Key messages
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Most medications (uterotonics) to prevent excessive blood loss after childbirth (postpartum haemorrhage (PPH)) are more effective than no treatment.
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Ergometrine plus oxytocin, and misoprostol plus oxytocin are most effective compared with oxytocin (standard treatment).
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All uterotonics, except for carbetocin, are associated with an increased risk of unwanted effects compared with oxytocin.
What is postpartum haemorrhage, and how is it treated?
Postpartum haemorrhage (PPH) is excessive blood loss, of more than 500 mL, in the first 24 hours after childbirth. It is the most common reason mothers die in childbirth worldwide. Treatments, such as blood transfusion or hysterectomy, are a burden on women's health and health services. To reduce the risk of PPH, clinicians often give medication to make the uterus (womb) contract - a uterotonic. Uterotonics include oxytocin, misoprostol, ergometrine, carbetocin, injectable prostaglandins and combinations of these medications. They may cause unwanted effects, including nausea, vomiting, diarrhoea and fever. Oxytocin is currently recommended as the standard medication to reduce the risk of PPH.
What did we want to find out?
We aimed to find out which uterotonic is most effective in preventing PPH and has the fewest unwanted effects. We were interested in how well they prevented blood loss (more than 500 mL and more than 1000 mL); whether additional uterotonics or a blood transfusion were needed; and unwanted effects.
What did we do?
We collected and analysed all the relevant, trustworthy studies that investigated uterotonics to prevent PPH.
What did we find?
We found 122 studies involving 121,931 women, in 48 countries. Most women gave birth normally (vaginally), in hospital.
All uterotonics are more effective in preventing blood loss than placebo (sham medicine) or no treatment. We are not sure about injectable prostaglandins and ergometrine because we did not find much evidence about them. The two most effective uterotonics were ergometrine plus oxytocin, and misoprostol plus oxytocin.
Blood loss of 500 mL or more
Based on our results, for vaginal birth, 83 women in 1000 given oxytocin would experience blood loss of 500 mL or more.
Compared with oxytocin:
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ergometrine plus oxytocin reduces the likelihood of blood loss of 500 mL or more. Of 1000 women having a vaginal birth, 63 given ergometrine plus oxytocin would experience blood loss of 500 mL or more;
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misoprostol plus oxytocin probably reduces the likelihood of blood loss of 500 mL or more. Of 1000 women having a vaginal birth, 58 given misoprostol plus oxytocin would experience blood loss of 500 mL or more;
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carbetocin makes little or no difference; injectable prostaglandins and ergometrine probably make little or no difference. We are uncertain about the effects of misoprostol.
Blood loss of 1000 mL or more
Based on our results, for vaginal birth, 24 women in 1000 given oxytocin would experience blood loss of 1000 mL or more.
Compared with oxytocin:
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carbetocin and injectable prostaglandins probably, and misoprostol plus oxytocin may make little to no difference;
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misoprostol may be less effective than oxytocin; 30 of 1000 women having a vaginal birth given misoprostol may experience blood loss of 1000 mL or more;
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we are uncertain about the effects of ergometrine, and ergometrine plus oxytocin.
Other results
Compared with oxytocin:
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misoprostol plus oxytocin probably reduces the need for additional uterotonics and the need for blood transfusion;
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carbetocin probably makes little or no difference to the need for blood transfusion;
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we are less sure about the other medications.
Unwanted effects
Compared with oxytocin:
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misoprostol probably increases the likelihood of diarrhoea and may increase the likelihood of nausea, vomiting and fever;
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injectable prostaglandins may increase the likelihood of diarrhoea;
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ergometrine probably increases the likelihood of nausea and vomiting, and may increase the likelihood of high blood pressure, headache and diarrhoea;
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ergometrine plus oxytocin may increase the likelihood of nausea, vomiting and diarrhoea;
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misoprostol plus oxytocin probably increases the likelihood of nausea, vomiting and diarrhoea, and may increase the likelihood of fever;
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carbetocin was associated with few unwanted effects.
We found similar results whether women gave birth normally or by caesarean section, in hospital or in the community, were at high or low risk for PPH, received a high or low dose of misoprostol, and whether they received one single large injection or an infusion (drip) of oxytocin, or both.
What are the limitations of the evidence?
We found little information about home births or about women giving birth by caesarean section, or who had other illnesses and who were at high risk of having PPH. We did not differentiate between the different doses and methods of giving the different uterotonics. Not all the studies provided information about unwanted effects, and they used different methods to measure blood loss.
How up to date is the evidence?
This evidence is up to date until 5 February 2024.
Most agents are effective for preventing PPH when compared with placebo or no treatment. Ergometrine plus oxytocin, and misoprostol plus oxytocin may be more effective than the current standard oxytocin. All agents, except for carbetocin, are associated with an increased risk of some side effects compared with oxytocin.
Postpartum haemorrhage (PPH) is the leading cause of maternal mortality worldwide. Prophylactic uterotonic agents can prevent PPH, and are routinely recommended. The current World Health Organization (WHO) recommendation for preventing PPH is 10 IU (international units) of intramuscular or intravenous oxytocin. There are several uterotonic agents for preventing PPH but there is still uncertainty about which agent is most effective with the least side effects. This is an update of a Cochrane Review which was first published in April 2018 and was updated to incorporate results from a recent large WHO trial.
