Preventing postpartum hemorrhage: A network meta-analysis on routes of administration of uterotonics

•All women are administered uterotonic drugs for preventing postpartum hemorrhage.•Carbetocin given by an intravenous bolus is better than intramuscular oxytocin.•Intramuscular ergometrine + oxytocin is also better than intramuscular oxytocin.•Oxytocin works best when given by an intravenous bolus than intramuscularly. To perform a network meta-analysis to specify the route of administration that maximises the effectiveness of each of the available prophylactic uterotonics without increasing the risk for side effects. Literature searches on 12th September 2022 included: CENTRAL, MEDLINE, Embase, CINAHL, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform. The reference lists of the retrieved study records were also searched. Population: Randomized controlled trials involving women in the third stage of labour after a vaginal or caesarean delivery in hospital or community settings. Interventions: Systemically administered prophylactic uterotonics of any route and dose for primary postpartum hemorrhage prevention. Comparison: Any other prophylactic uterotonic, or a different route or dose of a given uterotonic, or placebo, or no treatment. Outcomes (primary): postpartum hemorrhage ≥ 500 mL and ≥ 1000 mL. Risk of bias and trustworthiness assessments were performed, according to Cochrane’s guidance. Direct, indirect and network meta-analyses were conducted, and results were summarized either as risk ratio or mean difference with 95% confidence intervals for dichotomous and continuous outcomes, respectively. The certainty of generated evidence was assessed according to the GRADE approach. Cumulative probabilities were calculated and the surface under the cumulative ranking curve was used to create a ranking of the available drugs. One hundred eighty-one studies involving 122,867 randomised women were included. Most studies were conducted in hospital settings in lower-middle income countries and involved women delivering vaginally. When compared with intramuscular oxytocin, carbetocin (RR 0.58, 95 % CI 0.40–0.84) and oxytocin (RR 0.75, 95 % CI 0.59–0.97) by an intravenous bolus, and intramuscular ergometrine plus oxytocin combination (RR 0.71, 95 % CI 0.56–0.91) are probably more effective in preventing primary postpartum hemorrhage. Intramuscularly administered oxytocin and carbetocin by an intravenous bolus have a favourable side effects profile. Generated evidence was generally moderate and global inconsistency was low. Carbetocin a