Hormone treatment offered to women at high risk of miscarriage

Bleeding during early pregnancy is common for many women and for most it doesn’t affect their pregnancy. For around one in three women though, bleeding is the first sign that a miscarriage may occur (a threatened miscarriage). 

Miscarriages are common during the first 12 weeks of pregnancy and affect up to one in six pregnancies. Although the cause isn’t always clear, some miscarriages may be linked to a drop in the progesterone hormone as the pregnancy develops. Progesterone is produced by a woman before and during pregnancy to prepare her uterus to accept and maintain a growing baby. Earlier small studies suggested that giving progesterone to women with early pregnancy bleeding may reduce their risk of miscarriage, but the evidence was uncertain. As Arri Coomarasamy, Professor of Gynaecology at the University of Birmingham, explained: 

“Miscarriage is not just an isolated physical event; it affects the prospects of future pregnancy outcomes. The role of progesterone in preventing miscarriage among women with early pregnancy bleeding has been studied and debated for about 60 years - what we lacked was high quality evidence to routinely offer it to women.”
- Professor Arri Coomarasamy

In 2012, NICE guidance on the management of miscarriage recommended that a large trial was needed to confirm the perceived benefits of progesterone in women with early pregnancy bleeding. In response to this, the NIHR Health Technology Assessment (HTA) Programme awarded £1.8 million funding to Professor Coomarasamy and a team from the University of Birmingham to conduct the Progesterone in Spontaneous Miscarriage (PRISM) study.

With the support of the NIHR-funded Birmingham Clinical Trials Unit, more than 4,000 women with early pregnancy bleeding were recruited from 48 hospitals around the UK. All the women were aged between 16 and 39 years and in the first 12 weeks of pregnancy. To test whether progesterone could prevent miscarriage, each woman was randomly assigned to receive either 400mg progesterone twice daily as vaginal pessaries (2079 women) or a placebo of identical appearance (2074 women). They took their treatment from the time they presented with bleeding until 16 completed weeks of their pregnancy or earlier if a miscarriage occurred. The team followed the women’s pregnancies to record whether progesterone treatment resulted in more live babies being born than taking the placebo. 

Published in The New England Journal of Medicine, the study showed that the higher the number of previous miscarriages in a woman who is currently bleeding in early pregnancy, the greater the benefit of progesterone treatment was. PRISM found that 4% more babies were born to those given progesterone who had previously had one or two miscarriages (76%) compared with women taking the placebo (72%). The benefit was even greater for women with three or more miscarriages. They saw a 15% increase in the number of babies born in the progesterone group (72%) compared with the placebo group (57%). 

When the number of babies born to all women in the study were considered, progesterone didn’t prevent enough miscarriages to make it more effective than the placebo overall. Only 3% more women in the progesterone group had a baby compared with the placebo group. 

Commenting on the team’s findings, Professor Coomarasamy said: “The finding that women who are at risk of a miscarriage because of current pregnancy bleeding and a history of a previous miscarriage could benefit from progesterone treatment has huge implications for practice.” 

“We estimate that progesterone treatment could result in an additional 8,450 live births per year in the UK."
- Professor Coomarasamy

Samantha participated in the PRISM trial after experiencing bleeding at seven weeks’ pregnant. She had previously suffered a miscarriage. She received progesterone from nine weeks, and her son was born in February 2018. Samantha said: “The bleeding stopped within a week of starting the trial. Of course, we’ll never know whether or not I would have miscarried if I had not taken part in the trial, or if I had been part of the group that received the placebo, either way I feel fortunate and happy that I did participate.” 

Although miscarriages are common in early pregnancy, affecting around 140,000 women each year in the UK, they have a significant physical and emotional impact. From a financial point of view, the diagnosis, treatment and care for those women costs the NHS more than £350 million each year. PRISM’s economic analysis of progesterone treatment, published in British Journal of Obstetrics and Gynaecology, indicated that progesterone treatment could be cost-effective at around £204 per patient.

The large-scale PRISM study provided robust clinical and economic evidence to influence the 2021 update of NICE guidance for the management of miscarriage. The guidance now recommends that twice-daily progesterone is offered to women with early pregnancy bleeding who have previously had at least one miscarriage.

Reflecting PRISM’s findings, NICE also recommended that progesterone isn’t given to women with no previous history of miscarriage or for those with a previous miscarriage but not bleeding in their current pregnancy. Women in these situations should receive usual supportive care. 

Professor Coomarasamy is also Director of Tommy’s National Centre for Miscarriage Research, with which the PRISM team collaborated to provide the new evidence. The Centre is supported by the pregnancy and baby loss charity, Tommy’s, to further research into the causes and treatment of miscarriage. Commenting on the impact for pregnant women from the updated guidelines, Tommy’s Interim Director of Research, Policy and Information, Kate Fitch, said: “We were extremely pleased to see NICE update their guidance to include progesterone as an effective treatment for women with early pregnancy bleeding and a history of miscarriage, meaning families will no longer have to fight to access the latest clinical best practice.”

Kate continued: “If NICE's updated guidance is adopted by every Early Pregnancy Unit and by every GP, and the right women at the right time are prescribed progesterone treatment, this development should help end some of the current inequalities in miscarriage care in the UK.”

The PRISM team have published widely and shared their findings internationally, presenting at many conferences, including at the Royal College of Obstetricians and Gynaecologists World Congress in Obstetrics and Gynaecology. They also produced material for a digital awareness-raising campaign around miscarriage research in 2016, successfully raising the profile of maternal health research with the press. 

In 2017, the PRISM team and colleagues at the University of Birmingham coordinated a fundraising campaign through which more than £70,000 was raised to support further research into the causes and prevention of miscarriage. 

Throughout the study, the public and patients’ perspectives were represented by members of the Miscarriage Association and Tommy’s charity to ensure that their research and approaches were acceptable to those affected by miscarriage. Professor Coomarasamy continued to engage patients in shaping research through his contribution to the development of the James Lind Alliance’s Miscarriage Priority Setting Partnership. Funded by the NIHR, the James Lind Alliance brings patients and clinicians together in partnerships to identify and prioritise the most important questions that need to be answered by miscarriage research. The PSP’s top priority was for further research to prevent miscarriage. 

Comment from Professor Coomarasamy: “Our research has shown that progesterone is a robust and effective treatment option but we know it’s not yet reaching everyone who might benefit. The focus should now be on wide-scale implementation of this effective treatment throughout the UK, and indeed throughout the world.”

The study was funded by the NIHR Health Technology Assessment (HTA) Programme.

More information about the study is available on the NIHR’s Funding & Awards website.

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