To identify the most effective uterotonic agent(s) to prevent PPH with the fewest side effects, and generate a ranking according to their effectiveness and side effect profile.
On 5 February 2024, we searched CENTRAL, MEDLINE, Embase and CINAHL in collaboration with the Cochrane Information Specialist.
All randomised controlled trials or cluster-randomised trials comparing the effectiveness and side effects of uterotonic agents with other uterotonic agents, placebo or no treatment for preventing PPH were eligible for inclusion. Quasi-randomised trials were excluded. Randomised trials published only as abstracts were eligible if sufficient information could be retrieved.
At least three review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We estimated the relative effects and rankings for preventing PPH ≥ 500 mL and PPH ≥ 1000 mL as primary outcomes. Secondary outcomes included blood loss and related outcomes, morbidity outcomes, maternal well-being and satisfaction and side effects. Primary outcomes were also reported for pre-specified subgroups, stratifying by mode of birth, prior risk of PPH, healthcare setting, dosage, regimen and route of administration. We performed pairwise meta-analyses and network meta-analysis to determine the relative effects and rankings of all available agents.
The network meta-analysis included 196 trials (135,559 women) involving seven uterotonic agents and placebo or no treatment, conducted across 53 countries (including high-, middle- and low-income countries). Most trials were performed in a hospital setting (187/196, 95.4%) with women undergoing a vaginal birth (71.5%, 140/196).
Relative effects from the network meta-analysis suggested that all agents were effective for preventing PPH ≥ 500 mL when compared with placebo or no treatment. The three highest ranked uterotonic agents for prevention of PPH ≥ 500 mL were ergometrine plus oxytocin combination, misoprostol plus oxytocin combination and carbetocin. There is evidence that ergometrine plus oxytocin (RR 0.70, 95% CI 0.59 to 0.84, moderate certainty), carbetocin (RR 0.72, 95% CI 0.56 to 0.93, moderate certainty) and misoprostol plus oxytocin (RR 0.70, 95% CI 0.58 to 0.86, low certainty) may reduce PPH ≥ 500 mL compared with oxytocin. Low-certainty evidence suggests that misoprostol, injectable prostaglandins, and ergometrine may make little or no difference to this outcome compared with oxytocin.
All agents except ergometrine and injectable prostaglandins were effective for preventing PPH ≥ 1000 mL when compared with placebo or no treatment. High-certainty evidence suggests that ergometrine plus oxytocin (RR 0.83, 95% CI 0.66 to 1.03) and misoprostol plus oxytocin (RR 0.88, 95% CI 0.70 to 1.11) make little or no difference in the outcome of PPH ≥ 1000 mL compared with oxytocin. Low-certainty evidence suggests that ergometrine may make little or no difference to this outcome compared with oxytocin meanwhile the evidence on carbetocin was of very low certainty. High-certainty evidence suggests that misoprostol is less effective in preventing PPH ≥ 1000 mL when compared with oxytocin (RR 1.19, 95% CI 1.01 to 1.42). Despite the comparable relative treatment effects between all uterotonics (except misoprostol) and oxytocin, ergometrine plus oxytocin, misoprostol plus oxytocin combinations and carbetocin were the highest ranked agents for PPH ≥ 1000 mL.
Misoprostol plus oxytocin reduces the use of additional uterotonics (RR 0.56, 95% CI 0.42 to 0.73, high certainty) and probably also reduces the risk of blood transfusion (RR 0.51, 95% CI 0.37 to 0.70, moderate certainty) when compared with oxytocin. Carbetocin, injectable prostaglandins and ergometrine plus oxytocin may also reduce the use of additional uterotonics but the certainty of the evidence is low. No meaningful differences could be detected between all agents for maternal deaths or severe morbidity as these outcomes were rare in the included randomised trials where they were reported.
The two combination regimens were associated with important side effects. When compared with oxytocin, misoprostol plus oxytocin combination increases the likelihood of vomiting (RR 2.11, 95% CI 1.39 to 3.18, high certainty) and fever (RR 3.14, 95% CI 2.20 to 4.49, moderate certainty). Ergometrine plus oxytocin increases the likelihood of vomiting (RR 2.93, 95% CI 2.08 to 4.13, moderate certainty) and may make little or no difference to the risk of hypertension, however absolute effects varied considerably and the certainty of the evidence was low for this outcome.
Subgroup analyses did not reveal important subgroup differences by mode of birth (caesarean versus vaginal birth), setting (hospital versus community), risk of PPH (high versus low risk for PPH), dose of misoprostol (≥ 600 mcg versus < 600 mcg) and regimen of oxytocin (bolus versus bolus plus infusion versus infusion only).
Supported by UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), a cosponsored programme executed by the WHO (Award No. HQHRP2220228-22.1-74309).
Cochrane Library; Registration number: CD011689 and protocol [and previous versions] available via DOI: 10.1002/14651858.CD011689 [DOI: 10.1002/14651858.CD011689.pub3 and DOI: 10.1002/14651858.CD011689.pub2]