Micronized vaginal progesterone to prevent miscarriage: a critical evaluation of randomized evidence

Research output: Contribution to journalReview articlepeer-review


  • Jan J Brosens
  • Siobhan Quenby
  • Mary D Stephenson
  • Sony Sierra
  • Ole B Christiansen
  • Rachel Small
  • Jane Brewin
  • Tracy E Roberts
  • Rima Dhillon-Smith
  • Hannah Noordali
  • Argyro Papadopoulou
  • Abey Eapen
  • Matt Prior
  • Gian Carlo Di Renzo
  • Kim Hinshaw
  • Ben W Mol
  • Mary Ann Lumsden
  • Yacoub Khalaf
  • Andrew Shennan
  • Mariette Goddijn
  • Madelon van Wely
  • Maya Al-Memar
  • Phil Bennett
  • Tom Bourne
  • Raj Rai
  • Lesley Regan

External organisations

  • Department of Obstetrics and Gynecology, University of Illinois College of Medicine at Chicago, Chicago, IL.
  • Department of Obstetrics and Gynaecology, University of Toronto, Ontario, Canada and TRIO Fertility, Toronto Ontario, Canada.
  • Centre for Recurrent Pregnancy Loss of Western Denmark, Department of Obstetrics and Gynaecology, Aalborg University Hospital, Aalborg, Denmark.
  • University Hospitals Birmingham NHS Foundation Trust
  • Tommy's Charity, Laurence Pountney Hill, London, United Kingdom.
  • Carver College of Medicine, University of Iowa Health Care, Iowa City, IA.
  • Sunderland Royal Hospital, City Hospitals Sunderland NHS Foundation Trust, Sunderland, United Kingdom.
  • The University of Warwick
  • Imperial College London
  • University of Amsterdam
  • King's College London
  • University of Glasgow
  • Monash University
  • University of Perugia
  • I.M. Sechenov First Moscow State Medical University
  • Newcastle upon Tyne Hospitals NHS Foundation Trust


Progesterone is essential for the maintenance of pregnancy. Several small trials have suggested that progesterone supplementation may reduce the risk of miscarriage in women with recurrent or threatened miscarriage. Cochrane Reviews summarized the evidence and found that the trials were small with substantial methodologic weaknesses. Since then, the effects of first-trimester use of vaginal micronized progesterone have been evaluated in 2 large, high-quality, multicenter placebo-controlled trials, one targeting women with unexplained recurrent miscarriages (the PROMISE [PROgesterone in recurrent MIScarriagE] trial) and the other targeting women with early pregnancy bleeding (the PRISM [PRogesterone In Spontaneous Miscarriage] trial). The PROMISE trial studied 836 women from 45 hospitals in the United Kingdom and the Netherlands and found a 3% greater live birth rate with progesterone but with substantial statistical uncertainty. The PRISM trial studied 4153 women from 48 hospitals in the United Kingdom and found a 3% greater live birth rate with progesterone, but with a P value of .08. A key finding, first observed in the PROMISE trial, and then replicated in the PRISM trial, was that treatment with vaginal micronized progesterone 400 mg twice daily was associated with increasing live birth rates according to the number of previous miscarriages. Prespecified PRISM trial subgroup analysis in women with the dual risk factors of previous miscarriage(s) and current pregnancy bleeding fulfilled all 11 conditions for credible subgroup analysis. For the subgroup of women with a history of 1 or more miscarriage(s) and current pregnancy bleeding, the live birth rate was 75% (689/914) with progesterone vs 70% (619/886) with placebo (rate difference 5%; risk ratio, 1.09, 95% confidence interval, 1.03-1.15; P=.003). The benefit was greater for the subgroup of women with 3 or more previous miscarriages and current pregnancy bleeding; live birth rate was 72% (98/137) with progesterone vs 57% (85/148) with placebo (rate difference 15%; risk ratio, 1.28, 95% confidence interval, 1.08-1.51; P=.004). No short-term safety concerns were identified from the PROMISE and PRISM trials. Therefore, women with a history of miscarriage who present with bleeding in early pregnancy may benefit from the use of vaginal micronized progesterone 400 mg twice daily. Women and their care providers should use the findings for shared decision-making.

Bibliographic note

This is a critical evaluation of randomised evidence from two large multicentre trials on progesterone supplementation in early pregnancy. Results from these studies and background evidence support a beneficial effect of progesterone supplementation for women with early pregnancy bleeding and previous miscarriages. Women and their care providers are advised to use the findings for shared decision-making by an international consensus group.


Original languageEnglish
Pages (from-to)167-176
Number of pages10
JournalAmerican journal of obstetrics and gynecology
Issue number2
Early online date31 Jan 2020
Publication statusPublished - Aug 2020


  • bleeding, luteal phase deficiency, meta-analysis, recurrent miscarriage, threatened miscarriage, vaginal micronized progesterone