone—drug, needle,
syringe, and swab—is US$3.88 per couple-year of pro
tection (CYP) for DMPA and $6.30 per year for NET EN
when given every two months. This calculation uses
estimated average commodity costs on the international
market: $0.92 per dose of DMPA, $1.00 per dose of NET
EN, and $0.05 for needle, syringe, and swab (195).
Cyclofem, at $.45 to $.65 per dose, costs an estimated
$5.40 to $7.80 per year (108). The comparable commod
ity cost of OCs is $3.00 per CYP (195). Costs of service
delivery are not included in these amounts.
• Ease of injection. Providers may find DMPA easier to
inject than the more viscous NET EN. DMPA injection
may be less painful because the needle is smaller (167,
281).
• Providing equipment for different injectables. Injections
of DMPA are given with a 21-to 23-gauge needle, while
the wider-bore 19-gauge needle is better for NET EN. An
injection of NET EN with a needle appropriate for DMPA
is more difficult for the provider and more painful for the
client (281). Both Cyclofem and Mesigyna may be in
jected with a 21-23 gauge needle (223). Logistics man
agers must be able to ensure that service sites receive the
right needles with each order (134).
• Keeping track of schedules in community-based distri
bution (CBD) programs. Setting up work schedules may
be difficult if field workers are responsible for several
injectables al once (134). Program managers in Matlab,
Bangladesh, decided not to introduce Cyclofem into the
CBD program because of the potential logistical and
scheduling problems (211).
POPULATION REPORTS
Programs just starting out generally begin with one inject
able. The Philippines, for example, has chosen to offer only
DMPA for the first five years (51). The Mexican family
planning program, which first offered NET EN in 1979, is
now adding Cyclofem (205, 245). IPPF suggests this ap
proach to avoid logistical problems: provide only one pro
gestin-only injectable, and. if there is demand, one monthly
injectable (138).
Accurately projecting numbers of users. Assumptions that
use will always increase by 10% next year are generally
inaccurate. More accurate estimates can be based on histori
cal data indicating changes in number of users and numbers
of vials dispensed, on current service statistics, or on surveys
of the population served by the program, which can identify
women intending to use injectables. Such surveys,are espe
cially important for DMPA, use of which may Inct'ease now
that it is becoming more available. Also, programs need to
anticipate changes in demand in response to communica
tion campaigns (229, 333).
Ordering well in advance—at least three months and pref
erably six months (118). The Family Planning Association of
Sri Lanka, for example, orders a 1-year supply of DMPA,
about 100,000 vials, when they have five months of stock
remaining (2). Also, advance orders should be coordinated
with communication campaigns.
Training providers in logistics. In some cases clinics run out
of injectables because clinic staff fail to reorder until there
are no supplies left. Clinic staff can be trained to collect and
use the basic information needed to decide when and how
much to order: average monthly consumption, losses of
stock that has been damaged or whose expiration date has
passed, stock on hand (inventory), and lead time—the time
between ordering and receiving supplies (37).
Shortening the pipeline. Some programs have speeded the
passage of contraceptives from the manufacturer to the
provider. The Philippines Department of Hdahh has re
moved two levels in the distribution chain. Contraceptives
and other drugs used to pass from the central warehouse
through regional, provincial, and district warehouses and
storerooms before reaching the local health unit. In the new
chain, drugs and supplies move directly from the central
warehouse to the provincial or city warehouse, saving at
least six months (260). Some programs speed delivery by
ordering DMPA shipped by air rather than by sea (55, 114).
Ordering needles and syringes. Packed separately from
contraceptives, needles and syringes may be subject to
duties that have been reduced or eliminated for injectables
and other contraceptives. Delivery of needles and syringes
is then delayed until duties are paid. Packed together, nee
dles and syringes have the same status as injectables.
To make up for diversion to other uses, programs should
order extra needles and syringes. Some suggest ordering
twice as many needles and syringes as doses of injectable (246).
An efficient logistics system can help providers prevent
transmission of infections. If providers run short of needles
and syringes, they may be tempted to reuse equipment: At
the same time many programs must destroy and dispose of
hundreds or thousands of needles and syringes every day.
The national family planning program in Bangladesh, for
example, uses 250,000 disposable needles and syringes
every month (177) (see p. 25).
POPULATION REPORTS
Eligibility Criteria
Programs sometimes unnecessarily exclude women from
using injectables. Programs may want to review clinical
guidelines for injectables to allow the widest access consis
tent with good care.
Two expert groups have recently collaborated on docu
ments that help programs set up clinical guidelines for
contraceptives. To help bring eligibility criteria for contra
ceptives up to date, WHO established a scientific working
group that first met in March 1994. This was the first attempt
to develop a worldwide consensus on eligibility criteria for
contraceptives (332). Also, to help programs establish appro
priate procedures for providing contraceptives, USAID es
tablished a Technical Guidance Working Group made up-of
representatives of USAID Cooperating Agencies (299).
In updating eligibility criteria, the WHO expert group clas
sified medical conditions into four categories:
• Category 1: A condition for which there is no restriction
on the use of a contraceptive method;
• Category 2: A condition for which the advantages of
using the method usually outweigh the theoretical or
proven risks;
• Category 3: A condition for which the theoretical or
proven risks usually outweigh the advantages of using a
method; and
• Category 4: A condition that poses an unacceptable
health risk associated with the use of the contraceptive
method.
WHO Eligibility Criteria
Differences Between
Progestin-Only Injectables and
Combined Oral Contraceptives
The recommendations of eligibility criteria for progestin-only
injectables and combined oral contraceptives (OCs), formulated
by the WHO scientific working group on improving access to
quality care in family planning, are similar for most conditions.
For some, however, the estrogen in combined OCs makes a
difference. Thus the working group made important distinctions
between DMPA/NET EN and combined OCs for women with
the following conditions:
Condition
_____ Category
DMPA/NET EN OCs
Breastfeeding
Six weeks to six months after delivery
1
Postpartum
Three weeks or less and not breastfeeding 1
Smoking and age greater than 35
Light (fewer than 20 cigarettes)
1
Heavy (20 cigarettes or more)
1
History of hypertension
2
Deep venous thrombosis/pulmonary embolism1* I
Complicated valvular heart disease
I
Recurrent severe headaches with focal
d
neurologic symptoms0
2 Z3U
■ Sickle-cell disease
I
3
3
3
4
3
4
4
4
3-
“For description ofcategories 1-4. see text, this page.
h Women with varicose veins may use either DMPA/NETEN or combinedOCs.
