We set out to look for evidence from randomised controlled trials on the effectiveness and safety of oxytocin injected into a vein, compared with injection into muscle, to prevent excessive bleeding immediately after vaginal birth.
What is the issue?
Most maternal deaths occur within the first 24 hours after delivery. Up to one-fourth of them are caused by excessive bleeding (called postpartum haemorrhage). In low-income countries, drugs to prevent or treat postpartum haemorrhage (uterotonics) are not always available. Oxytocin is one such drug. Oxytocin prevents excessive postpartum bleeding by helping the uterus to contract. It is given to the mother by injection into a vein or into muscle during or immediately after the birth of her baby.
Why is this important?
Blood loss after the birth of the baby depends on how quickly the placenta separates from the uterus and how well the uterus contracts to close the blood vessels that carried blood to the placenta.
Oxytocin given directly into a vein has an almost immediate effect which lasts for a relatively short time. When injected into muscle, oxytocin takes a few minutes to act, but the effect is longer-lasting. Giving injections into a vein requires special skills and sterile equipment that may not always be available. In contrast, injection into muscle is quick and requires relatively less skill.
Oxytocin injected into a vein may sometimes cause serious side effects, such as a sudden drop in blood pressure, especially when given rapidly in a small amount of solution (undiluted).
What evidence did we find?
We searched for evidence from randomised controlled trials on 19 December 2019 and identified seven studies (involving 7817 women). The studies compared oxytocin injected into a vein with injection into muscle during or immediately after the vaginal birth of the baby. All studies were conducted in hospitals and mostly recruited women giving birth vaginally to one baby at term. In all but two studies, both women and hospital staff were aware of how the oxytocin was given. This may have had an impact on results. Overall, the included studies were at moderate or low risk of bias, and the certainty of the generated evidence was generally moderate to high.
We found that women receiving oxytocin through a vein were at lower risk for blood loss of 500 mL or more (six trials; 7731 women) and blood transfusion (four trials; 6684 women) compared with women receiving oxytocin into muscle. There was high-certainty evidence for both of these outcomes. The administration of oxytocin through a vein probably reduced the risk for severe blood loss of 1000 mL or more, compared with oxytocin into muscle (four trials; 6681 women; moderate-certainty evidence). The two highest-quality studies (1512 women) found that oxytocin injection into a vein reduced the risk for blood loss of 1000 mL or more, compared with oxytocin injection into muscle. Although the two ways of giving oxytocin may have been similar in terms of women requiring additional medications to contract the uterus, we have little confidence in these results (six trials; 7327 women; low-certainty evidence). Both routes of oxytocin were safe with probably same number of women experiencing side effects, including low blood pressure (four trials; 6468 women; moderate-certainty evidence). Probably fewer women receiving oxytocin through a vein experienced serious complications related to excessive bleeding, such as admission to intensive care, loss of consciousness, or organ failure (four trials; 7028 women; moderate-certainty evidence). No mother died in any of the included studies.
The studies did not report on women's and health personnel's satisfaction with either route of oxytocin administration.
What does this mean?
Oxytocin is more effective when given through a vein than oxytocin injected into muscle for preventing excessive bleeding soon after vaginal birth. Giving oxytocin into a vein did not cause additional safety concerns and had similar side effects compared with oxytocin injected into muscle. Future studies need to consider the acceptability of the two different ways of giving oxytocin to women and healthcare providers as important study outcomes. It is also important to investigate whether the benefits of giving oxytocin into a vein outweigh the higher cost.
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.
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.