Uterotonics for management of retained placenta.

Rationale: Retained placenta is a significant cause of maternal death from postpartum haemorrhage. Traditionally, it is managed by manual removal under anaesthesia, which carries risks of haemorrhage, infection, and uterine perforation. Uterotonics may offer an alternative for delivering the retained placenta since they induce uterine contractions. However, evidence regarding uterotonic agents for retained placenta is still limited.

Objectives: To assess the benefits and harms of uterotonics for women with retained placenta after vaginal delivery for preventing postpartum haemorrhage.

Search methods: We searched CENTRAL, MEDLINE, Embase, CINAHL, ClinicalTrials.gov, and WHO ICTRP; and checked references of included studies and pertinent systematic reviews to identify additional studies. The latest search date was 25 April 2024.

Eligibility criteria: We included randomised controlled trials (RCTs) and non-randomised studies of interventions in women who underwent vaginal delivery with retained placenta comparing one uterotonic with another uterotonic, placebo, or no treatment. We excluded studies that compared different uterotonics administered by umbilical vein injection.

Outcomes: Our main outcomes were manual removal of the placenta; postpartum haemorrhage of 1000 mL or more; adverse effects, such as shivering; blood transfusion; maternal death; severe morbidity (admission to the intensive care unit); and blood loss in millilitres. The primary time point of interest for all outcomes was the end of the study period.

Risk of bias: We used the Cochrane RoB 2 tool to assess bias in RCTs and the ROBINS-I tool to assess bias in non-randomised studies of interventions.

Synthesis methods: We synthesised results for each outcome using a random-effects meta-analysis, where possible, employing Mantel-Haenszel with risk ratio (RR) or inverse variance with mean difference (MD), as appropriate. Where this was not possible due to the nature of the data, we synthesised results using narrative synthesis methods. We used GRADE to assess the certainty of evidence for each outcome.

Included studies: We included five studies with 560 women, comprising four RCTs and one non-randomised study. The studies were conducted in the Netherlands, Tanzania, and Egypt. Three RCTs compared uterotonics (sulprostone or misoprostol) with placebo or no treatment. One RCT compared oxytocin, intravenous carbetocin, and sublingual misoprostol. One non-randomised study compared intraumbilical oxytocin to oxytocin infusion.

Synthesis of results: Systemic uterotonic agents versus placebo or no treatment Sulprostone or misoprostol may result in little to no difference in the rate of manual removal of the placenta (RR 0.82, 95% confidence interval (CI) 0.54 to 1.27; 3 RCTs, 244 women; low-certainty evidence), and probably results in little to no difference in postpartum haemorrhage (RR 0.80, 95% CI 0.55 to 1.15; 2 RCTs, 194 women; moderate-certainty evidence), and blood transfusion (RR 0.72, 95% CI 0.43 to 1.22; 3 RCTs, 244 women; moderate-certainty evidence) compared to placebo or no treatment. We are very uncertain about the effect of misoprostol on shivering (RR 10.00, 95% CI 1.40 to 71.49; 1 RCT, 70 women; very low-certainty evidence) and the effects of uterotonic agents on mean blood loss (MD -205.26 mL, 95% CI -536.31 to 125.79; 3 RCTs, 244 women; very low-certainty evidence). No study assessed maternal death or severe morbidity. Intravenous carbetocin versus sublingual misoprostol Intravenous carbetocin probably does not reduce the need for manual removal of the placenta (RR 0.79, 95% CI 0.52 to 1.20; 1 RCT, 185 women; moderate-certainty evidence), and may not reduce blood transfusion (RR 0.48, 95% CI 0.09 to 2.58; 1 RCT, 185 women; low-certainty evidence) compared to sublingual misoprostol. The study did not assess postpartum haemorrhage of 1000 mL or more, adverse effects (shivering), maternal death, severe morbidity, and blood loss. Sublingual misoprostol versus oxytocin intraumbilical venous injection Sublingual misoprostol probably results in little to no difference in the rate of manual removal of the placenta (RR 1.09, 95% CI 0.73 to 1.61; 1 RCT, 187 women; moderate-certainty evidence) and may not reduce the need for blood transfusion (RR 1.05, 95% CI 0.27 to 4.09; 1 RCT, 187 women; low-certainty evidence) compared to oxytocin intraumbilical venous injection. The study did not assess postpartum haemorrhage of 1000 mL or more, adverse effects (shivering), maternal death, severe morbidity, and blood loss. Intravenous carbetocin versus oxytocin intraumbilical venous injection Intravenous carbetocin probably does not reduce the rate of manual removal of the placenta (RR 0.86, 95% CI 0.56 to 1.32; 1 RCT, 190 women; moderate-certainty evidence), and may result in little to no difference in reducing blood transfusions (RR 0.51, 95% CI 0.10 to 2.72; 1 RCT, 190 women; low-certainty evidence) compared to intraumbilical venous injection. The study did not assess postpartum haemorrhage of 1000 mL or more, adverse effects (shivering), maternal death, severe morbidity, and blood loss. Oxytocin infusion versus oxytocin intraumbilical venous injection The evidence from one non-randomised study is very uncertain about the effect of oxytocin infusion on manual removal of the placenta compared to oxytocin intraumbilical venous injection (RR 0.90, 95% CI 0.71 to 1.13; 1 study, 35 women; very low-certainty evidence). The study did not assess our other outcomes of interest.

Authors' conclusions: Current evidence suggests that uterotonic agents (such as misoprostol and sulprostone) may result in little to no difference in the rates of manual removal of the placenta, and probably result in little to no difference in postpartum haemorrhage and the need for blood transfusions, compared to placebo or no treatment in the management of retained placenta. The evidence is very uncertain about their effects on blood loss and the effect of misoprostol on shivering. There is probably little to no difference in effects and there may be no difference in safety between one uterotonic agent over another. We found no useable data for maternal death and admission to the intensive care unit. Further large-scale studies are necessary to evaluate uterotonics versus placebo, compare different uterotonic agents, or assess combined uterotonic regimens. Additional research should focus on identifying specific adverse effects, maternal satisfaction and well-being, breastfeeding rates at discharge, and postpartum anaemia.

Funding: This Cochrane review was funded by UNDP-UNFPA-UNICEF-WHO-World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP).

Registration: Registration (13 July 2024): Prospero, CRD42024564386.