The Committee did not recommend the deletion of the indication for prevention
of PPH from the listing of misoprostol from EML. The Committee considered
that the new evidence presented in this re-submission was insufficient to support
any change to the current listing.
The Committee reiterated that misoprostol remains an effective
alternative for prevention of PPH in resource-poor, community and rural
settings where oxytocin is unavailable or cannot be safely administered. The
listing of misoprostol on the EML supports its appropriate use in such settings
and is consistent with the 2018 WHO recommendations for uterotonics for the
prevention of PPH.
The application requested the deletion of misoprostol from the EML for the
indication of prevention of postpartum haemorrhage.
Misoprostol was added to the EML in 2011 for prevention of PPH in settings
where parenteral uterotonics are not available or feasible. It was, and remains
listed with a conditional note specifying that its use in PPH is limited to
circumstances where oxytocin is not available or cannot be safely used.
This was the fourth application from Drs Sevcikova and Pollock
requesting deletion of misoprostol from the EML for prevention of PPH. Most
recently in 2017, the Expert Committee did not recommend deletion, noting
that very few new clinical data were included in the application. The Committee
considered that the evidence presented was insufficient to support deletion.
The Expert Committee once again acknowledged that misoprostol
is less effective than oxytocin infusion and is associated with adverse events,
particularly vomiting and shivering. The circumstances of use have not changed;
misoprostol remains an alternative for the prevention of PPH in resource-poor,
community and rural settings where intravenous oxytocin is not available or
cannot be safely administered (2).
Public health relevance
Obstetric haemorrhage, especially PPH, is responsible for more than a quarter
of all maternal deaths worldwide (3). In most low-income countries, PPH is the
leading cause of maternal deaths.
The same evidence presented in the 2017 application was included in the current
application. Only evidence not previously considered by the Committee is
To update the evidence base presented and considered in previous
applications, the current application undertook a literature search for
randomized controlled trials (RCTs) assessing misoprostol use in community
and home birth settings in low- and middle-income countries (LMICs)
published between November 2016 and November 2018. This search identified
two systematic reviews (1, 4), one of which was excluded as it included trials
conducted in hospitals (4). No additional RCTs conducted in low-resource
settings were identified.
The application presented results extracted from a sub-group analysis
from the Cochrane systematic review by Gallos et al for the comparison of
misoprostol versus placebo or no treatment from three trials conducted in the
community setting (5–7).
Efficacy outcomes and effect size:
Death: RR 1.00 [95%CI 0.10 to 9.59]
PPH ≥ 1000 ml: RR 0.59 [95%CI 0.39 to 0.88]
Blood transfusion: RR 0.14 [95%CI 0.02 to 1.15]
Severe maternal morbidity: RR 1.00 [95%CI 0.14 to 7.05]
PPH ≥ 500 ml: RR 0.73 [95%CI 0.56 to 0.96]
Additional uterotonics: RR 0.50 [95%CI 0.12 to 1.98]
Blood loss: MD −43.79 [95%CI −58.09 to −29.49]
Change in haemoglobin:MD −2.12 [95%CI −3.46 to −0.77]
Safety outcomes and effect size:
Nausea: RR 1.12 [95%CI 0.74 to 1.70]
Vomiting: RR 1.27 [95%CI 0.80 to 2.01]
Headache RR 0.94 [95%CI 0.32 to 2.77]
Shivering RR 2.71 [95%CI 2.33 to 3.15]
Fever RR 2.87 [95%CI 0.90 to 9.18]
Diarrhoea RR 3.11 [95%CI 1.28 to 7.51]
(RR: risk ratio, MD: mean difference)
Gallos et al reported no important differences were identified in the subgroup analysis by hospital or community setting (1).
Commenting on the quality of available evidence, the application noted
that all community studies have important shortcomings either due to small
numbers; use of alternative uterotonics in the control arm; confounding due
to management practice and subjective assessment; and with one exception (6)
(in which the numbers were very small), exclusion of high-risk women. PPH
incidence fell in both the control and intervention groups in both the trials (5, 7)
that informed the 2011 decision to add misoprostol to the EML. This suggests
factors other than misoprostol use are crucial in determining outcomes.
No new safety data (beyond that presented above) were included in the current
Cost / cost effectiveness
The 2018 WHO recommendations state that as misoprostol is inexpensive and
can also be used by lay health workers in community settings, it is associated with
moderate savings and is probably cost-effective, especially when implemented in
settings with a shortage of skilled health personnel (8).
The 2018 WHO recommendations for uterotonics for the prevention of PPH
(8) recommend use of an effective uterotonic during the third stage of labour
for all births. Misoprostol 400 µg or 600 µg, orally is a recommended option for
1. Gallos ID, Papadopoulou A, Man R, Athanasopoulos N, Tobias A, Price MJ et al. Uterotonic agents
for preventing postpartum haemorrhage: a network meta-analysis. Cochrane Database Syst Rev.
2. The selection and use of essential medicines. Report of the WHO Expert Committee, 2017
(including the 20th WHO Model List of Essential Medicines and the 6th WHO Model List of
Essential Medicines for Children) (WHO Technical Report Series, No. 1006). Geneva: World
Health Organization; 2017. Available from https://apps.who.int/iris/bitstream/handle/10665/
259481/9789241210157-eng.pdf, accessed 30 October 2019.
3. Say L, Chou D, Gemmill A, Tuncalp O, Moller AB, Daniels J et al. Global causes of maternal death: a
WHO systematic analysis. Lancet Glob Health. 2014;2(6):e323–33.
4. Abd El Aziz MA, Iraqi A, Abedi P, Jahanfar S. The effect of carbetocin compared to misoprostol in
management of the third stage of labor and prevention of postpartum hemorrhage: a systematic
review. Syst Rev. 2018;7(1):170.
5. Derman RJ, Kodkany BS, Goudar SS, Geller SE, Naik VA, Bellad MB et al. Oral misoprostol in
preventing postpartum haemorrhage in resource-poor communities: a randomised controlled
trial. Lancet. 2006;368(9543):1248–53.
6. Hoj L, Cardoso P, Nielsen BB, Hvidman L, Nielsen J, Aaby P. Effect of sublingual misoprostol on
severe postpartum haemorrhage in a primary health centre in Guinea-Bissau: randomised double
blind clinical trial. BMJ. 2005;331(7519):723.
7. Mobeen N, Durocher J, Zuberi N, Jahan N, Blum J, Wasim S et al. Administration of misoprostol
by trained traditional birth attendants to prevent postpartum haemorrhage in homebirths in
Pakistan: a randomised placebo-controlled trial. BJOG. 2011;118(3):353–61.
8. WHO recommendations: uterotonics for the prevention of postpartum haemorrhage. Geneva:
World Health Organization; 2018. Available from https://apps.who.int/iris/bitstream/handle/
10665/277276/9789241550420-eng.pdf?ua=1&ua=1, accessed 29 September 2019.