KATHMANDU, Nepal — Each year, around 70,000 women die due to excessive bleeding after childbirth, known as postpartum hemorrhage, or PPH. Despite a 44 percent reduction in global maternal mortality since 1990, PPH remains a contributor to the leading direct cause of maternal deaths — almost all of which occur in developing countries.
Most of these deaths are preventable. Oxytocin is the drug of choice against PPH, administered immediately after childbirth. The injectable uterotonic works by helping the uterus contract quickly, thereby reducing the risk of bleeding.
The Q-Mat indicates when a woman is experiencing dangerous levels of PPH. But one of the main challenges to the innovation's effectiveness is the lack of expertise in treating PPH at many small facilities.
But the drug has a major failing: It needs to be transported and stored between 2-8 degrees Celsius. This makes it challenging to use in areas that need it most, where power supply and infrastructure issues can make delivery all but impossible. The drug’s sensitivity to heat means that countless women don’t get the life-saving drug after childbirth — even once administered, the drug may fail to work.
A new, heat-stable uterotonic called carbetocin could have the potential to save tens of thousands of women’s lives in developing countries who would otherwise die from PPH.
Working in partnership
In 2013, the World Health Organization was approached by MSD for Mothers, a philanthropic initiative of MSD, as well as Ferring Pharmaceuticals, to explore the potential carbetocin — an oxytocin analog — had in reducing the incidence of maternal deaths by preventing PPH.
Unlike oxytocin, heat-stable carbetocin has one very clear advantage: It does not require refrigerated storage or transport.
The heat-stable carbetocin trial, led by WHO, looked at 29,645 women who gave birth vaginally in 10 places: Britain, Argentina, Egypt, India, Kenya, Singapore, Nigeria, South Africa, Thailand, and Uganda between July 2015 and January this year. Each woman was randomized to receive either a single injection of heat-stable carbetocin or oxytocin, immediately after giving birth. The results, published in August, found that both drugs were equally effective in preventing PPH, which is defined as a blood loss of 500ml or more within 24 hours of birth.
A. Metin Gülmezoglu, coordinator for the maternal and perinatal health and preventing unsafe abortion team at WHO, said the drug was an exciting alternative to oxytocin.
“Heat-stable carbetocin can be kept at 36 degrees Celsius for three years,” said Gülmezoglu, who was involved with the study, known as the WHO CHAMPION Trial Group.
“That is a huge advantage when you are dealing with a periphery level health system where you have frequent power outages and where managing a cold chain is more problematic. I think having a heat-stable and quality-assured uterotonic for PPH prevention will have a significant impact in countries like India where hemorrhage-related deaths are still one of the major causes of maternal deaths,” he said.
The drug can also survive for six months at 40 degrees and three months at 50 degrees, Gülmezoglu added.
Jeffrey Smith, vice president of technical leadership at Jhpiego — an international non-profit organization focused on reducing maternal deaths — agreed.
“If a drug like carbetocin can sit on the shelf and remain stable for a prolonged period and be as effective as oxytocin, then it really does have the potential to change how providers prevent PPH,” Smith, an obstetrician-gynecologist, said.
He envisioned the drug would be most beneficial in countries where drug delivery systems faced monumental challenges, including those affected by conflict and disease outbreaks.
“In West Africa where health systems are weak and when a crisis like Ebola makes fragile health systems even more challenged … that’s where having stocks of drugs available becomes critically important,” Smith said.
A push for accessibility
The development of a new drug inevitably raises myriad questions. How much will it cost? And will it be accessible and affordable to those who need it?
Suresh Pattathil, CEO of Ferring India, one of the three countries where the drug is being manufactured, said the company was working to make the drug as affordable as possible to 90 low-income countries.
“Part of the agreement [with MSD and WHO] was that if the trial comes out with positive results, then Ferring would supply the drug for the public market at a price which is very low,” he said. “It’s still being determined but it’s almost at the same price as the manufacturing price.”
He added that Ferring would rely on private sector sales to generate revenue but stressed its aim was to enable “as many women to benefit from carbetocin as possible” not to “generate huge revenue.”
Meanwhile, WHO is in the process of updating its 2012 recommendations for the prevention and treatment of PPH, which is expected to be released by the end of the year. Gülmezoglu expects heat-stable carbetocin to be added to the list of recommended drugs for PPH prevention, and subsequently to WHO’s List of Essential Medicines, alongside oxytocin.
At the same time, Ferring is in the process of getting heat-stable carbetocin approved by various regulatory bodies and by countries wishing to use it. Gülmezoglu said WHO was campaigning Ferring to “reduce the price as much as possible.”
“We want the drug to be affordable. That is a is a key point in our involvement in the project — not just drug availability but making sure it’s affordable and accessible.”
“Maternal health remains one of the great injustices of our time … carbetocin is very important but the manufacturer needs to ensure that the price point is appropriate … and we, as civil society, have to hold them accountable.”— Jeffrey Smith, vice president of technical leadership, Jhpiego
In recent years oxytocin has come under fire for its misuse among health care workers, particularly in South Asia, which is driven by a lack of adequate health care worker training and the unregulated availability of the drug. To this extent, experts warn that before carbetocin is rolled out, health care workers must be adequately trained.
“For all carbetocin’s promise, there must be great effort on implementation,” Smith said. “Providers and governments must work together to make policies and standards and to train providers. All of those things for a new drug are formidable.”
Gülmezoglu agreed: “Oxytocin is so ubiquitous. People are using it in a relaxed way, which is not good. Gradually as people feel more comfortable with carbetocin, its use will increase. We have to do our best to prevent misuse and abuse.”
Because of its longer half-life, the drug stays in the body longer and has the potential to cause more complications — something health practitioners should be aware of, Gülmezoglu said. While heat-stable carbetocin is not a panacea to combating deaths from PPH, there are high hopes it will contribute greatly to reducing global maternal mortality.
“Maternal health remains one of the great injustices of our time,” Smith said. “Carbetocin is very important but the manufacturer needs to ensure that the price point is appropriate … and we, as civil society, have to hold them accountable.”
Update, October 11, 2018: This article has been updated to reflect that the trial focuses on a heat-stable form of carbetocin, and that MSD for Mothers is the philanthropic arm of MSD that approached the WHO.