Background:

Postpartum haemorrhage (PPH) is the leading cause of maternal mortality worldwide. Prophylactic uterotonic drugs can reduce blood loss and are routinely recommended. There are several uterotonic drugs for preventing PPH, but it is still debatable which drug or combination of drugs is the most effective.

Objectives:

To identify the most effective and cost-effective uterotonic drug(s) to prevent PPH, and generate a ranking according to their effectiveness and side-effect profile.

Methods:

The Cochrane Pregnancy and Childbirth’s Trials Register (1 June 2015), ClinicalTrials.gov and the World Health Organization (WHO)’s International Clinical Trials Registry Platform (ICTRP) were searched for unpublished trial reports (30 June 2015). In addition, reference lists of retrieved studies (updated October 2017) were searched for randomised trials evaluating uterotonic drugs for preventing PPH. The study estimated relative effects and rankings for preventing PPH, defined as blood loss of ≥ 500 ml and ≥ 1000 ml. Pairwise meta-analyses and network meta-analysis were performed to determine the relative effects and rankings of all available drugs and combinations thereof [ergometrine, misoprostol (Cytotec^®; Pfizer Inc., New York, NY, USA), misoprostol plus oxytocin (Syntocinon^®; Novartis International AG, Basel, Switzerland), carbetocin (Pabal^®; Ferring Pharmaceuticals, Saint-Prex, Switzerland), ergometrine plus oxytocin (Syntometrine^®; Alliance Pharma plc, Chippenham, UK), oxytocin, and a placebo or no treatment]. Primary outcomes were stratified according to the mode of birth, prior risk of PPH, health-care setting, drug dosage, regimen and route of drug administration. Sensitivity analyses were performed according to study quality and funding source, among others. A model-based economic evaluation compared the relative cost-effectiveness separately for vaginal births and caesareans with or without including side effects.

Results:

From 137 randomised trials and 87,466 women, ergometrine plus oxytocin, carbetocin and misoprostol plus oxytocin were found to reduce the risk of PPH blood loss of ≥ 500 ml compared with the standard drug, oxytocin [ergometrine plus oxytocin: risk ratio (RR) 0.69, 95% confidence interval (CI) 0.57 to 0.83; carbetocin: RR 0.72, 95% CI 0.52 to 1.00; misoprostol plus oxytocin: RR 0.73, 95% CI 0.6 to 0.9]. Each of these three strategies had 100% cumulative probability of being ranked first, second or third most effective. Oxytocin was ranked fourth, with an almost 0% cumulative probability of being ranked in the top three. Similar rankings were noted for the reduction of PPH blood loss of ≥ 1000 ml (ergometrine plus oxytocin: RR 0.77, 95% CI 0.61 to 0.95; carbetocin: RR 0.70, 95% CI 0.38 to 1.28; misoprostol plus oxytocin: RR 0.90, 95% CI 0.72 to 1.14), and most secondary outcomes. Ergometrine plus oxytocin and misoprostol plus oxytocin had the poorest ranking for side effects. Carbetocin had a favourable side-effect profile, which was similar to oxytocin. However, the analysis was restricted to high-quality studies, carbetocin lost its ranking and was comparable to oxytocin. The relative cost-effectiveness of the alternative strategies is inconclusive, and the results are affected by both the uncertainty and inconsistency in the data reported on adverse events. For vaginal delivery, when assuming no adverse events, ergometrine plus oxytocin is less costly and more effective than all strategies except carbetocin. The strategy of carbetocin is both more effective and more costly than all other strategies. When taking adverse events into consideration, all prevention strategies, except oxytocin, are more costly and less effective than carbetocin. For delivery by caesarean section, with and without adverse events, the relative cost-effectiveness is different, again because of the uncertainty in the available data.

Limitations:

There was considerable uncertainty in findings within the planned subgroup analyses, and subgroup effects cannot be ruled out.

Conclusions:

Ergometrine plus oxytocin, carbetocin and misoprostol plus oxytocin are more effective uterotonic drug strategies for preventing PPH than the current standard, oxytocin. Ergometrine plus oxytocin and misoprostol plus oxytocin cause significant side effects. Carbetocin has a favourable side-effect profile, which was similar to oxytocin. However, most carbetocin trials are small and of poor quality. There is a need for a large high-quality trial comparing carbetocin with oxytocin; such a trial is currently being conducted by the WHO. The relative cost-effectiveness is inconclusive, and results are affected by uncertainty and inconsistency in adverse events data.

Study registration:

This study is registered as PROSPERO CRD42015020005; Cochrane Pregnancy and Childbirth Group (substudy) reference number 0871; PROSPERO–Cochrane (substudy) reference number CRD42015026568; and sponsor reference number ERN_13–1414 (University of Birmingham, Birmingham, UK).

Funding:

Funding for this study was provided by the National Institute for Health Research Health Technology Assessment programme in a research award to the University of Birmingham and supported by the UK charity Ammalife (UK-registered charity 1120236). The funders of the study had no role in study design, data collection, data synthesis, interpretation or writing of the report.

Article history

The research reported in this issue of the journal was funded by the HTA programme as project number 14/139/17. The contractual start date was in May 2015. The draft report began editorial review in November 2016 and was accepted for publication in May 2018. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Declared competing interests of authors

Ioannis Gallos, Metin Gülmezoglu, Justus Hofmeyr and Arri Coomarasamy have been involved in one or more previous or ongoing trials related to the use of uterotonics for the prevention of postpartum haemorrhage that were considered for inclusion in this review. Ferring Pharmaceuticals (Saint-Prex, Switzerland) and Novartis Pharmaceuticals UK Ltd (Surrey, UK) have supplied carbetocin and oxytocin to these studies. Ioannis Gallos, Metin Gülmezoglu, Justus Hofmeyr and Arri Coomarasamy have not participated in decisions regarding inclusion of these trials in this review or any tasks related to them such as data extraction or quality assessment. Arri Coomarasamy is involved in a World Health Organization-sponsored randomised controlled trial of carbetocin versus oxytocin, supported by Merck for Mothers (Merck & Co., Inc., Kenilworth, NJ, USA). Metin Gülmezoglu was involved in a large multicentre trial included in the review as part of the central co-ordination unit. As part of the central co-ordination unit, he is also involved in an ongoing World Health Organization-sponsored randomised controlled trial of carbetocin versus oxytocin supported by Merck for Mothers. Abi Merriel is part-funded by Ammalife (a UK-registered charity 1120236) and the Birmingham Women’s NHS Foundation Trust. Harry Gee and Arri Coomarasamy are trustees of Ammalife. Jonathan Deeks is a member of the Health Technology Assessment (HTA) Commissioning Board and the HTA Efficient Study and Designs Board.