Progesterone to prevent miscarriage in women with early pregnancy bleeding: The PRISM RCT

Research output: Contribution to journalArticlepeer-review

Authors

  • Ilias Goranitis
  • Chidubem B. Ogwulu
  • Helen Williams
  • Ioannis Gallos
  • Abey Eapen
  • Jane Daniels
  • Amna Ahmed
  • Ruth Bender-Atik
  • Kalsang Bhatia
  • Cecilia Bottomley
  • Jane Brewin
  • Meenakshi Choudhary
  • Fiona Crosfill
  • Shilpa Deb
  • W. Colin Duncan
  • Andrew Ewer
  • Kim Hinshaw
  • Thomas Holland
  • Feras Izzat
  • Jemma Johns
  • Mary Ann Lumsden
  • Padma Manda
  • Jane E. Norman
  • Natalie Nunes
  • Caroline E. Overton
  • Kathiuska Kriedt
  • Siobhan Quenby
  • Sandhya Rao
  • Jackie Ross
  • Anupama Shahid
  • Martyn Underwood
  • Nirmala Vaithilingham
  • Linda Watkins
  • Catherine Wykes
  • Andrew W. Horne
  • Davor Jurkovic
  • Lee Middleton

External organisations

  • Melbourne School of Population and Global Health
  • Birmingham University
  • University of Iowa Carver College of Medicine
  • University of Nottingham, Faculty of Medicine and Health Sciences
  • Sunderland Royal Hospital
  • Miscarriage Association
  • Burnley General Hospital
  • University College Hospital
  • Tommy’s
  • Royal Victoria Infirmary
  • Royal Preston Hospital
  • Nottingham University Hospital (City Campus)
  • University of Edinburgh, College of Medicine and Veterinary Medicine
  • Guy’s and St Thomas’ NHS Foundation Trust
  • University Hospital Coventry
  • King's College Hospital NHS Foundation Trust
  • University of Glasgow
  • The James Cook University Hospital
  • West Middlesex University Hospital
  • St. Michael's Hospital
  • Warwick Medical School
  • Whiston Hospital
  • Whipps Cross Hospital
  • Royal Shrewsbury and Telford Hospital NHS Trust
  • Queen Alexandra Hospital
  • University of Liverpool
  • East Surrey Hospital

Abstract

Background: Progesterone is essential for a healthy pregnancy. Several small trials have suggested that progesterone therapy may rescue a pregnancy in women with early pregnancy bleeding, which is a symptom that is strongly associated with miscarriage. Objectives: (1) To assess the effects of vaginal micronised progesterone in women with vaginal bleeding in the first 12 weeks of pregnancy. (2) To evaluate the cost-effectiveness of progesterone in women with early pregnancy bleeding. Design: A multicentre, double-blind, placebo-controlled, randomised trial of progesterone in women with early pregnancy vaginal bleeding. Setting: A total of 48 hospitals in the UK. Participants: Women aged 16–39 years with early pregnancy bleeding. Interventions: Women aged 16–39 years were randomly assigned to receive twice-daily vaginal suppositories containing either 400 mg of progesterone or a matched placebo from presentation to 16 weeks of gestation. Main outcome measures: The primary outcome was live birth at ