Postpartum haemorrhage (PPH) is the leading cause of maternal mortality worldwide.
Prophylactic uterotonic drugs can prevent PPH, and are routinely recommended. There
are several uterotonic drugs for preventing PPH but it is still debatable which drug
is best. To identify the most effective uterotonic drug(s) to prevent PPH, and generate
a ranking according to their effectiveness and side‐effect profile. We searched Cochrane
Pregnancy and Childbirth’s Trials Register (1 June 2015), ClinicalTrials.gov and
the World Health Organization (WHO) International Clinical Trials Registry Platform
( ICTRP ) for unpublished trial reports (30 June 2015) and reference lists of retrieved
studies. All randomised controlled comparisons or cluster trials of effectiveness
or side‐effects of uterotonic drugs for preventing PPH. Quasi‐randomised trials and
cross‐over trials are not eligible for inclusion in this review. 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. We performed pairwise
meta‐analyses and network meta‐analysis to determine the relative effects and rankings
of all available drugs. We stratified our primary outcomes according to mode of birth,
prior risk of PPH, healthcare setting, dosage, regimen and route of drug administration,
to detect subgroup effects.The absolute risks in the oxytocin are based on meta‐analyses
of proportions from the studies included in this review and the risks in the intervention
groups were based on the assumed risk in the oxytocin group and the relative effects
of the interventions. This network meta‐analysis included 140 randomised trials with
data from 88,947 women. There are two large ongoing studies. The trials were mostly
carried out in hospital settings and recruited women who were predominantly more than
37 weeks of gestation having a vaginal birth. The majority of trials were assessed
to have uncertain risk of bias due to poor reporting of study design. This primarily
impacted on our confidence in comparisons involving carbetocin trials more than other
uterotonics. The three most effective drugs for prevention of PPH ≥ 500 mL were ergometrine
plus oxytocin combination, carbetocin, and misoprostol plus oxytocin combination.
These three options were more effective at preventing PPH ≥ 500 mL compared with oxytocin,
the drug currently recommended by the WHO (ergometrine plus oxytocin risk ratio (RR)
0.69 (95% confidence interval (CI) 0.57 to 0.83), moderate‐quality evidence; carbetocin
RR 0.72 (95% CI 0.52 to 1.00), very low‐quality evidence; misoprostol plus oxytocin
RR 0.73 (95% CI 0.60 to 0.90), moderate‐quality evidence). Based on these results,
about 10.5% women given oxytocin would experience a PPH of ≥ 500 mL compared with
7.2% given ergometrine plus oxytocin combination, 7.6% given carbetocin, and 7.7%
given misoprostol plus oxytocin. Oxytocin was ranked fourth with close to 0% cumulative
probability of being ranked in the top three for PPH ≥ 500 mL. The outcomes and rankings
for the outcome of PPH ≥ 1000 mL were similar to those of PPH ≥ 500 mL. with the evidence
for ergometrine plus oxytocin combination being more effective than oxytocin (RR 0.77
(95% CI 0.61 to 0.95), high‐quality evidence) being more certain than that for carbetocin
(RR 0.70 (95% CI 0.38 to 1.28), low‐quality evidence), or misoprostol plus oxytocin
combination (RR 0.90 (95% CI 0.72 to 1.14), moderate‐quality evidence) There were
no meaningful differences between all drugs for maternal deaths or severe morbidity
as these outcomes were so rare in the included randomised trials. Two combination
regimens had the poorest rankings for side‐effects. Specifically, the ergometrine
plus oxytocin combination had the higher risk for vomiting (RR 3.10 (95% CI 2.11 to
4.56), high‐quality evidence; 1.9% versus 0.6%) and hypertension [RR 1.77 (95% CI
0.55 to 5.66), low‐quality evidence; 1.2% versus 0.7%), while the misoprostol plus
oxytocin combination had the higher risk for fever (RR 3.18 (95% CI 2.22 to 4.55),
moderate‐quality evidence; 11.4% versus 3.6%) when compared with oxytocin. Carbetocin
had similar risk for side‐effects compared with oxytocin although the quality evidence
was very low for vomiting and for fever, and was low for hypertension. Ergometrine
plus oxytocin combination, carbetocin, and misoprostol plus oxytocin combination were
more effective for preventing PPH ≥ 500 mL than the current standard oxytocin. Ergometrine
plus oxytocin combination was more effective for preventing PPH ≥ 1000 mL than oxytocin.
