Ultrasound being performed on pregnant patient.

Women prescribed a vaginal progesterone treatment in the first trimester of pregnancy appear to be approximately 39% less likely to develop the potentially fatal condition preeclampsia, a new review of international research suggests.

Dr Pedro Melo from the University of Oxford, and Dr Adam Devall and Professor Arri Coomarasamy from the University of Birmingham, along with researchers from other Institutions collaborating through the Tommy’s National Centre for Miscarriage Research, 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.

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.

Dr Adam Devall, Institute of Metabolism and Systems Research, University of Birmingham.

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.