BOOK REVIEWS
A thorough critique of Depo-Provera
Anant Phadke
An epidemiological review of the injectable contraceptive
Depo-Provera. C Sathyamala. Medico Friend Circle, Forum For Woman's Health,
Mumbai, 2000. pp. 160, Rs 100.
Long-acting injectable hormonal contraceptives are
highly controversial. Health activists, especially feminist health activists,
are against these invasive female contraceptives whereas most doctors,
gynaecologists and health officials feel it is a good contraceptive choice for
those women who want to choose a temporary method but are less likely to use
other female contraceptives properly. This book by a feminist epidemiologist and
health advocate argues that Depot Medroxy Progesterone Acetate or DMPA (brand
name Depo-Provera) is too hazardous a contraceptive choice. Based on a thorough
review of the epidemiologically significant published studies (about 200
scientific papers and monographs), Sathyamala deals with the various issues
related to efficacy of DMPA in field conditions and its safety for women and
their offspring.
Effectiveness in practice
Depo-Provera is touted
as a highly effective contraceptive. But the book points out that in field
conditions, its use-effectiveness in low: "In a follow-up of a group of
'new' contraceptors, it was found that 40% of the interviewed women (n = 899)
had not received their first injection during the right time of their
reproductive cycle." (p.17) Also: "A randomised, multinational, comparative
clinical trial with the two injectable contraceptives, Depo-Provera and
Noristerat, showed that for Depo-Provera, the gross cumulative discontinuation
at 1 year due to both medical and non-medical reasons, was 28.8 ( 1.6) per 100
women year (WHO, 1977). Among non-medical reasons for discontinuation, almost
50% was due to failure to return within the specified period of time for the
next injection." (p. 18).
Menstrual disturbances
DMPA causes
significant menstrual disturbances. The pro-DMPA lobby tends to belittle this
problem. But for women, these menstrual disturbances are not a minor issue.
In many women DMPA causes excessive menstrual
bleeding. The book quotes evidence: "The phase III clinical trials carried out
by ICMR with Depo-Provera found that in a total of 131 women given 150 mg
Depo-Provera every three months, for whom data was collected over a period of
eight months, there was a high incidence (50%) of heavy and/or prolonged
bleeding or amenorrhoea (ICMR, 1975)." (p. 21) "In the multinational
comparative clinical trial of the WHO, 70.6% of the women on Depo Provera did
not experience even one normal cycle for the duration of the study (WHO, 1981)."
(p. 21-22) "In another multicentric study comparing Depo-Provera 100mg and
150 mg, 12% of the women discontinued because of spotting, irregular, prolonged
or heavy bleeding (WHO, 1986)." (p. 22)
Some commentators discount the significance of
heavy bleeding, pointing out that haemoglobin levels amongst DMPA users are not
lower. But the book argues that if we monitor serum ferritin levels, we find
that the use of long acting injectable contraceptives leads to a fall in S.
ferritin levels even without lower haemoglobin levels. It may be pointed out
that some symptoms of anaemia, such as fatigue, are related to low serum
ferritin levels even with normal haemoglobin levels.
For the
majority of women, DMPA causes amenorrhoea. Upjohn (the maker of the brand
Depo-Provera) has admitted this. "As women continue using Depo-Provera, fewer
experience intermenstrual bleeding and more experience amenorrhoea. By month 12
amenorrhoea was reported by 55% of women, and by month 24 amenorrhoea was
reported by 68% of women using Depo-Provera." (p. 31) DMPA protagonists
consider this side-effect beneficial as they think that this will improve
women's haemoglobin levels. First, haemoglobin levels have not been found to be
better amongst DMPA users. Second, though those in support of DMPA consider
DMPA-induced amenorrhoea a boon, Indian women do not think so. Most women in
India believe that monthly menstrual flow is necessary to get rid of 'impure'
menstrual blood accumulated in the uterus. This misconception is deep rooted and
hence amenorrhoea in the absence of pregnancy is not acceptable to them. This
leads to discontinuation of DMPA. Third, the pathophysiology of this amenorrhoea
is not so benign; it is due to ovarian and endometrial atrophy (p. 31) which may
possibly be irreversible. When these arguments are taken together, it is seen
that menstrual disturbances are significant for women and cannot be discounted
as minor.
Hypo-oestrogenic state, osteoporosis
Prolonged
administration of progestogens tends to inhibit the secretion of estrogen,
leading to menopause-like symptoms. The book quotes a Swedish study
which reveals this consequence of DMPA: "A more recent study (Solheim, 1992)
assessed the impact of Depo-Provera on he quality of life of women who had used
the contraceptive for at least one year. Of the 451 Swedish women who answered a
mailed questionnaire, a decrease in libido was reported by 25% users which was
associated with both duration of use as well as the woman's age (the younger the
woman, the greater the loss of libido); vaginal dryness was reported by 13% of
the users and was significant when correlated with loss of libido (p<0.001);
night sweats by 35%, and hot flushes by 12%." (p. 45)
Loss of libido has been documented in this study.
However it is considered a minor side-effect by the patriarchal health care
system. The same health care system does not consider DMPA a good male
contraceptive on the grounds that it reduces libido in men!
Sathyamala points out that other studies have shown
similar results. Hence "The UK clinical and Scientific Committee has
recommended that serum estradiol levels should be estimated in Depo-Provera
users with more than two years of amenorrhoea and/or the presence of
climacteric-like symptoms. A serum estradiol level under 150 pmo/L on two
separate occasions has been suggested as indicative of a need for estrogen
supplementation or a change of contraceptive method (Cayley, 1998)." (p.
42)
One result of a hypo-estrogenic state induced by
DMPA is osteoporosis. The book quotes a number of studies, some of which clearly
show that DMPA induces osteoporosis. Sathyamala concludes that despite the
variability in the results of all these studies and their limitations, a general
consensus seems to be emerging that Depo-Provera does have a negative effect on
bone mass. She points out that the implications of this effect for women in
India are ominous because a substantial proportion of Indian women, especially
from the poorer strata, already suffers from calcium deficiency.
The author further argues that since DMPA induces
osteoporosis, other groups not suitable candidates for DMPA-use include
lactating mothers and adolescents. Lactating mothers anyway loose calcium
through breast-milk. It is notable that DMPA-users showed osteoporosis despite
an intake of calcium of more than 1250 mg a day. Adolescence is the age
when bony growth has its last spurt before it reaches its full
potential. The book quotes a study which shows that DMPA-use during
this period interferes with achieving adequate calcification of growing bones in
adolescents. All these facts about DMPA-induced osteoporosis further weaken the
case for DMPA.
Other metabolic effects
The author quotes
studies which show that DMPA interferes with the blood pressure-regulating
mechanism; has adverse effect on the lipid metabolism; increases the risk of
coagulation of blood; impairs glucose tolerance; tends to increase weight;
causes galactorrhoea and reduces the lipid content of breast-milk. DMPA
protagonists tend to discount these side-effects. But a humane approach
would conclude that these side-effects are unacceptable.
Cancer risk
The best part of this book is the
chapter "Depo-Provera and cancer risk". Whether or not DMPA significantly
increases breast cancer risk has been one of the key controversial issues
regarding approval of DMPA as a contraceptive. The controversy arose because of
the findings from toxicological studies which raised the possibility of breast
and endometrial cancers amongst DMPA-users. In 1984, following a five-day public
hearing, the Public Board of Inquiry recommended that DMPA should not be
approved for contraceptive use in the USA. In 1991, the results of a
multinational case-controlled study launched by the WHO to assess the risk of
breast, cervical, endometrial and liver cancers due to DMPA, were
published. These concluded that DMPA does not enhance the overall risk of
malignancy. These results were the basis for the approval given by the US FDA to
DMPA as a contraceptive, followed by approval by the Drugs Controller of
India.
The book has dared to critically examine this WHO
study. The author argues that because of the long recall period of
up to 23 years, it is unlikely that the women included in this study would have
given an accurate history of drug exposure. Second, because of a specific
exclusion clause in the study design, there has perhaps been an under
representation of cases with a history of DMPA use. Further, the book
questions the selection of the location of the study: "Chiang Mai is also the
province where Depo-Provera was introduced by McDaniel of McCormick hospital as
a regular contraceptive even before the Upjohn Company had submitted the new
drug application to use USFDA for approval as a contraceptive (McDaniel, 1968).
Given this, the enthusiasm for Depo-Provera may have led to the differential
probing of controls and cases for history of exposure." It is not clear to the
reviewer whether McCormick hospital conducted this 'WHO study'. If it did, the
author's objection is valid. Lastly, "Based on the natural history of
breast cancer, it has been estimated that the latent interval could be 30 years
or more… In the WHO study, among the women in the study population, 76% of the
cases and 78% of the controls had reported 'months since first use' of DMPA as
being less than 13 years. Thus, one of the major limitation of this study is
that sufficient time period has not elapsed between exposure and the study
period to account for a latent period of 20 to 30 years." (p. 73-74)
Taken together, this methodological criticism puts
a question mark on the scientific validity of the conclusions of the WHO
study.
The author also points out that though the WHO
study did not find an overall association of the risk of breast cancer with DMPA
use, it did find a doubling of the risk if DMPA is used at a younger age.
This would mean that DMPA should not be used in younger women for
contraception.
Return of fertility, impact on progeny
Unlike
other contraceptives, DMPA use causes a delay in return of fertility after
discontinuation of use. This delay is 6-8 months on an average and is more
for women over 30 years of age; 15% of this sub-group was still not pregnant at
the end of 48 months of discontinuation. The reviewer would like to point out
that there is, however, no evidence that DMPA causes irreversible infertility.
Hence if DMPA users are clearly told about the delay in return of fertility and
if they accept this non-damaging side-effect, it cannot be the basis for not
approving DMPA as a contraceptive. The author quotes Goodman Gillman that DMPA
"...should be used only if the possibility of permanent infertility is
acceptable to the patient". However, this statement is absent in the subsequent
edition.
Though the issue of approval of DMPA as a
contraceptive hinged on its carcinogenic potential, the issue of DMPA's
mutagenic, teratogenic potential is equally important. Yet this has been
sidetracked. The evidence cited by the author on this aspect is damning
indeed. Some studies have specifically looked at the risk of DMPA-induced
teratogenicity, mutagenecity. The results of the 'Chiang Mai Study' in Thailand
show "The relative risk of polydactyly and syndactyly associated with
Depo-Provera use was 4.8 as compared with non-use and was statistically
significant (p<0.05). Among women under the age of 30 years, the relative
risk was 5.7 (p<0.01)." (p. 102) "The prevalence of chromosomal
anomalies in Depo-Provera users was 4.1/1000 births (5/1229) and that in
non-contraceptors was 0.49/1000 births (2/4023)…Down syndrome was the most
common chromosomal anomaly observed in this study; the incidence in
non-contraceptors was 0.25/1000 and that in Depo-Provera users was 2.4/1000, a
ten-fold increase." (p. 102).
It may be argued that birth defects would occur
only after failure of contraception and hence the chances of this happening in a
population of DMPA users are very low. First, even if the overall chances are
low, such a high relative risk for such serious side-effects such as birth
defects is unacceptable. Secondly the active drug and its metabolites are
detectable in the blood for as long 200 days. Hence women who discontinue DMPA
after a couple of injections may become pregnant within six months (the delay in
return to fertility is less in case of early discontinuation) and their foetuses
would get exposed to DMPA. Under field conditions, some women may get DMPA
even if they are pregnant. Taken together, a substantial number of
foetuses may get exposed to DMPA. The book points out that "In the
three-year study period on in utero exposure to Depo-Provera and pregnancy
outcome (Pardthaisong and Gray, 1991), the investigators were able recruit
1,573 women who had been exposed in utero either accidentally or after they had
conceived. This indicates that under field situations, a large number of
pregnancies will be exposed to Depo-Provera." (p. 112)
To me, this risk of mutagenecity is good enough
reason to reject DMPA as a contraceptive.
The book tries to marshal evidence to show that
DMPA ingested by infants through breast-milk has short-term and long-term
deleterious effects on their health. However, except for the finding of a fall
in the lipid content of breast-milk of DMPA users, all other side-effects have
to be controlled by socio-economic variables to assess the impact of DMPA per
se. The studies quoted to have done this do not support the book's claim
of other deleterious effects.
Conclusion
Overall the book presents a
solid epidemiological critique of DMPA as a contraceptive. It demonstrates that
leading gynaecologists are off the mark in their assessment of safety of DMPA.
Worse, they favoured DMPA despite formidable evidence against it. WHO and US FDA
approval is presumably under the pressure of the population control lobby.
The book was researched and written without
funding. The printing was supported by donations from well wishers and members
of the two publishing organisations. Overall, this is a product of the author's
and a small group's determination to expose the irrationality of DMPA as a
contraceptive. It is a must for anybody seriously interested in women's health
issues.
Copies are available from: Medico Friend Circle,
11, Archana Apartment, 163 Solapur Road, Hadapsar, Pune 411028. Dr. C.
Sathyamala, 121, pocket B, SFS flats, Sukhdev Vihar, New Delhi, 110025. Forum
For Women's Health, 2, Vishwadeep, 95 Bhau Daji Road, Matunga, Mumbai 400 019
This review was first published in BODHI (No. 59,
July-August 2005, pp 93-96). It is published in IJME, with some editorial
changes, with permission of the Editor. The printed issue contains a condensed
version of what is available on the website.
ANANT PHADKE, Centre for Enquiry into Health and Allied
Themes, Pune, INDIA. Address for correspondence: 8, Ameya Ashish Society, Kokan
Express Hotel lane, Kothrud, Pune 4110038. INDIA. Email:amol_p@vsnl.com