'That is, severe headaches that cause trouble seeing, speaking, or moving.
JFor Initiation ofmethod.
'For continuation ofmethod ifcondition develops during use.
Leading Article
Page 6 of 7
alternative contraceptive method, with the aim of ensuring a certain margin of
safety in the indication and of trying to eliminate the term
’contraindications' [33]. The eligibility criteria for the injectable contraceptives
are reviewed extensively by Laneta Dorflinger; the acceptability of the method is
discussed by Pablo Lavin; while indications in special circumstances such as
adolescence, post partum and during perimenopause, are described by Mamdouh
M. Shaaban.
References
1. Junkmann K. Ober protrahiert wirksame Gestagene. Naunyn Schmiedeberg's Arch Exp Pathol
Pharmakoi 1954; 223: 244-53.
2.
Lande RE. Popul Rep 1995; 23(2).
3.
Zanartu J. A new approach to fertility control: long-acting injectable progestogens. Adv Fertil
Control 1968; 3: 41-3.
4.
Coutinho EM, Carlos de Souza J. Conception control by monthly injections of
medroxyprogesterone suspension and long-acting oestrogen. J Reprod Fertil 1968; 15: 209-14.
5.
Kesseru E, et al. Fertility control with norethindrone enanthate, a long-acting parenteral
progestogen. Acta Eur Fertil 1973; 4:203-321.
6.
Kesserii-Koos E, Larranaga-Legufa A, Hurtado-Koo H, Scharff JJ. Nuevas perspectives Para los
anticonceptivos inyectables. Adv Contracept 1994; 10 (suppl 1): 69-77.
7.
Liskin LS, Blackburn MS. Hormonal contraception: new long acting methods. Popul Rep Ser K
1987; 3.
8.
Declaration of IMAP on injectable contraception. IPPF Med Bull 1999; 33(2).
9.
Hall P, Garza Flores J. Anticonceptivos inyectables de accion prolongada. In: Perez Palacios G,
Garza Flores J, Hall P, eds. Avances recientes en regulacion de la fertilidad. Vol 1. Mexico:
Editorial Piensa SA de CV, 1987.
10.
Sang GW, Shao QX, Ge RS, et al. A multicentred phase III comparative clinical trial of
Mesigyna, Cyclofem and Injectable No. 1 given monthly by intramuscular injection to Chinese
women. Contraception 1995; 51: 185-92.
11.
Newton JR, D'Arcangues C, Hall PE. Once-a-month combined injectable contraceptives. J
Obstet Gynecol 1994; 14 (suppl 1): 41-53.
12.
Facts about once-a-month injectable contraceptives: memoran dum from a WHO meeting. Bull
WHO 1993; 77: 677-89.
13.
Garza Flores J, Hall P Anticonceptivos inyectables mensuales. In: Perez Palacios G, Garza
Flores J, Hall P, eds. Avances recientes en regulacidn de la fertilidad. Vol 1. Mexico: Editorial
Piensa SA de CV, 1987.
14.
Koetsawang S. Once-a-month injectable contraceptives: efficacy and reasons for
discontinuation. Contraception 1994; 49: 387-96.
15.
Gray RH, Pardthaisong T, McDaniel EB, et al. The timing of the first injection of Depoprovera.
j^PFMed Bull 7975; 9(5).
H6. Zanartu J, Aguilera E, Munoz G, Peliowski H. Effect of a longacting contraceptive progestogen
on lactation. Obstet Gynecol 1976; 47:174-6.
17.
Toddywalla VS, Joshi L, Virkar K. Effect of contraceptive steroids on human lactation. Am J
Obstet Gynecol 1977; 127: 245-9.
18.
Karim M, Ammar R, el-Mahgoub S, et al. Injected progestogen and lactation. BrMed J 1971; 1:
200-3.
19.
Peralta O, Diaz S, Croxatto HB. Planificacion familiar durante el periodo de lactancia. Rev Chil
Pediatr 1989; 60 (2 suppl): 19-23.
20.
Koetsawang S, Nukulkarn P, Fotherby K, et al. Transfer of contraceptive steroids in milk of
women using long-acting gestagens. Contraception 1982; 25: 321-31.
21.
Saxena BN, Shrimanker K, Grudzinskas JG. Levels of contraceptive steroids in breast milk and
plasma of lactating women. Contraception 1977; 16: 605-13.
22.
Jimenez J, Ochoa M, Soler MP, Portales P. Long-term follow-up of children breast-fed by
mothers receiving depot medroxyprogesterone acetate. Contraception 1984; 30: 523-33.
23.
Koetsawang S, Boonyaprakob V, Suvanichati S, et al. Longterm study of growth and
development of children breast-fed by mothers receiving depoprovera during lactation. In:
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Zatuchni Gl, Goldmith A, Shelton JD, Sciarra JJ, eds. Long-acting contraceptive delivery systems.
Philadelphia, PA: Harper and Row, 7984; 378-87.
24.
Diaz S, Peralta 0, Juez G, et al. Fertility regulation in nursing women: III. Short-term influence
of a low-dose combined oral contraceptive upon lactation and infant growth. Contraception 7983;
27: 1-11.
25.
Croxatto HB, Diaz S, Peralta 0, et al. Fertility regulation in nursing women: IV Long-term
influence of a low-dose combined oral contraceptive initiated at day 30 post partum upon
lactation and infant growth. Contraception 1983; 27: 13-25.
26.
Peralta 0, Diaz S, Juez G, et al. Fertility regulation in nursing women: V. Long-term influence
of a low-dose combined oral contraceptive initiated at day 90 post partum upon lactation and
infant growth. Contraception 1983; 27: 27-38.
27.
Fraser IS. Vaginal bleeding patterns in women using once-a month injectable contraceptives.
Contraception 1994; 49: 399-1120.
28.
Hall PE. The introduction of Cyclofem into national family planning programmes: experience
from studies in Indonesia, Jamaica, Mexico, Thailand and Tunisia. World Health Organization Task
Force on Research on Introduction and Transfer of Technologies for Fertility Regulation.
Contraception 1994; 49: 489-507.
29.
Fraser IS, Weisberg E. A comprehensive review of injectable contraception with special
emphasis on depot medroxyprogesterone acetate. Med J Aust 1981; 1 (1 supply: 3-9.
