What is the issue?
The most common reason why mothers die during childbirth is excessive bleeding, which is known as postpartum haemorrhage, when blood loss equals or exceeds 500 mL. This emergency condition is usually caused by failure of the uterus to contract and close the vessels that carried blood to the placenta. The World Health Organization (WHO) recommends giving drugs that make the uterus contract more effectively (uterotonic drugs) and reduce the risk for excessive bleeding. Although these drugs are given to the mother immediately after the birth of her baby, some women will still experience heavy bleeding and will require further treatment.
Why is this important?
The administration of uterotonic drugs is the main treatment when prevention fails, and excessive bleeding occurs. Available uterotonic treatments include oxytocin, carbetocin, ergometrine, misoprostol, injectable prostaglandins, and combinations of these drugs, which differ in terms of effectiveness and side-effects. The aim of this Cochrane Review is to identify the best drug with the least side-effects for treating excessive bleeding after childbirth.
What evidence did we find?
We searched for evidence in May 2020 and found seven studies involving 3738 women. Women gave birth mostly vaginally in hospital settings and had received uterotonic drugs to prevent postpartum haemorrhage. The drugs used for treating heavy bleeding in these studies were misoprostol (tablets dissolved under the tongue, pills or rectal suppositories), oxytocin (given into a vein or muscle), a combination of misoprostol with oxytocin and a combination of Syntometrine® (ergometrine plus oxytocin combination injected into muscle) with oxytocin.
Two studies, involving 1787 women, compared misoprostol with oxytocin for the initial treatment of excessive bleeding after birth. We found that misoprostol probably increases the risk of requiring a blood transfusion compared with oxytocin and may also increase the risk of suffering an additional blood loss of 1000 mL or more after initiation of treatment and until the bleeding stops. From the available data, we cannot learn much for the outcomes of suffering an additional blood loss of 500 mL or more, maternal death or severe illness related to excessive blood loss, and the need for additional uterotonic drugs to stop the bleeding. In terms of side-effects, misoprostol increases the risk for vomiting and may also increase the incidence of fever compared with oxytocin.
Four studies, involving 1881 women, compared misoprostol given in combination with oxytocin against oxytocin given alone. The drug combination makes little or no difference to the use of additional uterotonics, and blood transfusion compared with oxytocin given alone. However, we were not able to identify which of these drugs works best for reducing additional blood loss of 500 mL or more, additional blood loss of 1000 mL or more, and maternal death or severe illness related to excessive blood loss. In terms of side-effects, the drug combination increases the occurrence of both fever and vomiting.
One trial with only 64 women compared misoprostol with Syntometrine® combined with oxytocin. The available evidence was of very low certainty and thus we were unable to identify the best performing drug among them.
We also compared the combination of misoprostol and oxytocin against misoprostol alone. These drugs have not been compared directly in studies. However, both drugs have been compared against oxytocin, and thus we were able to compare them indirectly. The drug combination probably reduces the risk of blood transfusion and may reduce the risk of additional blood loss of 1000 mL or more, but makes little or no difference to vomiting compared with misoprostol alone. However, we cannot learn much for the outcomes of additional blood loss of 500 mL or more, maternal death or severe illness related to excessive blood loss, use of additional uterotonic drugs, and fever.
What does this mean?
We found that oxytocin is probably more effective than misoprostol and is also associated with less side-effects. Giving misoprostol together with oxytocin probably does not improve effectiveness and increases side-effects. The evidence for most available drugs used as first-line treatment of postpartum haemorrhage is limited, with no evidence found for several drugs currently in use.
The available evidence suggests that oxytocin used as first-line treatment of PPH probably is more effective than misoprostol with less side-effects. Adding misoprostol to the conventional treatment of oxytocin probably makes little or no difference to effectiveness outcomes, and is also associated with more side-effects. The evidence for most uterotonic agents used as first-line treatment of PPH is limited, with no evidence found for commonly used agents, such as injectable prostaglandins, ergometrine, and Syntometrine®.
Postpartum haemorrhage (PPH), defined as a blood loss of 500 mL or more after birth, is the leading cause of maternal death worldwide. The World Health Organization (WHO) recommends that all women giving birth should receive a prophylactic uterotonic agent. Despite the routine administration of a uterotonic agent for prevention, PPH remains a common complication causing one-quarter of all maternal deaths globally. When prevention fails and PPH occurs, further administration of uterotonic agents as 'first-line' treatment is recommended. However, there is uncertainty about which uterotonic agent is best for the 'first-line' treatment of PPH.
To identify the most effective uterotonic agent(s) with the least side-effects for PPH treatment, and generate a meaningful ranking among all available agents according to their relative effectiveness and side-effect profile.
We searched the Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (5 May 2020), and the reference lists of all retrieved studies.
