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Cochrane Review identifies alternative drugs better to prevent PPH

New evidence from a Cochrane Review, led by a University of Birmingham scientist, suggests that alternative drugs may be more effective than the standard drug currently used to stop postpartum haemorrhage (PPH).

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 uterotonic drug called Oxytocin which contracts the uterus has become standard practice across the world.

In this study, researchers from the Cochrane Pregnancy and Childbirth Group have reviewed the data of the births of 88,000 women who took part in 140 randomised trials, with the aim of identifying which uterotonics (including oxytocin, as well as misoprostol, ergometrine, carbetocin or combinations of these) are most effective in preventing excessive bleeding after childbirth and have the least side-effects.

The Cochrane Review found that ergometrine plus oxytocin; misoprostol plus oxytocin; and carbetocin on its own, were more effective drugs for reducing excessive bleeding at childbirth rather than the current standard use of oxytocin on its own.

The team analysed all the available evidence to compare all of the drugs and calculated a ranking among them, providing robust effectiveness and side-effect profiles for each drug. Side-effects can include vomiting, high blood pressure and fever.

University of Birmingham clinician scientist Dr Ioannis Gallos, of the Cochrane Pregnancy and Childbirth Group and review author, said: "Whilst death from postpartum haemorrhage is a rare complication, it is the most common reason why mothers die in childbirth worldwide and happens because a woman's womb has not contracted strongly enough after birth and results in excessive bleeding.

"Currently, to reduce excessive bleeding at childbirth, the standard practice across the world is to administer to women after childbirth a drug called oxytocin – uterotonic which contracts the uterus and stimulates contractions to help push out the placenta.

"However, there are a number of other uterotonics and combinations of these drugs that can be given that may be more effective.

"By analysing data from 140 different clinical trials involving over 88,000 women, we have been able to use the evidence more efficiently to compare all of these drugs and calculate a ranking among them, providing robust effectiveness and side-effect profiles for each drug.

"Our research has highlighted which drugs may be more effective than oxytocin and we hope that this could impact existing recommendations and save mothers lives worldwide."

This Cochrane review is expected to be updated later this year to incorporate the results of some key ongoing studies which will report their findings in coming months, including a large study involving around 30,000 women across 10 different countries comparing the effectiveness of carbetocin versus oxytocin for preventing bleeding in women having a vaginal birth, and a UK-based trial involving more than 6,000 women comparing carbetocin, oxytocin and ergometrine plus oxytocin combination.

Background: 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.
Objectives: To identify the most effective uterotonic drug(s) to prevent PPH, and generate a ranking according to their effectiveness and side-effect profile.
Search methods: 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.
Selection criteria: 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.
Data collection and analysis: 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.
Main results: 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.
Authors' conclusions: 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.

Ioannis D Gallos, Helen M Williams, Malcolm J Price, Abi Merriel, Harold Gee, David Lissauer, Vidhya Moorthy, Aurelio Tobias, Jonathan J Deeks, Mariana Widmer, Özge Tunçalp, Ahmet Metin Gülmezoglu, G Justus Hofmeyr, Arri Coomarasamy

[link url="https://www.birmingham.ac.uk/news/latest/2018/04/childbirth-bleeding-drugs-cochrane-review.aspx"]University of Birmingham material[/link]
[link url="http://cochranelibrary-wiley.com/doi/10.1002/14651858.CD011689.pub2/abstract;jsessionid=2039827BEB3497679CD359302F313979.f02t02"]Cochrane Database of Systemic Reviews abstract[/link]

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