Prescribing vaginal progesterone treatment early in pregnancy appears to reduce risk of developing preeclampsia – a potentially fatal condition – by approximately 39%, a recent research review suggests.

Collaborating through the Tommy’s National Centre for Miscarriage Research, Dr Pedro Melo from the University of Oxford, and Dr Adam Devall and Professor Arri Coomarasamy from BHP member the University of Birmingham have analysed the findings of 11 recent studies involving 11,640 women.

These studies were originally designed to explore the impact of progesterone on reducing miscarriage or preterm birth rates. In every study, data were also collected on whether the same treatment affected rates of preeclampsia or other high blood pressure (hypertensive) disorders in women during pregnancy.

The review, published in the British Journal of Obstetrics and Gynaecology, concludes that vaginal progesterone appears to reduce risk of hypertensive disorders in pregnancy, but only when treatment is started in the first trimester.

The review showed that, compared to a placebo, 400 mg of vaginal progesterone used twice a day was associated with a 39% reduction in preeclampsia and a 29% reduction in the rate of other hypertensive disorders such as gestational hypertension.

Starting progesterone early in pregnancy appears to be critical: no clear evidence was found through this review to suggest that starting progesterone in the second or third trimesters had an effect.

Frequency, quantity, and method of use are also important: 400 mg used twice daily as a vaginal capsule showed a benefit in reducing risk of preeclampsia and other hypertensive disorders but using 400 mg once a day did not.

“The recent PROMISE and larger PRISM trials led to an exciting breakthrough in finding evidence that progesterone can reduce miscarriage risk in some women when used in the first trimester. This evidence led to updated NICE guidelines in 2021 recommending its use. But the signal we found in the data for progesterone’s effectiveness in reducing hypertensive disorders had not previously been demonstrated.

“These are exciting preliminary findings, but it must be stressed that they were secondary results of trials focusing on the use of progesterone for the prevention of miscarriage and preterm birth, not preeclampsia. We need a large randomised controlled trial focusing specifically on women and birthing people at risk of preeclampsia to confirm our hypothesis that progesterone supplementation may tackle abnormal implantation in this subgroup of people” said Dr Pedro Melo, lead author of the study at the Tommy’s National Centre for Miscarriage Research at the University of Birmingham and the Nuffield Department of Women’s and Reproductive Health at the University of Oxford.

Dr Adam Devall, Institute of Metabolism and Systems Research, University of Birmingham, added: “The preliminary finding from this study suggests vaginal micronised progesterone might reduce the risk of preeclampsia. The researchers are calling for a large multi-centre clinical trial to explore the effects of progesterone in women at risk of preeclampsia.”

The 11 studies analysed focused on groups of pregnant women who either had a history of recurrent pregnancy loss or had a threatened miscarriage (i.e., they were experiencing early pregnancy bleeding). The review recommends that future studies are needed to explore the link further, to find out whether the reductions of 29-39% are relevant to all women and birthing people and whether the effect could be larger for those who have risk factors for preeclampsia.

Preeclampsia is a condition that affects some pregnant women, usually during the second half of pregnancy or soon after their baby is delivered. Preeclampsia can lead to fetal growth restriction which can cause premature birth. If severe, it can be dangerous, sometimes even fatal, for mothers.

Progesterone plays an important role in implantation of the embryo as it helps make the tissue lining the uterus receptive to implantation. By giving vaginal progesterone, researchers believe it is possible to combat problems with the lining of the womb and partly correct abnormal implantation, helping support successful development of the blood vessels in the placenta. This would reduce the chance of developing conditions such as preeclampsia.

“This research further supports Tommy’s calls for women with a history of miscarriage and pregnancy bleeding to be given progesterone in the early stages of pregnancy. We must continue to keep exploring progesterone’s potential and improve understanding of what it can be used for, who it works best for, when, and how” explained Kate Davies, Research Director at Tommy’s.

“We cannot allow another 40 years to pass by with no new medicines for pregnant women” – Professor Katie Morris reflects on BHP’s Pregnancy Policy Commission and its work since the publication of the Healthy Mum, Healthy Baby, Healthy Future report in 2022. 

Most pregnant women will have a healthy pregnancy and give birth to healthy babies. An increasing number of women, however, will either have one or more health conditions before they become pregnant which require on-going treatment, or they may develop complications of pregnancy which require treatment.

The care of these women is severely hampered by a lack of suitable medicines, that we definitively know to be safe and effective for use in pregnancy or during breastfeeding. As a consequence, women and babies worldwide continue to become sick and die during or immediately after pregnancy. Despite this, over the last 40 years, only two new medicines have been approved for use in pregnancy.

Birmingham Health Partners‘ 2021 report, ‘Safe and Effective Medicines for Use in Pregnancy: A Call to Action’ highlighted the absence of research and information on the safety of medicines in pregnancy. It also drew attention to the urgent health needs of this neglected group both nationally and internationally, and the potential for saving and improving millions of lives globally.

As a direct response to this report the University of Birmingham and Birmingham Health Partners convened a Policy Commission focussing on the UK, canvassing knowledge and opinions from key parties including patient groups, the pharmaceutical industry, scientists, clinicians, NHS leaders, regulators and insurers. It aimed to explore the scale of the problems that are preventing the evaluation and development of safe medicines for use in pregnancy and collected recommendations for how these could be overcome.

The Commission report was published in May 2022 and entitled “Healthy Mum, Healthy Baby, Healthy Future.” It made a series of eight recommendations related to advocacy, widening participation of pregnant women in clinical trials, updating information on existing medicines, de-risking the insurance process for clinical trials, incentivising industry to develop pregnancy specific medicines, establishing a UK-wide network of research centres, improving the use of routine data, and appointing a UK steering committee to deliver these recommendations.

Over the last year, members of the Commission have been working to develop the steering group and engage with industry and insurance companies to drive forward these recommendations. There are challenges in driving this agenda forwards which can be broadly described as a de-prioritisation of women’s health, and particularly pregnancy, by industry and in the delivery of clinical trials related to workforce and capacity.

Without combined efforts from all stakeholders; public, scientific, clinical, industry, regulatory and governmental sectors, we will not see any progress. The first step will be through co-ordinated efforts via the recently formed steering committee and renewed approaches for engagement with industry and insurance providers.

We cannot allow another 40 years to pass by with no new medicines for pregnant women.

Together these stakeholders must advocate for change, respond to research and funding issues, and, where necessary, work to change official guidance or law to enable progress in this much neglected area.

The UK is well placed to become a global pioneer of maternal health research innovation. We have the health infrastructure of our NHS, with its birth-to-death records. Our medicines regulator is able to fast-track drug development and make changes to streamline the process, as well as working globally with Europe, the US and other regions. We are already a global hub for insurance – and we can support and build on this to add to our potential in becoming a leader in clinical studies for medicines in pregnancy.

There is an urgent need for action to address the underserved area of medicines use in pregnancy. Without it, women and babies will continue to die when they could be saved. They will continue to experience long-term health effects, disability and distress, which might be avoided. It is no longer ethical to deny pregnant women and their unborn babies access to safe, modern medicines that the rest of the population enjoys.

Professor R. Katie Morris MBChB, PhD, MRCOG, Professor of Obstetrics and Maternal Fetal Medicine
Director of Birmingham Clinical Trials Unit
Honorary Consultant Maternal Fetal Medicine, Birmingham Women’s and Children’s Hospital