30 Haiba NA, el-Habashy MA, Said SA, et al. Clinical evaluation of two monthly injectable
contraceptives and their effects on some metabolic parameters. Contraception 1989; 39: 619-32.
31. Giwa-Osagie OF. Metabolic effects of once-a-month combined injectable contraceptives.
Contraception 1994; 49: 421-33.
32.
Bassol S, Garza Flores J. Review of ovulation return upon discontinuation of once-a-month
injectable contraceptives. Contraception 7994; 49: 441-53.
33.
World Health Organization. Improving access to quality care in family planning. Medical
eligibility criteria for initiating and continuing use of contraceptive methods. Geneva: WHO, 1996.
http ://www.medforum.nl/gynfo/leading_article 1 .htm
4/15/2008
Page 1 of 3
Indian Journal of Medical Ethics
DISCUSSION
Injectables as a choice - evidence-based lessons
Siddhivinayak Hirve
Newer, better contraceptive methods may not result in increased reproductive choice if health systems cannot ens
contraceptive services.
Though extensively researched and used by over 16 million women in 130 countries DMPA's controversial history
use by national family planning programmes worldwide. Early clinical trials were abandoned due to the adverse U:
opposition by health advocates in India. After US FDA approval DMPA was licensed for use in 1993 in India condi
marketing surveillance by its manufacturer for side-effects. Since 1994, injectables are available through commerc
marketing channels but not in the public sector. In 1995, a panel favoured the use of injectables rather than Norpl;
of the ease of dispensing injectables and the prohibitive expense of Norplant. A recommendation was made in 19!
injectables in suitably equipped centres in the public sector with appropriate screening, counseling and medical be
on good clinical practice and post-introduction surveillance for side effects and management. Women activists opj
in the national family welfare programme for reasons of safety and fundamental inadequacies in providing quality <
ensuring informed choice and consent. The debate on injectables touches wider issues of gaps in existing populal
policies, a lack of male responsibility and involvement in reproductive health, and vested interests of multinational!
Injectables have the lowest failure rates among methods of contraception. This efficacy is dependent on approprie
injection, and repeat injections. The typical acceptor is a woman in her early 30s, with two or three living children,
rather than space her children. Women prefer injectables to pills or IUDs. Acceptors include first-time contraceptiv
the convenience, effectiveness and perceived safety. They also include women who switch to injectables after exp
effects with other contraceptives. An initial high acceptance of injectables is not sustained as most women experie
disturbances resulting in one-year discontinuation rates of 15 to 50%. Menstrual disturbance as a reason for discc
and culture-specific, with high discontinuation rates seen amongst women in Pakistan, where women are less like
amenorrhoea; in contrast, infrequent bleeding was less likely to result in discontinuation than frequent heavy bleec
women. Tolerance thresholds and partner attitudes to menstrual disruption need to be studied. Protagonists of injt
underplay the side-effect of menstrual disturbances as not being harmful or life-threatening. This is not to underpk
perception of side-effects as a reason for discontinuation. High discontinuation rates may be due to poor selection
attributes of the contraceptive or just the inability of the services to ensure continued use of the injectable. Alternai
as a measure for the woman's freedom of choice to opt out of the method, if she dislikes it.
Another concern is the reversibility of injectables. The median delay to return to fertility (8-9 months after last injec
higher than barrier methods, OCs, or IUDs. Large variations are seen amongst women from different populations,
differences in the nutritional, metabolic and fertility status. Return to fertility is not affected by duration of injectable
implying that women can safely use injectables for even delaying their first pregnancy.
How safe are injectables?
This is probably the most controversial and researched aspect. Studies of Chinese women show bone mineral los
than previously projected (0.4-1% per annum) and unrelated to duration of DMPA use. Debates on DMPA-induce<
and its effect on pubertal skeletal growth in adolescence, or the risk of aggravation or acceleration of osteoporosis
I vis a vis the benefits of contraception, have been largely speculative. Though WHO recommends its use amongst
lactating women, India chose to play it safe by recommending that use of injectables be avoided in adolescents.
Adverse effect on blood pressure and thrombosis has not been reported. One study has shown glucose intolerant
term DMPA use. There is no link between breast cancer and long-term DMPA use. An increased risk was seen in
in long-term users suggesting that DMPA may trigger the growth of existing breast tumours rather than turn norms
Prolonged use of DMPA may cause in situ cervical carcinoma but not invasive cervical carcinoma; hence the nee<
monitoring for cervical cancer.
In utero exposure to DMPA shows equivocal findings of its effect on birth weight and birth defects. DMPA and NE‘
breast milk in lactating women. There is no effect, or insignificant effect, on breast milk or subsequently on infant c
hair development was delayed significantly in girls. Increased aggression responses in adolescents and an enhan
sexuality have been seen.
Service delivery issues
Screening, counselling on mode of action, side effects and their management are crucial. Poor follow-up of clients
and lack of knowledge on side effects management are programme weaknesses. Standardised protocols for coun
provider skills are needed. Women attending FP clinics in the Philippines were not well informed about the range i
http://www.issuesinmedicalethics.org/131di012.html
4/15/2008
Indian Journal of Medical Ethics
Page 2 of 3
Studies amongst private providers in India showed that they did not promote indiscriminate use of DMPA. Howeve
to develop standardised protocols for counselling and improve provider skills. Medical procedures were not explaii
clients reported that providers did not inform them about side-effects resulting in most women with side-effects noi
clinic for assistance. Many DMPA programme dropouts reported that clinic staff were not caring or courteous. Fine
counselling of women by providers in terms of content and quality. Periodic orientation for providers on issues rels
eligibility, side-effects management and counselling and skills to counter rumours were some strategies suggester
improve quality of care.
Preference for a female provider and supply shortage often turned away would-be DMPA acceptors or resulted in
Distance and inconvenience of clinic timings sometimes resulted in clinic switching or DMPA discontinuation. Cliei
adversely affect DMPA use. Acceptance is highest when DMPA is offered free. However, free services cannot sus
acceptance.
Though DMPA and NETEN may have similar effectiveness, continuation rates and side-effects, the service delive
very different. To avoid field worker confusion, error, disruption of field worker routines, simplify managerial and st
recommended to use either DMPA or NETEN (not both) in the same geographical area as there are significant dif
dosage regimes, needles etc.) that affect service delivery.
