Effect of sublingual misoprostol on severe postpartum haemorrhage in a primary health centre in Guinea-Bissau: randomised double blind clinical trial
BMJ 2005; 331 doi: https://doi.org/10.1136/bmj.331.7519.723 (Published 29 September 2005) Cite this as: BMJ 2005;331:723
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I read your article with great interest and am pleased to see
additional research on misoprostol for prevention of postpartum
hemorrhage. Under the section, Treatment protocol and consent, you state
that the staff at the health centre where the study was conducted included
four midwives and one physician. An expatriate midwife joined them and
trained them in controlled cord traction.
Controlled cord traction is a component of the very effective
intervention: active management of the third stage of labor. However,
active management of the third stage of labor includes three components:
1)administration of a uterotonic drug (oxytocin 10 IU IM is the drug of
choice) after the birth of the baby followed by the 2) use of controlled
cord traction; and 3) massage of the uterus after the delivery of the
placenta.)1 Were the four midwives and physician trained in and did
they use all three components of active management of the third stage of
labor during the study?
If your staff were trained and did use active management of the third
stage of labor (with controlled cord traction as one component) then the
amount of blood loss (45% in the misoprostol group and 51% in the control
group with blood loss of >500 mL) is a very unusual finding and differs
significantly from previous studies using active management of the third
stage of labor. (Bristol(2)and Hinchingbrooke(3)trials found 5.9% and
6.8% PPH in the group using active management and 17.9% and 16.5% PPH
without the use of active management, respectively.)
However, if controlled cord traction was used without prior use of an
uterotonic drug then your study may exemplify a concern raised by New
Zealand midwives at the recent International Confederation of Midwives
Congress held in Brisbane, Australia in July 2005. Their experience
suggested that the use of controlled cord traction without the uterotonic
drug could increase bleeding and cause additional problems.
Thank you.
1. Joint Statement Management of the Third Stage of Labour to Prevent
Post-Partum Haemorrhage, International Confederation of Midwives &
International Federation of Gynaecologists and Obstetricians.
Managing Complications in Pregnancy and Childbirth: A guide for
midwives and doctors, WHO/RHR/00.7, 2000
2. Prendiville et al. 1988. The Bristol third stage trial: active
versus physiological management of the third stage of labor. BMJ
297:1295–1300.
3. Rogers J et al. 1998. Active versus expectant management of third
stage of labour: The Hinchingbrooke randomised controlled trial. Lancet
351(9104): 693–699.
Competing interests:
None declared
Competing interests: No competing interests
We are delighted to see a growing interest in misoprostol to prevent
postpartum haemorrhage (PPH). Indeed, the relative risk observed by Høj
and colleagues (1) for severe PPH of misoprostol v. non-misoprostol
treated women is very similar to that which we observed in our community
based trial of oral misoprostol v. ergometrine for prevention of PPH (2).
However, the incidence of PPH in our study was much closer to that
normally expected. Most studies measuring postpartum blood loss describe
rates of PPH (>=500 ml) ranging from 10%-20% and severe PPH (>=1000
ml) from 1%-4%.
We wonder if Høj et al can tell why their primary care centre
incidence of PPH (45% in the misoprostol and 51% in the control group) and
severe PPH (8% in the misoprostol and 17% control group) is so much
higher. In trying to understand this, could the authors tell us what
percent of women (with and without PPH and severe PPH) in each study group
received oxytocin in the second and the third stage of labour? Did any
women receive oxytocin for treatment of PPH? And what percent of women in
each group with and without PPH and severe PPH had episiotomies? Also, we
would like to understand why Figure 1 indicates higher incidence of heavy
blood loss in the misoprostol than control group, whereas the categorical
data in Table 3 reflect the opposite?
Finally, as with our study, the one maternal death occurred in the
misoprostol group. Perhaps it is time to conduct a specific trial that
measures the impact of administering misoprostol in the third stage of
labour on maternal death as a primary endpoint.
We thank the authors in advance for their response.
1 Høj L., Cardoso P., Nielsen B.B., Hvidman L., Nielsen J., Aaby P.
Effect of sublingual misoprostol on severe postpartum haemorhhage in a
primary health centre in Guinea-Bissau: randomized double blind controlled
trial. BMJ 2005;331;723-7.
2 Walraven G, Blum J, Dampha Y, Sowe M, Morison L, Winikoff B, Sloan N.
Misoprostol in the management of the third stage of labour in the home
delivery setting in rural Gambia; a randomised controlled trial. British
Journal of Obstetrics and Gyneacology 2005;112:1277-1283.
Competing interests:
None declared
Competing interests: No competing interests
The histograms in both figure 1 and 2 seem to suggest that the blood
loss was greater in the misoprostol group than in the placebo group. I
wonder if there has been an error and the labels for the 2 groups
accidentally reversed. Could the authors please check this so that a
correction can be published if necessary?
Competing interests:
None declared
Competing interests: No competing interests
Dear Susan C Morgan.
Misoprostol has been on the market since 1985 and is approved for
prevention of gastroduodenal ulcers in doses of up to 800 µg daily in a
group of patients in whom cardiovascular and cerebrovascular diseases are
common. No one has questioned the risk/benefit ratio in this relatively
mild condition. Delivery under circumstances described in our trial is an
extremely unsafe event and 2-4 deaths in 661 deliveries are to be
expected. The best possible method to obtain a cause of death – verbal
autopsy - was carried out for the single death in our trial, but - as in
the majorities of deaths in settings without post-mortems, para-clinical
tests and experienced doctors - a clear cause of death was not found.
Profound analysis concerning one event in a randomised trial of 661
participants is not possible; instead the event was appropriately reported
for inclusion in meta-analyses to come. With one table and one paragraph
dedicated to side effects we do not understand the argument ‘complete
absence of safety reporting’, and the allegation ‘complete dismissal of
any relationship to the active intervention’ is simply not true. We
maintain our conclusion: IF the drug is found to be consistently
beneficial and safe, sublingual misoprostol should be offered to labouring
women at the start of the third stage of labour if injectable uterotonics
are not available.
Safe motherhood in rural Africa is not accomplished without innovative
research.
Competing interests:
None declared
Competing interests: No competing interests
We welcome the work of Høj et al. and their careful randomised
controlled trial on the use of sublingual misoprostol to prevent post
partum haemorrhage (PPH) in a health centre in Guinea Bissau (BMJ 2005;
331; 723). As the authors point out, most women in Africa do not deliver
in a health facility and the challenge is to transfer this encouraging
data to the village level.
We would like to draw attention to a culturally appropriate way to
measure blood loss at the village level (1) and to demonstrations in
Tanzania and the Gambia where traditional birth attendants (TBAs) used
misoprostol responsibly and effectively during home births (2, 3).
Moreover, evidence shows that when appropriately counseled, women can
correctly use misoprostol in home births even in the absence of a trained
TBA (4).
Ethically, we felt it was not possible to conduct a placebo control
for treatment of PPH when TBAs have no alternative way of stopping
haemorrhage. In addition to the Tanzanian study similar intervention
trials are ongoing in Nigeria, Bangladesh and soon to start in Afghanistan
and Ethiopia.
Senior government officials in Uganda and Kenya have endorsed the use
of misoprostol to control PPH and the government of India is encouraging
the use of sublingual or oral misoprostol for the prevention of PPH at
home births, recently having added misoprostol to the official guidelines
for skilled attendance (5). We hope that with the additional important
work of Høj et al. that use of this life-saving technology will spread.
Sincerely,
Godfrey Mbaruku MD, PhD
Regional Medical Officer,
Consultant Obstetrician Gynaecologist,
Regional Hospital, Maweni,
P.O.Box 125,
KIGOMA.
TANZANIA.
Email: mbarukug@yahoo.com
Friday E. Okonofua MD, PhD
Professor of Obstetrics and Gynecology & Executive Director,
International Federation of Gynecology and Obstetrics and Obstetrics
(FIGO)
Email: wharc@hyperia.com
Khama Rogo MD, PhD
Lead Health Sector Specialist, Pop/MCH
Africa Region,
The World Bank,
Email: krogo@worldbank.org
Dr. Harshad Sanghvi
Medical Director, JHPIEGO
1615 Thames Street, Suite 200,
Baltimore, Maryland 21231-3492,
Email:hsanghvi@jhpiego.net
Ndola Prata MD, MSc;
Anke Hemmerling MD, MPH;
Farnaz Vahidnia MD, MPH;
Malcolm Potts MB, Bchir, PhD
Bixby Program in Population, Family Planning and Maternal Health,
School of Public Health, UC Berkeley,
314 Warren Hall,
Berkeley, CA 94720-7360
Email: ndola@berkeley.edu
References
1. Prata N., Mbaruku G., Campbell M. Using the kanga to measure
postpartum blood loss. International Journal of Gynaecology and Obstetrics
2005; 89(1):49-50.
2. Prata N., Mbaruku G., Campbell M., Potts M., Vahidnia F. Controlling
postpartum hemorrhage after home births in Tanzania Int J Gyn and Obs
2005 90(1):51-5.
3. Walraven G, Blum J, Dampha Y, Sowe M, Morison L, Winikoff B, et al.
Misoprostol in the management of the third stage of labour in the home
delivery setting in rural Gambia: a randomised controlled trial. BJOG
2005; 112(9):1277-83.
4. Sanghvi HCG, Gulardi, W., Chanpong G., Fishel J, Ahmed S, Zulkarnain
M. Prevention of postpartum hemorrhage study, West Java, Indonesia,
JPHIEGO, 2004.
5. Maternal Health Division, Department of Family Welfare, Ministry of
Health & Family Welfare, (Government of India) Guidelines for
antenatal care and skilled attendance at birth by ANMs and LHVs. MOH;
2005.
Competing interests:
None declared
Competing interests: No competing interests
The pragmatic double-blind study of sub-lingual misoprostol versus
placebo in a primary health care setting where it is not possible to give
the standard treatment of intravenous oxytocin is to be commended.
However, despite some efficacy being shown (reduction of the incidence of
the severer haemorrhages but not in the primary endpoint of all post-
partum haemorrhages) the safety message from the trial was lost. It is
recognised that safety issues are inadequately reported on in published
trials (refs 1-3) and although mortality was reported under side effects
this issue was then not evaluated any further. In this trial report no
safety issues were mentioned in the abstract and only the minor symptoms
of shivering and mild fever were noted in the conclusion. It is only on
closer reading of the safety section that it comes to light that the 1
death occurred in the active arm of the study. A clear cause of death was
not obtained which is regrettable. It was a sudden death only 90 minutes
post-partum and it was noted that the woman had lost 1417ml of blood. In
these circumstances it would appear reasonable to include adverse event to
misoprostol as a possible cause for the death. It is known that
misoprostol can cause hypotension which could be particularly hazardous in
the context of blood loss and undiagnosed cardiovascular or
cerebrovascular disease.
Use of any therapy is dependent on assessing that
the risk/benefit of treatment is favourable when undue emphasis is put on
borderline efficacy without balancing comments in the conclusions of the
safety issues may give false reassurance that a treatment is appropriate
for off-label use. In this trial it was not the complete absence of safety
reporting but a complete dismissal of any relationship to the active
intervention.
