Tommy's National Centre for Miscarriage Research, Institute of Metabolism and Systems Research, University of Birmingham, C/o Academic Unit, 3rd Floor, Birmingham Women's Hospital Foundation Trust, Mindelsohn Way, Birmingham, UK, B15 2TG.
The Cochrane Database of Systematic Reviews. 2018;4:CD011689.
BACKGROUND Postpartum haemorrhage (PPH) is the leading cause of maternal mortality worldwide. Prophylactic uterotonic drugs can prevent PPH, and are routinely recommended. There are several uterotonic drugs for preventing PPH but it is still debatable which drug is best. OBJECTIVES To identify the most effective uterotonic drug(s) to prevent PPH, and generate a ranking according to their effectiveness and side-effect
profile. SEARCH METHODS We searched Cochrane Pregnancy and Childbirth's Trials Register (1 June 2015), ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) for unpublished trial reports (30 June 2015) and reference lists of retrieved studies. SELECTION CRITERIA All randomised controlled comparisons or cluster trials of effectiveness or side-effects of uterotonic drugs for preventing PPH.Quasi-randomised trials and cross-over trials are not eligible for inclusion in this review. DATA COLLECTION AND ANALYSIS At least three review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We estimated the relative effects and rankings for preventing PPH ≥ 500 mL and PPH ≥ 1000 mL as primary outcomes. We performed pairwise meta-analyses and network meta-analysis to determine the relative effects and rankings of all available drugs. We stratified our primary outcomes according to mode of birth, prior risk of PPH, healthcare setting, dosage, regimen and route of drug administration, to detect subgroup effects.The absolute risks in the oxytocin are based on meta-analyses of proportions from the studies included in this review and the risks in the intervention groups were based on the assumed risk in the oxytocin group and the relative effects of the interventions. MAIN RESULTS This network meta-analysis included 140 randomised trials with data from 88,947 women. There are two large ongoing studies. The trials were mostly carried out in hospital settings and recruited women who were predominantly more than 37 weeks of gestation having a vaginal birth. The majority of trials were assessed to have uncertain risk of bias due to poor reporting of study design. This primarily impacted on our confidence in comparisons involving carbetocin trials more than other uterotonics.The three most effective drugs for prevention of PPH ≥ 500 mL were ergometrine plus oxytocin combination, carbetocin, and misoprostol plus oxytocin combination. These three options were more effective at preventing PPH ≥ 500 mL compared with oxytocin, the drug currently recommended by the WHO (ergometrine plus oxytocin risk ratio (RR) 0.69 (95% confidence interval (CI) 0.57 to 0.83), moderate-quality evidence; carbetocin RR 0.72 (95% CI 0.52 to 1.00), very low-quality evidence; misoprostol plus oxytocin RR 0.73 (95% CI 0.60 to 0.90), moderate-quality evidence). Based on these results, about 10.5% women given oxytocin would experience a PPH of ≥ 500 mL compared with 7.2% given ergometrine plus oxytocin combination, 7.6% given carbetocin, and 7.7% given misoprostol plus oxytocin. Oxytocin was ranked fourth with close to 0% cumulative probability of being ranked in the top three for PPH ≥ 500 mL.The outcomes and rankings for the outcome of PPH ≥ 1000 mL were similar to those of PPH ≥ 500 mL. with the evidence for ergometrine plus oxytocin combination being more effective than oxytocin (RR 0.77 (95% CI 0.61 to 0.95), high-quality evidence) being more certain than that for carbetocin (RR 0.70 (95% CI 0.38 to 1.28), low-quality evidence), or misoprostol plus oxytocin combination (RR 0.90 (95% CI 0.72 to 1.14), moderate-quality evidence)There were no meaningful differences between all drugs for maternal deaths or severe morbidity as these outcomes were so rare in the included randomised trials.Two combination regimens had the poorest rankings for side-effects. Specifically, the ergometrine plus oxytocin combination had the higher risk for vomiting (RR 3.10 (95% CI 2.11 to 4.56), high-quality evidence; 1.9% ve