The Thailand experiences highlight the need for diligent follow-up, surveillance for side-effects, and accurate recoi
experience illustrates the need for transparency and flexibility of the health system to respond to concerns voiced
The initial uptake of injectables is usually high; sustaining it is difficult because of inadequate preparation, poor tra
logistics management. This resulted in poor counselling, lack of informed choice, poor selection of women and ott
Injectables were prematurely withdrawn from the national programme in the Philippines, to be re-introduced more
Ethical concerns
Whether injectables undermine or further a woman's reproductive rights needs to be examined in the context of pc
injectable has to be evaluated from a rights perspective in terms of who controls it, its purpose, safety, effectivene
benefits, reversibility, and equally important concerns of availability, accessibility, affordability and quality of servic
inception, India's FP programme has been driven by demographic goals of population control resulting in promotic
controlled contraceptives. Recently we have a policy environment which reflects a commitment to widening contra
broader framework of reproductive health and reproductive rights. The National Population Policy 2000 seeks to p
sensitive quality services and supplies, information and counselling and widening contraceptive choice to enable v
to make informed choices and access quality health care services.
Women's groups have opposed injectables because of the potential for violation of reproductive rights as well as c
autonomy and safety. Addressing resource constraints, removing informational, physical and economic barriers at
quality of reproductive health care delivery - putting a reproductive rights framework into practice - presents a chai
opportunity to offer injectables and widen contraceptive choices for women. It is time to ensure a health system wl
social and gender inequalities, one that respects women's dignity and autonomy.
This paper derives from a scientific literature review, by the author, on the use of long-acting, progestin-only contn
South Asian context. The review was commissioned by the UNFPA. A report of the review, Progestin-only Injectal
.Facts File, was published by UNFPA India on October 15, 2004, and was available atwww.unfa.org.in/reports/17_
'accessed on December 18, 2004.
References:
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2.
3.
4.
5.
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Cundy T, Evans M, Roberts H, Reid IR. Bone density in women receiving depot-medroxyprogesterone ace:
contraception. BMJ. 1991; 303(6793): 13-16.
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Cundy T, Cornish J, Roberts H, Elder H, Reid IR. Spinal bone density in women using depot medroxyproge
contraception. Obstetrics & Gynecology. 1998; 92(4 Pt 1): 569-73.
Tang OS, Tang G, Yip PS, Li B, Fan S. Long-term depot-medroxyprogesterone acetate and bone mineral c
Contraception. 1999; 59(1): 25-9.
Petitti DB, Piaggio G, Mehta S, Cravioto MC, Meirik O. Steroid hormone contraception and bone mineral de
sectional study in an international population. The WHO study of Hormonal Contraception and Bone Health
Gynecology. 2000; 95(5): 736-44.
Tang OS, Tang G, Yip PS, Li B. Further evaluation on long-term depot-medroxyprogesterone acetate use z
density: a longitudinal cohort study. Contraception. 2000; 62(4): 161-4.
Berenson AB et al. a prospective controlled study of the effects of hormonal contraception on bone mineral
Gynecol 2001; 98(4):576-82.
Virutamasen P, Wangsuphachart S, Reinprayoon D, Kriengsinyot R, Leepipatpaiboon S, Gua C. Trabecula
depot-medroxyprogesterone acetate users. Asia-Oceania Journal of Obstetrics & Gynaecology. 1994; 20(3
Taneepanichskul S, Intaraprasert S, Theppisai U, Chaturachinda K. Bone mineral density in long-term depi
medroxyprogesterone acetate acceptors. Contraception. 1997a; 56(1): 1-3.
Taneepanichskul S, Intaraprasert S, Theppisai U, Chaturachinda K. Bone mineral density during long-term
Norplant implants and depot medroxyprogesterone acetate. A cross-sectional study of Thai women. Contn
(3): 153-5.
Perrotti M et al. Forearm density in long-term users of oral combined contraceptives and depot-medroxy pn
Fertility & Sterility, Sep 2001.
Merki-Feld GS et al. A prospective study on the effects of depot medroxyprogesterone acetate on trabeculz
after attainment of peak bone mass. British J of Obstetrics & Gynecology, 2000; 107(7): 863-9.
World Health Organization [WHO]. Special Programme of Research, Development and Research Training
Reproduction. Task Force on Long-Acting Systemic Agents for Fertility Regulation. Metabolic side-effects <
medroxyprogesterone acetate, 150 mg three-monthly, in undernourished lactating women. Bulletin Of The
Organization. 1986; 64(4): 587-94.
WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Breast cancer and depot-medroxyprog
multinational study. Lancet 1991; 338: 833-8.
UNFPA. Improving Reproductive Health: Expanding Contraceptive Choices - Experiences of Injectable Cot
and Providers. Findings of a Multi-centric Study. Draft Report. 2004.
Osteria TS, KantnerA. Postpartum family planning services in the Philippines: an assessment of current se
future program requirements. East-West Center Working Papers. Population Series No. 104. East-West Cz
Hawaii, Oct. [2], 58 p 1998.
Population Council. Asia and Near East Operations Research and Technical Assistance Project; Family Plz
Research and Training Program. Focus on the Philippine DMPA reintroduction program: continuing users v
Population Council Research News: Asia And Near East Operations Research And Technical Assistance F
2.
Redo DM, Bayan FB. Preferences for fertility-regulating methods and personnel in a free choice rural situa.
1986; 21(1): 6-13.
International Centre for Diarrhoeal Disease Research, Bangladesh. The case for one brand of injectables i
Bangladesh family planning program. Dhaka, Bangladesh, ICDDR.B, 1991 Mar. 3 p. MCH-FP Extension F
No. 16
Ahmad S, Islam MN, Rahman S. Determinants of acceptance of injectable contraception in Bangladesh. DI
Associates for Research Training and Computer Processing, 1992 [10], p32, 124,156.
Chumnijarskij T, Sunyavivat S, Onthuam Y et al. Study on the factors associated with contraceptive discom
Bangkok. Contraception. 1984; 29(3): 241-9.
Caleb-Varkey L, Vishwanath S, Townsend JW, Tiwari S. Analysis of price change on the perceptions and u
clients using reproductive health services in Uttar Pradesh, India. Final report. Sub-contract No. CI96.12A.
Population Council, Asia and Near East Operations Research and Technical Assistance Project, 1998 Mar
International Planned Parenthood Federation [IPPF], International Medical Advisory Panel [IMAP], Choice <
family planning programmes. IPPF MEDICAL BULLETIN. 1992; Apr;26(2):4.