All randomised controlled trials or cluster-randomised trials comparing the effectiveness and safety of uterotonic agents with other uterotonic agents for the treatment of PPH were eligible for inclusion.
Two review authors independently assessed all trials for inclusion, extracted data and assessed each trial for risk of bias. Our primary outcomes were additional blood loss of 500 mL or more after recruitment to the trial until cessation of active bleeding and the composite outcome of maternal death or severe morbidity. Secondary outcomes included blood loss-related outcomes, morbidity outcomes, and patient-reported outcomes. We performed pairwise meta-analyses and indirect comparisons, where possible, but due to the limited number of included studies, we were unable to conduct the planned network meta-analysis. We used the GRADE approach to assess the certainty of evidence.
Seven trials, involving 3738 women in 10 countries, were included in this review. All trials were conducted in hospital settings. Randomised women gave birth vaginally, except in one small trial, where women gave birth either vaginally or by caesarean section. Across the seven trials (14 trial arms) the following agents were used: six trial arms used oxytocin alone; four trial arms used misoprostol plus oxytocin; three trial arms used misoprostol; one trial arm used Syntometrine® (oxytocin and ergometrine fixed-dose combination) plus oxytocin infusion.
Pairwise meta-analysis of two trials (1787 participants), suggests that misoprostol, as first-line treatment uterotonic agent, probably increases the risk of blood transfusion (risk ratio (RR) 1.47, 95% confidence interval (CI) 1.02 to 2.14, moderate-certainty) compared with oxytocin. Low-certainty evidence suggests that misoprostol administration may increase the incidence of additional blood loss of 1000 mL or more (RR 2.57, 95% CI 1.00 to 6.64). The data comparing misoprostol with oxytocin is imprecise, with a wide range of treatment effects for the additional blood loss of 500 mL or more (RR 1.66, 95% CI 0.69 to 4.02, low-certainty), maternal death or severe morbidity (RR 1.98, 95% CI 0.36 to 10.72, low-certainty, based on one study n = 809 participants, as the second study had zero events), and the use of additional uterotonics (RR 1.30, 95% CI 0.57 to 2.94, low-certainty). The risk of side-effects may be increased with the use of misoprostol compared with oxytocin: vomiting (2 trials, 1787 participants, RR 2.47, 95% CI 1.37 to 4.47, high-certainty) and fever (2 trials, 1787 participants, RR 3.43, 95% CI 0.65 to 18.18, low-certainty).
According to pairwise meta-analysis of four trials (1881 participants) generating high-certainty evidence, misoprostol plus oxytocin makes little or no difference to the use of additional uterotonics (RR 0.99, 95% CI 0.94 to 1.05) and to blood transfusion (RR 0.95, 95% CI 0.77 to 1.17) compared with oxytocin. We cannot rule out an important benefit of using the misoprostol plus oxytocin combination over oxytocin alone, for additional blood loss of 500 mL or more (RR 0.84, 95% CI 0.66 to 1.06, moderate-certainty). We also cannot rule out important benefits or harms for additional blood loss of 1000 mL or more (RR 0.76, 95% CI 0.43 to 1.34, moderate-certainty, 3 trials, 1814 participants, one study reported zero events), and maternal mortality or severe morbidity (RR 1.09, 95% CI 0.35 to 3.39, moderate-certainty). Misoprostol plus oxytocin increases the incidence of fever (4 trials, 1866 participants, RR 3.07, 95% CI 2.62 to 3.61, high-certainty), and vomiting (2 trials, 1482 participants, RR 1.85, 95% CI 1.16 to 2.95, high-certainty) compared with oxytocin alone.
For all outcomes of interest, the available evidence on the misoprostol versus Syntometrine® plus oxytocin combination was of very low-certainty and these effects remain unclear.
Although network meta-analysis was not performed, we were able to compare the misoprostol plus oxytocin combination with misoprostol alone through the common comparator of oxytocin. This indirect comparison suggests that the misoprostol plus oxytocin combination probably reduces the risk of blood transfusion (RR 0.65, 95% CI 0.42 to 0.99, moderate-certainty) and may reduce the risk of additional blood loss of 1000 mL or more (RR 0.30, 95% CI 0.10 to 0.89, low-certainty) compared with misoprostol alone. The combination makes little or no difference to vomiting (RR 0.75, 95% CI 0.35 to 1.59, high-certainty) compared with misoprostol alone. Misoprostol plus oxytocin compared to misoprostol alone are compatible with a wide range of treatment effects for additional blood loss of 500 mL or more (RR 0.51, 95% CI 0.20 to 1.26, low-certainty), maternal mortality or severe morbidity (RR 0.55, 95% CI 0.07 to 4.24, low-certainty), use of additional uterotonics (RR 0.76, 95% CI 0.33 to 1.73, low-certainty), and fever (RR 0.90, 95% CI 0.17 to 4.77, low-certainty).