Excessive bleeding after childbirth (postpartum haemorrhage; PPH) is a major concern for every pregnant woman. It can lead to long-term ill health and death. The World Health Organisation (WHO) recommends the uterus-contracting (‘uterotonic’) drug oxytocin for prevention of PPH. In high-income countries, oxytocin is given as standard practice to halve a woman’s risk of PPH but in LMIC oxytocin is often ineffective because it is heat labile (i.e. effectiveness reduced at higher temperatures) and facilities for refrigerated storage and transport are generally not available. PPH during childbirth kills around 100,000 mothers and 80,000 babies each year in LMIC. Lack of an effective uterotonic medication is a major contributor to high maternal mortality in these countries. A heat-stable alternative would be more effective and potentially save many lives.
There are at least seven uterotonic medicines for preventing PPH, including the heat-stable drug carbetocin. In 2015, the National Institute for Health Research (NIHR) funded Coomarasamy (principal investigator), Gallos, Roberts, Deeks and Price at the University of Birmingham (UoB) to identify the most effective uterotonic drug for preventing PPH with the fewest adverse effects, using network meta-analysis (NMA); a complex statistical method to analyse data for multiple treatments from multiple studies [R1].
The NMA compared multiple drugs in a single coherent analysis. Gallos was the principal reviewer and Price and Deeks were statisticians on the study. They designed the NMA methods using a reputable Cochrane protocol and performed the statistical analysis of 140 randomised controlled trials involving 88,947 women. They reported the following key finding in April 2018 [R2]:
KF1: Three uterotonic drugs, including carbetocin, are more effective for the prevention of PPH than oxytocin.
In 2017, WHO prioritised the update of their existing (2012) recommendations on the use of uterotonics for prevention of PPH. This was in order to inform changes to practice and to work toward reducing global maternal mortality by 2030, in line with target 3.1 of the third Sustainable Development Goal. WHO identified the detailed NMA [R2] in progress in Cochrane Library by the UoB researchers. They invited Gallos to serve on the Evidence Synthesis Group for the recommendations and asked the UoB team to update their NMA to include the new evidence from the CHAMPION trial [R3] and other recent trials relating to other uterotonics [S1(i), p.8]. The updated NMA, published in December 2018, included 196 randomised controlled trials conducted across 53 countries (across all income levels) and involving 134,414 women. The study provided effectiveness and safety estimates for each of the uterotonic agents, reported a ranking for each drug and described the following key findings [R4]:
KF3: Carbetocin is superior to oxytocin, preventing for all births (vaginal and caesarean section) one more PPH event out of three (30% reduction) without any greater undesirable effects.
KF4: Using carbetocin as the drug of choice worldwide, could save more than 4 million women from suffering PPH each year and reduce related complications including death that are a particularly significant risk for women in LMIC.
Heat-stable carbetocin has a higher unit cost than oxytocin (£17.64 vs. £0.91). To assess whether carbetocin could be recommended for general healthcare, its cost-effectiveness and affordability compared with other uterotonics had to be considered. Using pooled data from the NMA, Roberts developed a model-based cost-effectiveness analysis to compare from the perspective of the UK NHS as representative of a high-income country setting, the six different combinations of uterotonic drugs available [R5 & R6]. The study made the following key finding:
KF5: In developed countries, where the cost of PPH is high, carbetocin is the most cost-effective drug for the prevention of PPH.