Population Council. Rights, Technology and Services in Reproductive Health: Critical Issues in Reproduce
Ebert Program - report from a meeting 6-7 May 1999, Population Council, New York.
SIDDHIVINAYAK HIRVE, Director, Vadu Rural Health Programme, KEM Hospital, Pune, INDIA Address for corre;
Clover Gardens, 4 Naylor Road, Pune 411001 INDIA.
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DISCUSSION
Research on hire
Amit Sen Gupta
I recollect one of the first lectures in my first year of medical college where my venerable prof
the first thing that a doctor should have is confidence. If you kill a patient, kill him with confide
classic expression of the necessity felt by the medical profession to maintain a veneer of coni
face of relative uncertainty.
In such a setting, medical technology is often used, not as a legitimate tool for diagnosis and
prop to hide inadequacies regarding khowledge about what constitutes the best course of act
protect themselves from the anxieties which would otherwise accompany their relative ignora
seeks succour by immersing itself in the mindless pursuit of 'advanced' technology. The use c
becomes an end in itself rather than a means to relieving human suffering. The last century h
ECGs, sonography, computerised scanning and much more. Yet, instead of clearing the prev
medical practice, many of these tools have compounded the chaos. Not because it was inevil
control over these technologies has been the driving force behind the immensely profitable he
Patients are over-investigated, over diagnosed, over treated and under cared for because the
has to play second fiddle to large corporate interests.
Contract research
Medical research is often organised, paid for, commissioned or subsidised by the drug indust
commissioning such research are only looking for conclusions which will enable them to marl
reap profits. Nowhere is this more apparent than in the manner in which medical research is <
'seat' of the pharmaceutical industry, the United States.
An estimated 2 million Americans got hooked on to Redux (dexfenfluramine), a new anti-obes
the US by Wyeth-Ayerst, after it was approved by the US FDA in April 1996. At its peak popui
writing 85,000 new prescriptions a week. But a little more than a year after the drug's introduc
collapsed, as patients began to exhibit symptoms of damage to their hearts and lungs. Fearin
FDA banned the drug in September 1997. (1) The manner in which 'scientific' evidence was c
Redux is a shocking indictment of the system of medical research. In 1994, Wyeth had signer
contract with a medical publishing company called Excerpta Medica that offered pharmaceutt
invaluable tool: ready-made scientific articles, placed in leading medical journals, and carryinr
influential academic leaders. Excerpta laid out for Wyeth a schedule of nine articles, each witl
message aimed at a targeted audience, from primary care physicians to cardiologists to nursr
pharmacists. The articles had a 'writer' and an 'author' - but they weren't the same person. Th
lancer who was paid $5,000 to actually write the articles. The 'author' was often a top universi
paid $1,500 to review the work and assign his or her name to it for publication.
The Redux story clearly focuses on the growing reliance of university scientists on corporate •
research is now a multi-billion-dollar industry, with hundreds of testing and drug companies w
thousands of private doctors. Patients have become commodities, bought and traded by testi
doctors. The number of private doctors in research in the US since 1990 has almost tripled, a
earn as much as $500,000 to $1 million a year. Reports of fraud in drug trials are pouring in. I
weaknesses in the new system that has developed in recent years for testing experimental dr
the pharmaceutical industry rely on career researchers at academic medical centres, whose [
reputations are forged on the quality of their data. Rather, the industry has turned to thousanc
doctors for whom testing drugs is a sideline for making money.
Research in developing countries
Medical research in the developing world suffers from the problems of underdevelopment, on
superimposed the ills of a neo-colonial approach assumed by external research funding. In th
research is poorly funded, monitored and prioritised. The situation is compounded by foreign
research priorities. While, globally, medical research is fuelled by corporate interests; the mar
technology and pharmaceuticals in the developing world is very small. The size of the Indian
market, for example, is less than one-tenth of the market in the US or Japan. As a consequer
research in developing countries (largely, corporate sponsored research) focuses on areas ot
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home countries. Tropical medicine (itself a colonial construct) has a long history of descriptive
researchers but have no direct implications for participants. For example, a bibliography of re:
Papua New Guinea identifies 135 publications that describe Melanesian blood groups but onl
treating malaria (2). Different'styles' of foreign donor driven research are prevalent. (3). 'Post
western researchers request colleagues in developing countries to courier to them biological:
research' - where researchers travel to developing countries for short periods and take back t
The most prevalent is the practice of maintaining 'annexed sites' for field research, led and m;
staff. These 'annexed sites' attract promising academics away from national institutions, and I
findings are infrequently translated into policy and practice. Research fellows in 'annexed site
training there, but few return to national institutions. In a welcome development, India has rec
'annexed site' research and outsiders are now obliged to work through Indian institutions. Ho\
advantages of this move will, in all probability, be frittered away given the encouragement bei
sector R&D institutions to undertake contract research for corporate entities.
Drug companies have been known to perform research in developing countries that do not cc
Declaration of Helsinki and could not be conducted in the developed world. Reasons quoted 1
research in these countries, rather than developed countries, are lower costs, lower risk of litii
ethical review, the availability of populations prepared to give unquestioning consent, anticipa
of side effects because of lower consumer awareness, the desire for personal advancement t
the desire to create new markets for drugs. The commercial secrecy that surrounds early dim
safety and dose ranging in phase I trials in paid normal volunteers (that is, poor volunteers), r
preliminary research is unpublished, particularly when adverse effects are high and further de
abandoned. (3).
Medical research in India
There is, however, no denying that India (as a consequence of its size and ability to pledge gi
different from most developing countries. Real science and research is done mostly with publ
in non-profit institutions. But such indigenous research funding is still too small and too badly
address local priorities. A report published in 1997 in Current Science, a journal of the Indian
Sciences, suggested that most medical research in India is unrelated to the country's major h
report, based on an analysis of research publications from India indexed in the Medline datab
achievements in research have 'little influence' on healthcare delivery. It lamented that resear
concentrated in the fields of tertiary health care and new biology. (4)
There also exists a problem in defining local priorities. For long the two thrust areas for medic
have been vaccine research and research on contraceptive technologies (and recently, repro
priorities can be contested on the ground that they emanate from a view of public health that
vaccines as 'quick-fix' remedies for communicable diseases and contraception to control popi
the hype surrounding both these concerns, government-funded research in these areas has s
standard ethical guidelines.
