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A meta-analysis of 140 studies by investigators from the Cochrane Collaboration shows that oxytocin may not be the best choice for prevention of postpartum hemorrhage, despite the current recommendation from the World Health Organization (WHO). PLUS: Commentary on the findings from our Maternal Mortality Series Editor, Carolyn Zelop, MD.
A meta-analysis of 140 studies by investigators from the Cochrane Collaboration shows that oxytocin may not be the best choice for prevention of postpartum hemorrhage, despite the current recommendation from the World Health Organization (WHO). Ergometrine plus oxytocin, misoprostol pus oxytocin, and carbetocin, the authors said, are more effective than oxytocin alone.
The findings are from a network meta-analysis of 140 randomized trials with data from nearly 90,000 women. Most of the trials were done in hospitals and the women were predominantly > 37 weeks’ gestation. The authors sought to look at the relative effects and rankings of drugs used to prevent postpartum hemorrhage ≥ 500 mL and ≥ 1000 mL as primary outcomes. Results were stratified by mode of birth, prior risk of postpartum hemorrhage, healthcare setting, dosage, regimen, and route of drug administration.
For postpartum hemorrhage ≥ 500 mL, the researchers found that ergometrine plus oxytocin, carbetocin, and misoprostol plus oxytocin were most effective. The risk ratios (RRs) were 0.69 (95% confidence interval [CI] 0.57 to 0.83) for ergometrine plus oxytocin with moderate-quality evidence, 0.72 (95% CI 0.52 to 1.00) for carbetocin with very low-quality evidence, and 0.73 (95% CI 0.60 to 0.90) for misoprostol plus oxytocin with moderate-quality evidence. Given these findings, the authors said that 7.2% of women given ergometrine plus oxytocin, 7.6% given carbetocin, and 7.7% given misoprostol plus oxytocin would experience postpartum hemorrhage ≥500 mL, versus 10.5% of those given oxytocin alone.
Looking at postpartum hemorrhage ≥1000 mL as an outcome, the findings were similar: RR 0.77 for ergometrine plus oxytocin with high-quality evidence, RR 0.70 for carbetocin with low-quality evidence, and RR 0.90 for misoprostol plus oxytocin with moderate-quality evidence.
In terms of adverse effects, compared with oxytocin, ergometrine plus oxytocin had a higher risk of vomiting (RR 3.10) and hypertension (RR 1.77) and misoprostol plus oxytocin had a higher risk of fever (RR 3.18). The adverse effects profile for carbetocin was similar to that of oxytocin alone.
The studies reviewed by the authors included 11 that are ongoing, two of which will inform a future update of this meta-analysis. One of the latter studies is a multicenter trial of 30,000 women in 10 countries being led by WHO that is looking at effectiveness of room-temperature-stable carbetocin versus intramuscular oxytocin for prevention of postpartum hemorrhage after vaginal birth. The second ongoing study is a three-arm trial of carbetocin, oxytocin, and ergotamine plus oxytocin in more than 6000 women in UK.
Based on discussions with Cochrane’s consumer group, the researchers said there is a “need for more research into PPH outcomes identified as priorities for women and their families, such as women’s views regarding the drugs used, clinical signs of excessive blood loss, neonatal unit admissions and breastfeeding at discharge.” The authors also urged those conducting trials of uterotonic agents to consider measuring these outcomes and recommended future research comparing the effects of different dosages and routes of administration for the most effective drugs.
Comment from Maternal Mortality Series Editor Carolyn Zelop, MD
When we launched our maternal mortality series earlier this year, we reported based upon 2017 CDC data that maternal hemorrhage accounts for 11.4% of maternal deaths annually. The nationwide inpatient sample data examining maternal arrests in women admitted for delivery identified hemorrhage as the leading cause for maternal cardiac arrest.1 Our March issue focused upon obstetrical hemorrhage featuring Gary Dildy, MD’s exposÃ©. Decreasing risk of peripartum hemorrhage would certainly be an important strategy to combat maternal mortality.
This week, the Cochrane library released a network meta-analysis examining the relative effectiveness of uterotonic agents for prevention of postpartum hemorrhage. The results are compelling and provide further evidence-based interventions to alter current practice to decrease risk of peripartum hemorrhage. Currently, we manage the third stage of labor actively, utilizing oxytocin after delivery of the fetus’s anterior shoulder to prevent peripartum hemorrhage. This meta-analysis suggests that using a combination of oxytocin and an ergotrate such as methergine is superior to oxytocin alone in decreasing risk of peripartum hemorrhage ≥ 500 mL and ≥ 1000 mL, based upon high-quality evidence. Importantly, due to side effects of ergotrates, some patients, such as those with hypertension, may not be good candidates for routine use of this medication. Further details of other interventions proposed by this meta-analysis are listed above.
Ongoing trials with other agents such as tranexamic acid may guide future best practices. This review underscores the importance of ongoing research to provide evidence-based best practices to lower risk of peripartum hemorrhage.
Dr. Zelop is Director of Ultrasound, Fetal Echocardiography and Perinatal Research at Valley Hospital in Ridgewood, New Jersey, and Clinical Professor of Obstetrics and Gynecology at NYU School of Medicine, New York. She works actively with ACOG and the American Heart Association (AHA) on issues of maternal cardiac arrest and mortality.