Every six minutes, a mother dies from losing too much blood while giving birth. The tragedy is that this is almost always preventable. Research shows that 99% of maternal deaths occur in low- and middle-income countries (LMICs), with very few deaths in high-income countries like the UK.
Postpartum haemorrhage (PPH) is the world’s most common cause of maternal death, accounting for 27% of deaths - 99% of these deaths occur in LMICs. Research has also shown that the babies of mothers who die during childbirth have less than a 20% chance of surviving past their first month.
To prevent PPH, the routine administration of a uterus-contracting (‘uterotonic’) drug is standard practice across the world. Oxytocin is the most commonly used uterotonic drug for this purpose, and is recommended for all women giving birth. However, ensuring the quality of oxytocin is difficult, as it requires cold storage and refrigerated transport, often not available in LMICs. Hence, using a heat-stable medicine is tremendously advantageous in these settings for preventing maternal deaths from PPH.
There are several uterotonic drugs available for preventing PPH. Some of these drugs are heat-stable and do overcome the difficulties with cold storage and refrigerated transport. However, there used to be uncertainty about which drug was most effective with the least side-effects. In 2015, researchers from the University of Birmingham were awarded a grant by the National Institute for Health Research to carry out an evidence synthesis programme, with network meta-analysis, to identify which drug is most effective in preventing PPH with the best side-effect profile. The ‘network meta-analysis’ is an innovative type of evidence synthesis that allows comparisons of multiple drugs in a single, coherent analysis from all the available studies. The results, published in the Cochrane library, suggested that three uterotonic drugs, including the heat-stable drug carbetocin, were more effective than oxytocin, the medicine currently recommended by the World Health Organization (WHO).
In 2018, following the publication of the results of a large WHO-led trial (heat-stable carbetocin versus oxytocin), the UK arm of which was led by the University of Birmingham, university researchers were invited to lead the evidence synthesis on the effectiveness and safety of the uterotonics for prevention of PPH for the WHO to update their recommendations.
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Based on the available evidence, WHO stated that for settings where oxytocin is not available or its quality cannot be guaranteed, the use of other injectable uterotonics, including carbetocin, is recommended for the prevention of PPH. The evidence was also strong enough for carbetocin to be included in the WHO Model List of Essential Medicines, which consists of the most effective and safe medicines to meet the most important needs of a health system.
WHO, however, does note that carbetocin must be comparable in price to oxytocin. For LMICs, Ferring Pharmaceuticals and Merck signed a memorandum with WHO to make heat-stable carbetocin available in public sector facilities of high-burden countries at an affordable price (comparable to the United Nations Population Fund [UNFPA] price for the current standard, oxytocin). This price is subsidised at $0.31 +/- 10% per ampoule of heat-stable carbetocin (the UNFPA current price of Oxytocin is $0.27 per unit). Carbetocin is currently being registered in 90 LMICs, which will improve access to this life-saving uterotonic medicine. The universal use of carbetocin could save more than 4 million women every year from suffering PPH and related complications, including death.
Despite an effective prevention medicine, millions of women will still suffer PPH. It is a common complication of childbirth, affecting one in ten women giving birth, even when healthcare providers administer oxytocin or carbetocin to prevent it. Women often go on to bleed excessively before the complication is recognised and treated.
Arri Coomarasamy, Professor of Gynaecology & Reproductive Medicine at the University of Birmingham and the Joint Director of the WHO Collaborating Centre for Global Women’s Health, is clear on the scale of the global public health challenge faced by healthcare professionals. “High-quality childbirth care is available for mothers in countries like the UK where tried and tested methods for dealing with severe bleeding after birth are applied consistently. Yet, for women in LMICs, delayed detection and inconsistent treatment make PPH highly dangerous. Early detection and effective treatment could make the difference between life and death.”
Sparked by this global public health challenge, researchers at Birmingham are leading a global effort to tackle bleeding after childbirth, called the E-MOTIVE programme. The E-MOTIVE study is supported by the Institute of Global Innovation of the University of Birmingham and a $10.9M grant from the Bill & Melinda Gates Foundation. The E-MOTIVE programme is exploring a package of interventions that could save mothers around the world. The aim is to implement an early detection strategy and a ‘first response’ bundle of care for cutting down deaths and complications related to PPH by 25%. The programme will use a robust implementation strategy that focusses on simulation-based training, peer-assisted learning and local champions. The E-MOTIVE team will work with international partners and co-ordinating centres in Kenya, Tanzania, Nigeria, South Africa, and Sri Lanka to test the E-MOTIVE intervention in a large randomised trial across 80 health facilities, involving over 300,000 women. The trial is focussing in women giving birth vaginally, but the team will also develop a similar strategy for women giving birth by caesarean section.
The researchers are optimistic and believe that for most women, if healthcare providers detect the problem early and treat it efficiently, the bleeding will stop and the mother will be safe. If, however, the treatment does not succeed and a woman continues to bleed despite the first response treatment, then her life is at risk. This condition is called refractory PPH and would now require life-saving specialist treatment and invasive surgical procedures to ensure survival of the mother. The Birmingham team are also developing, with funding from the Medical Research Council in the UK, a provisional management package for these women who continue to bleed despite first response treatment. This programme, called the 'PPH ReAct' package, is due to be field-tested and piloted in five health facilities in Nigeria.
Dr Ioannis Gallos, from the Institute of Metabolism and Systems Research at the University of Birmingham stressed the importance of defining the optimal approach for managing refractory PPH. “There is an unmet need to define the optimal approach for managing refractory PPH. A management approach could achieve its intended goals only if it is widely accepted and used in everyday practice. Our work is therefore co-developed, implemented and evaluated with strong local partnerships from various LMICs. This is important to ensure meaningful and sustainable solutions to this problem that relentlessly kills a mother every 6 minutes somewhere in the world.”
Professor Arri Coomarasamy
Professor of Gynaecology and Reproductive Medicine
Professor Coomarasamy has published over 190 medical articles in high impact journals such as the New England Journal of Medicine, the Lancet, the British Medical Journal and the Cochrane Database of Systematic Reviews.
Dr Ioannis Gallos
Senior Lecturer in Global Maternal Health
Ioannis has carried out the first network meta-analysis in O&G within Cochrane with cost-effectiveness analysis for identifying the most effective and cost-effective uterotonic agents for preventing postpartum haemorrhage in collaboration with the World Health Organisation.
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