Unethical and dubious
The decades of the 1980s and '90s have thrown up numerous instances of unethical and dub
country. Research on long acting hormonal contraceptives like Net-En, Depo Provera and No
conducted without observing ethical requirements like informed consent and the need to folio1
A team headed by Dr G PTalwar at the National Institute of Immunology (Nil) persisted for ye
develop a contraceptive vaccine despite criticisms that these trials were being run unethically
passed through phase II clinical trials in the late 1980s. Only 80% of the women who receiver
adequate response necessary for contraception. More importantly, according to published re[
94 out of 162 women in the trial 'volunteered' for long-term follow-up. The Indian government
for phase III clinical trials of the vaccine but continued to fund the research on contraceptive v
were put on 'cold storage' only when Dr GP Talwar retired from the NIL In 1998 it was reveals
for Cytology and Preventive Oncology, had left cervical dysplasia (a pre-cancerous condition)
women to study the progress of the disease, without warning them or taking their consent. In
the lesions progressed to invasive cancer, and 62 women developed localised carcinoma of t
were treated. The study had been sponsored by the Indian Council for Medical Research, wh
down the ethical guidelines for medical research. The investigators said, in their defence, that
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written consent because most of the women in the study were illiterate and also because writ
mandatory when the study was launched! (5)
In 1997 the scandal surrounding trials on quinacrine sterilisation forced the Supreme Court of
Quinacrine was used in the treatment of malaria till it was replaced by better drugs. Some tim
renewed interest in its use in a method of'chemical' sterilisation. In June 1994, the WHO Con
Sterilisation Methods categorically stated that human trials with quinacrine should be stopped
the outcome of toxicological studies. In India, quinacrine sterilisation was carried out in the '9(
doctors involved' according to an early convert to the cause, Dr.Biral Mullick. Coordinating the
equipment in the country was Dr.J.K.Jain, former MP. There were widespread protests again:
Government of India denied granting approval. Finally, bowing to the public outcry, quinacrine
banned by the Drug Technical Advisory Board in 1997. (6)
There is a discernible pattern in all the above instances. All of them pertain to research on co
technologies, reproductive health and vaccine research. More importantly, all of them (except
quinacrine sterilisation) have been conducted in public funded institutions using public money
extreme laxity in existing regulatory institutions and mechanisms and also to the tendency of:
submit themselves to pressures when faced with so called 'national priorities'. Government sf
approved) research in India, seems to have been fraught with equally potent dangers as corp
research is globally.
The anarchy in medical research in the country is typified in three recent examples, only one
received some publicity. The last pertains to a clinical trial conducted on human subjects in th
Centre (RCC) in Kerala, with an experimental drug in advanced oral and cervical malignancie
conducted in collaboration with the John Hopkins University in the US. The drug used, M4N, i
of 'chaparral tea' made from leaves of the creosote bush, a common American desert plant, t
tea has been used over the years as an herbal remedy for cancer, it is also known for its toxic
While the trial was conducted in 1999 and 2000, the application for permission to conduct the
to the Drug Controller of India only in February 2001! Further, the Ministry of Health and Welf.
RCC was granted permission to import M4N from Johns Hopkins only in February 2, 2001. A|
procedural problems it now appears that the trials ignored basic norms regarding informed co
preliminary enquiry indicates that subjects enrolled in the trial were given the experimental dn
established treatment regimes, a clear violation of the Declaration of Helsinki on research on
trials had not been approved or reviewed by any of Johns Hopkins' institutional review boards
protection of human subjects, in spite of the Centre's claims that the permission for the trials \
basis of 'pre-clinical and other relevant data'.
Even more bizarre is the report of a trial of another 'anti-cancer' cure conducted in Calcutta in
conducted on 24 patients by a team comprising a private medical practitioner and a group of
scientists at the Indian Association for the Cultivation of Science, (IACS), a non-clinical organ
of the clinical trial have been published, of all places, in the Indian Journal of Physics! (7). Th<
coincidentally, is run by the IACS. The paper acknowledges that the trial was conducted throi
CSIR and DST and had the approval of the Institutional Ethics Committee of the IACS. Clearl
obtained from any body that is authorised to give such approval. The paper goes on to exhort
sincerely hope that researchers and clinicians with open minds will immediately make a conc<
and to further improve the present formulation and treatment." Worse still, the main ingredien
formulation is a chemical (methylglyoxal) purchased from the American warehouse supplier, I
Company, whose chemicals are laboratory grade, not intended to be used as drugs, i.e. not t
The third instance is the permission granted by the Ministry of Health and Family Welfare to c
long-acting hormonal contraceptive, Netethisterone Enanthoate (NetEn), in 12 medical colleg
the country in 2001. The Ministry has not released any other details regarding the purpose of
protocols to be followed. It is being presumed that the trials are a prelude to introduction of Nt
population control programme. Various health and women's groups have represented to the t
Rights Commission (NHRC) against conduct of the trials on the grounds that the introduction
mass population control programme is unacceptable given the drug's potential toxicity and th<
monitoring mechanism.
What informs medical practice?
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There is possibly an even more fundamental conundrum that faces medical research in a cou
Research output is, as yet, too insignificant and too unfocused to inform the practice of medic
The latter continues to be largely determined by medical research conducted in the West. Thi
given a novel twist recently by Dr Samiran Nundy in a letter to the British Medical Journal. He
the state of medical research in the country it made more sense to first attempt to regulate mt
country rather than regulate medical research (8): "That medical research in developing coun
of generally poor quality is well known, and it has not improved in the past 20 years. Should c
research ethics in developing countries when they barely exist? In my view the ethics of medi
important. To see how the public can be safeguarded from an inefficient and often corrupt me
receive comprehensive health care of a reasonable quality is paramount."
Such issues arise today because the research institutions in the country have singularly failec
cogent direction to the practice of medicine. It would almost appear as though the two work in
paradigms. Unless there is, at the least, an attempt to marry research with practice, public pe
research will continue to range from suspicion to derision.
References:
1. US Department of Health and Human Services. Statement by the Food and Drug Administ.
15,
1997.http://www. fda.gov/bbs/topics/NEWS/NEW00591.html
2.Hornabrook RW, Skeldon GHF. A bibliography of medicine and human biology of Papua Nt
Papua New Guinea Institute of Medical Research, 1977 (Monograph series No 5.). Cited in:
Implementing research findings in developing countries. BMJ 1998;317:531-535.
3.
Garner Paul etal. Implementing research findings in developing countries. BMJ 1998,317::
4.
Arunachalam S: How relevant is medical research done in India? A study based on Medlin
1997; 72: 912-22.