Competing interests:
None declared
Competing interests: No competing interests
Misoprostol in the third stage of labour and maternal mortality: a review
Misoprostol in the third stage of labour and maternal mortality: a
review (G. Justus Hofmeyr and A. Metin Gülmezoglu)
Introduction
We followed the responses following the paper by Høj et al with
interest. Misoprostol has strong uterotonic and known pharmacologic
effects on several organ systems. Pharmacologic effects other than on the
uterus might explain certain inconsistencies, such as the observation that
misoprostol labour induction is associated with an increased rate of
postpartum haemorrhage(1). Pharmacologic effects include inhibition of
platelet-activating factor, gastrointestinal protection against
nonsteroidal drug effects, irradiation injury, experimental gastric
cancer, enteropathy and constipation; inhibition of leukocyte adherence
and modulation of adhesion molecule expression; improved nutrient
absorption in cystic fibrosis; reduced cholesterol and severity of
peripheral vascular diseases; prolonged survival of cardiac and kidney
transplantation; cyclosporine synergy; effectiveness in acetaminophen and
ethanol hepatotoxicity, hepatitis and fibrosis, drug-induced renal damage,
interstitial cystitis, lupus nephritis, hepatorenal syndrome, periodontal
disease and dental repair; enhanced glycosaminoglycan synthesis in
cartilage after injury; prevention of ultraviolet-induced cataracts;
reduced intraocular pressure in glaucoma and ocular hypertension;
synergism with the anti-inflammatory and analgesic effects of diclofenac
or colchicines; reduced chemotherapy-induced hair loss; reduced recovery
time from burn injury; and effectiveness in treating sepsis, multiple
sclerosis and pancreatitis (2).
It is plausible that a drug with ubiquitous pharmacologic effects
might have unexpected adverse effects when used in the third stage of
labour. For the above reasons, we reviewed maternal mortality in
randomised trials of misoprostol used in the third stage of labour.
We searched The Cochrane Controlled Trials Register and the
electronic data base Pubmed/Medline were searched on the word
‘misoprostol’ in December 2005 for randomised comparisons of misoprostol
used for the prevention or treatment of postpartum haemorrhage, with
placebo or alternative methods (usually injectable uterotonics).
We identified 32 prevention and three treatment trials of postpartum
haemorrhage where misoprostol was used as one of the interventions. Of the
32 prevention trials 24 made no reference to maternal deaths. While it is
unlikely that maternal deaths would not have been reported had they
occurred, we have included only those trials in which the presence or
absence of maternal deaths was explicit, or has been confirmed by
communication with trial authors in the meta-analysis. Differences were
expressed as relative risks, with 95% confidence intervals.
Results
Of 10 deaths reported in 11 trials (23 803 women), 8 occurred in
women receiving misoprostol (relative risk 2.71, 95% confidence interval
0.80 to 9.2). In 24 trials no mention of maternal deaths was made.
Discussion
The primary motivation for the use of misoprostol in the third stage
of labour is to reduce maternal mortality. Because mortality is such a
rare outcome, no trials to date have been designed to assess the effect on
mortality. However, the occurrence of several deaths in trials in women
receiving misoprostol has raised concern.
The limitations of this quick review must be emphasised. Firstly, the
numbers are small with wide confidence limits, and are consistent, at the
95% confidence level, with anything between a modest reduction and a large
increase in maternal mortality with misoprostol. Secondly, this was a post
-hoc analysis in response to an observed clustering of maternal deaths,
and the statistical calculations need to be interpreted with
circumspection.
These results should not be construed as evidence of an adverse
effect of misoprostol on maternal mortality. On the basis of the results
we propose, for further investigation, the hypothesis that misoprostol may
have an as yet unexplained adverse effect on maternal homoeostatic
functions in the third stage of labour.
Conclusions
Because of the enormous potential benefits of an effective, orally
active third stage uterotonic, and the likelihood that misoprostol will be
used on a large scale worldwide, further research is essential to measure
the possible beneficial and harmful effects of misoprostol more
accurately. Enthusiasm for the use of misoprostol should not detract from
international efforts to ensure access for all childbearing women to
established, effective and safe uterotonics such as oxytocin.
References
1. Hofmeyr GJ. Induction of labour with misoprostol. Curr Opin Obstet
Gynecol. 2001;13:577-81
2. Davies NM, Longstreth J, Jamali F. Misoprostol therapeutics
revisited. Pharmacotherapy 2001; 21: 60-73.
Competing interests:
None declared
Competing interests: No competing interests