There is general agreement that oxytocin given either through the intravenous or intramuscular route is effective in reducing postpartum blood loss. However, it is unclear whether the subtle differences between the mode of action of these routes have any effect on maternal and infant outcomes. This review was first published in 2012 and last updated in 2018. To determine the comparative effectiveness and safety of oxytocin administered intravenously or intramuscularly for prophylactic management of the third stage of labour after vaginal birth. We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (19 December 2019), and reference lists of retrieved studies. Eligible studies were randomised trials comparing intravenous with intramuscular oxytocin for prophylactic management of the third stage of labour after vaginal birth. We excluded quasi-randomised trials. Two review authors independently assessed studies for inclusion and risk of bias, extracted data and checked them for accuracy. We assessed the certainty of the evidence with the GRADE approach. Seven trials, involving 7817 women, met the inclusion criteria for this review. The trials compared intravenous versus intramuscular administration of oxytocin just after the birth of the anterior shoulder or soon after the birth of the baby. All trials were conducted in hospital settings and included women with term pregnancies, undergoing a vaginal birth. Overall, the included studies were at moderate or low risk of bias, with two trials providing clear information on allocation concealment and blinding. For GRADE outcomes, the certainty of the evidence was generally moderate to high, except from two cases where the certainty of the evidence was either low or very low. High-certainty evidence suggests that intravenous administration of oxytocin in the third stage of labour compared with intramuscular administration carries a lower risk for postpartum haemorrhage (PPH) ≥ 500 mL (average risk ratio (RR) 0.78, 95% confidence interval (CI) 0.66 to 0.92; six trials; 7731 women) and blood transfusion (average RR 0.44, 95% CI 0.26 to 0.77; four trials; 6684 women). Intravenous administration of oxytocin probably reduces the risk of PPH ≥ 1000 mL, although the 95% CI crosses the line of no-effect (average RR 0.65, 95% CI 0.39 to 1.08; four trials; 6681 women; moderate-certainty evidence). In all studies but one, there was a reduction in the risk of PPH ≥ 1000 mL with intravenous oxytocin. The study that found a large increase with intravenous administration was small (256 women), and contributed only 3% of total events. Once this small study was removed from the meta-analysis, heterogeneity was eliminated and the treatment effect favoured intravenous oxytocin (average RR 0.61, 95% CI 0.42 to 0.88; three trials; 6425 women; high-certainty evidence). Additionally, a sensitivity analysis, exploring the effect of risk of bias by restricting analysis to those studies rated as 'low risk of bias' for random sequence generation and allocation concealment, found that the prophylactic administration of intravenous oxytocin reduces the risk for PPH ≥ 1000 mL, compared with intramuscular oxytocin (average RR 0.64, 95% CI 0.43 to 0.94; two trials; 1512 women). The two routes of oxytocin administration may be comparable in terms of additional uterotonic use (average RR 0.78, 95% CI 0.49 to 1.25; six trials; 7327 women; low-certainty evidence). Although intravenous compared with intramuscular administration of oxytocin probably results in a lower risk for serious maternal morbidity (e.g. hysterectomy, organ failure, coma, intensive care unit admissions), the confidence interval suggests a substantial reduction, but also touches the line of no-effect. This suggests that there may be no reduction in serious maternal morbidity (average RR 0.47, 95% CI 0.22 to 1.00; four trials; 7028 women; moderate-certainty evidence). Most events occurred in one study from Ireland reporting high dependency unit admissions, whereas in the remaining three studies there was only one case of uvular oedema. There were no maternal deaths reported in any of the included studies (very low-certainty evidence). There is probably little or no difference in the risk of hypotension between intravenous and intramuscular administration of oxytocin (RR 1.01, 95% CI 0.88 to 1.15; four trials; 6468 women; moderate-certainty evidence). Subgroup analyses based on the mode of administration of intravenous oxytocin (bolus injection or infusion) versus intramuscular oxytocin did not show any substantial differences on the primary outcomes. Similarly, additional subgroup analyses based on whether oxytocin was used alone or as part of active management of the third stage of labour (AMTSL) did not show any substantial differences between the two routes of administration. Intravenous administration of oxytocin is more effective than its intramuscular administration in preventing PPH during vaginal birth. Intravenous oxytocin administration presents no additional safety concerns and has a comparable side effects profile with its intramuscular administration. Future studies should consider the acceptability, feasibility and resource use for the intervention, especially in low-resource settings.
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