5.
MudurG: Indian study of women with cervical lesions called unethical. BMJ 1997; 314:101
6.
Mudur G: India to ban female sterilisation with malaria drug. BMJ 1998; 316: 955.
7.
Ray Manju et al. Implication of the bioelectronic principle in cancer therapy: treatment of c.
methylglyoxal-based formulation, UP, 2001; 75B (2): 73-77.
8.
Nundy Samiran. Let's consider ethics of medical practice first. Letters BMJ 2000;321:830.
Dr Amit Sen Gupta, Delhi Science Forum, D-158, Lower Ground Floor, Saket, New Delhi -11
Email:ctddsf@vsnl.com
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Leading Article
Gynaecology
Forum
Leading Article
Back
'□
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Up
I
Injectable hormonal contraceptives: an overview
Octavio Peralta
Department of Gynaecology and Obstetrics, San Borja Arriardn Hospital, Faculty of Medicine,
University of Chile, Santiago, Chile
Hormonal depot contraceptives containing only progestogen administered by
injection are the result of a series of studies initiated by Karl Junkmann in
Germany in 1953 [1]. Almost simultaneously, Schering synthesised the injectable
depot ester of the progestogen norethindrone, called norethindrone (or
norethisterone) enanthate (NET-EN), which was marketed under the name
Noristerat [2]. During this period, Upjohn in the USA developed
medroxyprogesterone acetate in its injectable depot form (DMPA), known under
its proprietary name Depo-Provera [2].
The initial clinical studies on progestogen-only injectables that analysed the
efficacy and safety of the method were mainly carried out in Latin America by
Zanartu in Chile [3], Coutinho in Brazil [4] and Kesserii in Peru [5], between 1963
and 1965. As a result of the outcomes of these clinical studies, NET-EN was put on
the market in Peru in 1967 [6]. At present, worldwide experience with NET-EN as
a contraceptive is based on more than 200,000 woman-years [2, 7] and it has
been registered as a contraceptive in more than 60 countries [8].
The efficacy and safety of DMPA have been studied extensively worldwide both as
a contraceptive and as a treatment for gynaecological disorders. More than 1000
publications describe its metabolism and safety [7, 9]. Numerous international
health institutions supported its licence as a contraceptive, but not until October
1992 did the United States Food and Drug Administration approve its use as a
contraceptive, 25 years after Upjohn first applied for approval.
DMPA is the most widely used injectable contraceptive formulation, having been
marketed in more than 130 developed and developing countries. Since its
introduction as a contraceptive, it has been used by more than 30 million women,
more than 100,000 of whom have done so for longer than 10 years. At present it is
estimated that approximately 13 million women worldwide are using it.
Combined once-a-month injectables contain a synthetic oestrogen in addition to
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Leading Article
Page 2 of 7
progestogen. This allows them to keep the contraceptive effect of progestogen
together with the added benefit of oestrogen to provide regular bleeding
simulating menstrual bleeding. Different combined once-a-month injectable
contraceptive formulations have been evaluated and used over the last four
decades. In China and neighbouring countries, the so-called Injectable No. 1 has
been developed, made up of 17a-hydroxyprogesterone caproate and estradiol
valerate, and this has been used by approximately 1 million women [10].
Deladroxate, an injectable formulation made up of dihydroxyprogesterone
acetophenide and estradiol enanthate, has been used for years in Latin America
[11, 12]. It is known in different countries under the names of Perlutal, Unalmes
or Agurin.
Table I: The two groups of injectable contraceptives.
Type
Progestogen
Oestrogen
Name
Two new combined once-a-month
Progcslogcn-only Depot medroxy
DMPA
injectable contraceptives have been
progesterone
acetate 13) mg
Depo-Pnwcra
studied by the WHO and other
Norcthisterone
NET-EN
A institutions during the last 20-30
enanthate 200 mg
Norislerat
years, namely Cyclofem (previously
OiiciNbrnonlh
McdroxyEstradiol
Cyelofem
known as Cycloprovera) and Mesigyna
combined
progesterone
cipionate 5 mg
acetate 25 mg
(registered in some countries as
Norethisterono
Estradiol
Mesigyna
enanthate 50 mg
Norigynon). Safety and efficacy
valerate 5 mg
studies for Cyclofem began in 1968
and the first clinical trials with Mesigyna started in 1974. Subsequent introductory
studies of these two combined injectable contraceptives, carried out in different
countries, confirmed the results of the clinical trials and supported their
commercialisation. Cyclofem and Mesigyna have demonstrated benefits and
advantages compared with other once-a-month injectables, as indicated by the
multicentre studies carried out by the WHO, and they are currently being
accepted by an ever-increasing number of countries as a good contraceptive
option [2, 11, 13].
Composition and dosage
Injectable contraceptives can be divided into two main groups according to their
hormonal composition (Table 1):
•
Progestogen-only injectables
1. Depot medroxyprogesterone acetate (DMPA or Depo-Provera): 1 ml injection
containing 150 mg DMPA in a microcrystalline aqueous suspension, administered
intramuscularly every 3 months.
2. Norethisterone enanthate (NET-EN or Noristerat):1 ml injection containing 200
mg NET-EN in castor oil, administered intramuscularly every 2 months.
Once-a-month combined injectables
1. Cyclofem/Cycloprovera: 25 mg medroxyproges terone acetate and 5 mg
estradiol cipionate.
2. Mesigyna/Norigynon: 50 mg NET-EN and 5 mg estradiol valerate.
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Both preparations are administered by deep intramuscular injection. The first
dose is administered during the first 5 days of menstrual bleeding and thereafter
every 30 days, plus or minus 3 days. The pharmacokinetics of the different
injectables are analysed in this issue by Josue Garza Flores and Teresa Navarrete.
Mechanism of action
Progestogen-only injectables
The main contraceptive effect is exerted through changes in the cervical mucus,
making it hostile to the penetration of spermatozoa. They also inhibit ovulation
and cause progestogenic changes in the endometrium [2, 7, 8].
Once-a-month combined injectables
The main effect is inhibition of ovulation. They also cause changes in the cervical
mucus and in endometrial morphology [2, 8].