Misoprostol plus oxytocin combination evidence is less consistent and may relate to
different routes and doses of misoprostol used in the studies. Carbetocin had the
most favourable side‐effect profile amongst the top three options; however, most carbetocin
trials were small and at high risk of bias. Amongst the 11 ongoing studies listed
in this review there are two key studies that will inform a future update of this
review. The first is a WHO‐led multi‐centre study comparing the effectiveness of a
room temperature stable carbetocin versus oxytocin (administered intramuscularly)
for preventing PPH in women having a vaginal birth. The trial includes around 30,000
women from 10 countries. The other is a UK‐based trial recruiting more than 6000 women
to a three‐arm trial comparing carbetocin, oxytocin and ergometrine plus oxytocin
combination. Both trials are expected to report in 2018. Consultation with our consumer
group demonstrated the need for more research into PPH outcomes identified as priorities
for women and their families, such as women’s views regarding the drugs used, clinical
signs of excessive blood loss, neonatal unit admissions and breastfeeding at discharge.
To date, trials have rarely investigated these outcomes. Consumers also considered
the side‐effects of uterotonic drugs to be important but these were often not reported.
A forthcoming set of core outcomes relating to PPH will identify outcomes to prioritise
in trial reporting and will inform futures updates of this review. We urge all trialists
to consider measuring these outcomes for each drug in all future randomised trials.
Lastly, future evidence synthesis research could compare the effects of different
dosages and routes of administration for the most effective drugs. What is the issue?
The aim of this Cochrane review was to find out which drug is most effective in preventing
excessive blood loss at childbirth and has the least side‐effects. We collected and
analysed all the relevant studies to answer this question. Why is this important?
Bleeding after birth is the most common reason why mothers die in childbirth worldwide.
Although most healthy women can cope well with some bleeding at childbirth, others
do not, and this can pose a serious risk to their health and even life. To reduce
excessive bleeding at childbirth, the routine administration of a drug to contract
the uterus (uterotonic) has become standard practice across the world. The aim of
this research was to identify which drug is most effective in preventing excessive
bleeding after childbirth with the least side‐effects. Different drugs given routinely
at childbirth have been used for preventing excessive bleeding. They include oxytocin,
misoprostol, ergometrine, carbetocin, and combinations of these drugs, each with different
effectiveness and side‐effects. Some of the side‐effects identified include: vomiting,
high blood pressure and fever. We analysed all the available evidence to compare all
of these drugs and calculated a ranking among them, providing robust effectiveness
and side‐effect profiles for each drug. What evidence did we find? We searched for
evidence in June 2015 and found 140 studies involving a total of 88,947 women. The
results suggest that an ergometrine plus oxytocin combination, carbetocin, and a misoprostol
plus oxytocin combination are the most effective drugs for preventing excessive bleeding
after childbirth and are more effective than the drug oxytocin currently recommended
by the World Health Organization (WHO). However, ergometrine plus oxytocin and misoprostol
plus oxytocin were the worst drugs for side‐effects, with carbetocin having the most
favourable side‐effect profile (less vomiting, high blood pressure and fever). More
effective drugs could probably prevent one out of three women from bleeding excessively
after childbirth compared to oxytocin. However, existing carbetocin studies were small
and of poor quality. What does this mean? We found that ergometrine plus oxytocin,
misoprostol plus oxytocin, and carbetocin were more effective drugs for reducing excessive
bleeding at childbirth than oxytocin which is the current standard drug used to prevent
this condition. Carbetocin has the least side‐effects among the top three drug options,
but to date studies of carbetocin were small and of poor quality. There are some ongoing
studies that are not yet complete, including two key studies. One is a large study
(involving around 30,000 women across 10 different countries) comparing the effectiveness
of carbetocin versus oxytocin for preventing PPH among women having a vaginal birth.
The other is a UK‐based trial (involving more than 6000 women) comparing carbetocin,
oxytocin and ergometrine plus oxytocin combination. Both trials are expected to report
in 2018 and these results will be incorporated when this review is updated. Consultation
with our consumer group has demonstrated a need for more research into PPH outcomes
identified as priorities for women and their families, such as women’s views regarding
the drugs used, clinical signs of excessive blood loss, neonatal unit admissions and
breastfeeding at discharge. Trials to date have rarely investigated these outcomes.
Consumers also considered the side‐effects of uterotonic drugs to be important and
these were often not reported. A set of standardised PPH outcomes are being developed
and will be incorporated in future updates of this review. We would hope that future
trials would also consider adopting those outcomes. Finally, future systematic reviews
could compare the effects of different doses and ways of administering the most effective
drugs.