Reformulation of postnatal haemorrhage prophylaxis could save thousands in lower income countries

Postnatal haemorrhage (PNH) is the loss of at least 500ml of blood after birth. It remains the most common cause of maternal mortality worldwide, responsible for around 30% of deaths, and disproportionately affects low- and middle-income countries. The main cause of PNH is an atonic uterus, where the loss of uterine muscle tone promotes blood flow; however, retained placental tissue, clotting disorders and tearing are also causes (Weeks, 2015).

Oxytocin is the current gold standard for PNH prophylaxis due to its established efficacy and safety. It is usually administered directly after delivery to encourage uterine contraction, clamping the blood vessels which reduces the probability of excessive bleeding (Mousa et al., 2014). However, oxytocin must be stored and transported between 2?8°C as warmer temperatures degrade its efficacy, depriving women of the high-quality medicine they deserve. Ensuring the maintenance of the cold chain, from production to patient, is a challenging task, especially in remote areas of many developing countries where access to electricity or refrigeration may be sporadic at best (Widmer, 2018).

To help improve access to PNH prophylaxis, the World Health Organization (WHO), Merck for Mothers (a philanthropic initiative from Merck Sharp & Dohme) and Ferring Pharmaceuticals collaborated to explore the potential benefits of heat-stable carbetocin over the existing oxytocin therapy by setting up the CHAMPION clinical trial, the largest trial ever conducted in PNH (Ferring, 2018).

 

It will help to save many lives of mothers in lower income countries"

The results, published in the New England Journal of Medicine, demonstrated that heat-stable carbetocin, an analogue of oxytocin, is just as safe and effective as oxytocin for the prevention of PNH after vaginal birth. As the carbetocin doesn’t require a cold chain (it can be stored in 30°C heat and 75% humidity for 3 years), the logistical issues associated with refrigeration are removed, which ultimately means that a greater number of women could benefit from a more reliable and effective prophylaxis.

The trial studied nearly 30,000 women across 10 countries: Argentina, Egypt, India, Kenya, Nigeria, Singapore, South Africa, Thailand, Uganda and the United Kingdom. Either heat-stable carbetocin or oxytocin were randomly administered immediately after birth, with blood being collected for up to 2 hours following. The volume of blood loss was measured and patients characterised. Even though heat-stable carbetocin does not need to be refrigerated, both drugs were kept in cold storage to maintain double-blinding.

The results showed that heat-stable carbetocin demonstrated similar efficacy to oxytocin as a PNH prophylactic agent. The frequency of blood loss of at least 500 ml or the use of additional uterotonic agents was 14.5% in the carbetocin group and 14.4% in the oxytocin group, with blood loss of at least 1000 ml in 1.51% in the carbetocin group and 1.45% in the oxytocin group, demonstrating that carbetocin is not inferior to oxytocin.

Furthermore, the cold storage of oxytocin was maintained throughout the study, which may not be the case in the uncontrolled, real-world environment. This suggests that the trial results may have underestimated the benefit of carbetocin (Widmer, 2018).

“The development of a drug to prevent postpartum haemorrhage that continues to remain effective in hot and humid conditions is very good news for the millions of women who give birth in parts of the world without access to reliable refrigeration,” says Dr Metin Gülmezoglu from the Department of Reproductive Health and Research at the WHO. "It will help to save many lives of mothers in lower income countries where most deaths occur,” he added.

These results have led the WHO to review its guideline recommendations for the prevention of PNH.

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References

Ferring. Ferring Pharmaceuticals and MSD announce completion of largest clinical trial ever conducted in postpartum haemorrhage. 2018. Available from: https://www.ferring.com/en/media/press-releases/ferring-pharmaceuticals-and-msd-announce-completion-of-largest-clinical-trial-ever-conducted-in-postpartum-haemorrhage/ (accessed 28^th June 2018).

Mousa HA, Blum J, Senoun GAE, et al. Treatment for primary postpartum haemorrhage. Cochrane Database of Systematic Reviews. 2014;(2):CD003249.

Weeks, A. The prevention and treatment of postpartum haemorrhage: what do we know, and where do we go to next? BJOG. 2015;122:202?10.

Widmer M, Piaggio G, Nguyen TMH, et al. Heat-stable carbetocin versus oxytocin to prevent hemorrhage after vaginal birth. The New England Journal of Medicine. 2018 [Epub ahead of print].