Efficacy
Both progestogen-only injectables and once-a-month combined injectables are
highly effective, with pregnancy rates between 0.1 and 0.4 after 12 months [2, 8,
14]. The efficacy of the injectable methods depends on the timing of the first
injection, adherence to the schedule, and on the injection technique. A study
carried out in Thailand [15] shows that delaying the first injection from the fifth
to the eighth day of the cycle, increases the pregnancy rate from 0.16 to 0.62
after 3 months of use. The maximum delay for the next DMPA injection should not
exceed 2 weeks, 1 week for NET-EN and 3 days for the once-a-month injectables.
Non-contraceptive benefits
In addition to preventing pregnancy, injectable contraceptives also have other
reported health benefits, having been shown to decrease menstrual blood loss,
increase plasma haemoglobin, and decrease dysmenorrhoea and pelvic
inflammatory disease [2, 7, 8]. Edith Weisberg and Ian Fraser discuss the non
contraceptive health benefits in this issue. Progestogen-only injectables decrease
the risk of endometrial cancer and possibly also the risk of ovarian cancer. The
relation between cancer and injectable contraceptives is reviewed in this issue by
Ramiro Molina Cartes.
Use in the post partum period
Progestogen-only injectables have not shown any adverse effects on lactation
with regard to quality of the milk, duration of lactation and infant growth [1619]. However, the progestogen is present in maternal milk in the same
concentration as in maternal plasma. DMPA reaches concentrations of 10 ng/ml in
the first week after its administration, decreasing to 0.5 ng/ml in the third
month. The concentrations of NETEN in maternal milk are lower than those of
medroxyprogesterone because the 19-nor-derivatives are less soluble in milk. The
estimated daily progestogen dose ingested by the infants of mothers using
progestogenonly injectable contraceptives is 0.3-10 pg DMPA and 0.5-2.4 pg NET
EN. These amounts have been estimated by taking the concentrations in maternal
milk and assuming that the infant ingests 600-700 ml milk a day [20, 21]. No
health problems were found in children whose mothers had used these methods,
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but the possible long-term effects on neuroendocrine mechanisms regulating the
reproductive process are not yet known [22, 23]. More studies and long-term
follow-up are necessary to answer this question.
Oestrogen-containing once-a-month combined injectables would behave in the
same way as the oral combined contraceptive pill and are therefore not
recommended during this period due to their possible adverse effects on the
duration of lactation and infant growth [24-26].
Side effects of injectable contraceptives
Irregular bleeding
Progestogen-only injectables
Irregular bleeding is the main side effect of progestogen-only contraceptive
methods. The initial use of injectables may cause irregular, unpredictable
bleeding, with or without intermittent spotting. Only 10% of women who use
DMPA report normal cycles during the first year of use. Irregular bleeding is usual
during the first 6 months, followed by delayed bleeding and/or amenorrhoea in
the months thereafter.
Menstrual irregularities with NET-EN are similar but of a lower intensity. The rate
of discontinuation after 1 year is estimated at 15% due to irregular bleeding and
12% due to amenorrhoea, but these figures vary considerably from one area to
another [2, 7, 8],
Once-a-month combined injectables
There are no major differences between the bleeding patterns of Cyclofem and
Mesigyna users. During 10-15 days after the first injection, most women have a
bleeding pattern similar to menstrual bleeding, and then they will bleed every 30
days in a regular manner, differentiating once-a-month combined injectables
from progestogen-only injectables. During the first 3-6 months of use, only 25% of
women experience some form of irregular bleeding and 12% develop prolonged
bleeding. The discontinuation rate due to irregular bleeding is between 5 and 12%
per year [2, 27].
Other side effects
Progestogen-only injectables
Most of the side effects associated with the use of progestogen-only injectables
are subjective and difficult to quantify. Some users gain weight during the first
year of use and some may subsequently continue to gain weight at the same rate
[7, 8], Between 3 and 19% of users report headaches or dizziness, a percentage
similar to that seen in the general population; few women discontinue this
method for these reasons.
Once-a-month combined injectables
Side effects are less common than those reported with progestogen-only
injectables and are similar to those reported by the users of combined pills:
headaches, dizziness, mastalgia, changes in body weight, etc. [28].
In their article, Edith Weisberg and Ian Fraser analyse in detail the beneficial and
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Leading Article
Page 5 of 7
adverse effects and changes in uterine bleeding with the use of injectable
contraceptives.
Metabolic effects
Progestogen-only injectables tend to cause mild changes in carbohydrate
metabolism. DMPA has a slight diabetogenic effect and should therefore be used
with caution in diabetic women. Both types of injectables may induce changes in
lipid metabolism, reducing HDL cholesterol and decreasing the HDL:LDL
cholesterol ratio [29-31]. The metabolic effects of injectable contraceptives are
reviewed by Luis Bahamondes.
Return to fertility
After discontinuation of progestogen-only injectables, there is generally a delay
in the return to fertility in comparison with the combined pill or with nonhormonal methods. The extent of this delay varies between different regions,
communities and women. After discontinuing use of DMPA, 50% of women became
pregnant in the 9 months following the last injection. After discontinuing once-amonth combined injectables, ovarian function recovers quickly: 39% of women
ovulated within the first 3 months and 78% within 6 months after discontinuing
the method. The return to fertility is considerably shorter with these injectables,
most women becoming pregnant during the first 6 months after discontinuing
treatment [2, 7, 8, 13, 32]. This subject is reviewed in this issue by Susana Bassol
Mayagoitia.
Interaction with other drugs
Drugs inducing liver enzymes, especially when used for prolonged periods of time,
may reduce the efficacy of hormonal contraceptives. This category of drugs
includes some antibiotics (rifampicin, griseofulvin), anticonvulsants and
barbiturates. To date there is insufficient knowledge with regard to the possible
interactions between these drugs and injectable contraceptives, and therefore it
is recommended that women who need these types of drugs for prolonged periods
of time use other contraceptive alternatives.
Counselling
’Counselling is an essential element for any couple visiting a family planning
centre to select a contraceptive method. Women choosing an injectable
contraceptive must be given clear information about the advantages and
disadvantages of the method, side effects, costs and comparisons with other
contraceptive methods. The differences between the two types of injectables
must be explained, especially with regard to menstrual irregularity and return to
fertility.
Eligibility criteria for using injectable contraceptives
The WHO has taken special care to revise and reach consent on the medical
criteria concerning recommendations for use of the different contraceptives.
Attempts have been made to standardise medical eligibility criteria to ensure that
the suggestions made during medical counselling are adequately supported by
scientific evidence. Accordingly, four categories have been established for each
http://www.medforum.nl/gynfo/leading_article 1 .htm
4/15/2008
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