Misoprostol as an adjunct to standard uterotonics for treatment of post-partum haemorrhage: a multicentre, double-blind randomised trial

Summary

Background

Post-partum haemorrhage is a leading cause of global maternal morbidity and mortality. Misoprostol, a prostaglandin analogue with uterotonic activity, is an attractive option for treatment because it is stable, active orally, and inexpensive. We aimed to assess the effectiveness of misoprostol as an adjunct to standard uterotonics compared with standard uterotonics alone for treatment of post-partum haemorrhage.

Methods

Women delivering vaginally who had clinically diagnosed post-partum haemorrhage due to uterine atony were enrolled from participating hospitals in Argentina, Egypt, South Africa, Thailand, and Vietnam between July, 2005, and August, 2008. Computer-generated randomisation was used to assign women to receive 600 μg misoprostol or matching placebo sublingually; both groups were also given routine injectable uterotonics. Allocation was concealed by distribution of sealed and sequentially numbered treatment packs in the order that women were enrolled. Providers and women were masked to treatment assignment. The primary outcome was blood loss of 500 mL or more within 60 min after randomisation. Analysis was by intention to treat. This study is registered, number ISRCTN34455240.

Findings

1422 women were assigned to receive misoprostol (n=705) or placebo (n=717). The proportion of women with blood loss of 500 mL or more within 60 min was similar between the misoprostol group (100 [14%]) and the placebo group (100 [14%]; relative risk 1·02, 95% CI 0·79–1·32). In the first 60 min, an increased proportion of women on misoprostol versus placebo, had shivering (455/704 [65%] vs 230/717 [32%]; 2·01, 1·79–2·27) and body temperature of 38°C or higher (303/704 [43%] vs 107/717 [15%]; 2·88, 2·37–2·50).

Interpretation

Findings from this study do not support clinical use of 600 μg sublingual misoprostol in addition to standard injectable uterotonics for treatment of post-partum haemorrhage.

Funding

Bill & Melinda Gates Foundation, and UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction.

Introduction

Haemorrhage is the leading cause of maternal mortality in low-resource settings:¹ an estimated 125 000 deaths are due to post-partum haemorrhage every year.² Maternal death from haemorrhage is rare in high-resource settings, suggesting that medical interventions for haemorrhage contribute substantially to survival. Conventional treatment of post-partum haemorrhage relies heavily on hospital-based interventions. However, post-partum haemorrhage is largely unpredictable,³ and can lead to death within hours. Simple treatment methods are needed for implementation at all levels of care.

Misoprostol is a prostaglandin E1 analogue that is widely marketed in tablet form, and is registered for use in the prevention and treatment of peptic ulcer disease. It is thermostable, can be taken orally, and is fairly inexpensive. Although misoprostol is less effective than oxytocin for prevention of post-partum haemorrhage,⁴ it has been promoted widely for the ease with which the drug can be taken,⁵ and the positive results from a trial of misoprostol administration by rural birth attendants in India.⁶ Concerns about misuse⁷ and side-effects⁸ have emerged, and misoprostol use for labour induction seems to increase post-partum blood loss.⁹

Clinical use of misoprostol for post-partum haemorrhage is based on weak evidence.10, 11 At the start of our study, three randomised trials of misoprostol for treatment of post-partum haemorrhage had been published.12, 13, 14 Lokugamage and colleagues¹² reported that 800 μg rectal misoprostol stopped post-partum haemorrhage significantly more effectively than did combined intramuscular syntometrine and intravenous syntocinon. However, in that trial treatment allocation was unblinded and the outcome was subjective assessment of clinical response, so investigator bias could have favoured the misoprostol group. Hofmeyr¹³ and Walraven¹⁴ and their colleagues did double-blind trials and showed reduced blood loss with misoprostol compared with placebo, both in combination with standard uterotonics, but the differences were not significant. In a meta-analysis of the results of these trials, misoprostol significantly reduced the primary outcome of additional blood loss of 500 mL or more (relative risk 0·57, 95% CI 0·34–0·96).¹⁵ However, in a systematic review, Mousa and Alfirevic¹⁶ concluded that evidence for any advantage from addition of misoprostol to standard uterotonic treatment was insufficient, and called for more safety data on misoprostol as adjunctive treatment for post-partum haemorrhage.¹⁶ The main side-effects of misoprostol are shivering and pyrexia, which are dose-dependent.11, 17

We aimed to establish whether further blood loss could be reduced with the addition of 600 μg misoprostol sublingually to standard uterotonic treatment (mostly oxytocin) in women with post-partum haemorrhage that was suspected to be caused by uterine atony in vaginal delivery. Findings from pharmacokinetic data show that sublingual administration results in the most rapid absorption, and the highest serum concentrations and bioavailability.18, 19 Reduced blood loss with this simple, inexpensive adjunctive treatment for post-partum haemorrhage could have major public health implications. Conversely, demonstration of lack of efficacy would provide evidence to help avoid further use of an ineffective and potentially harmful drug.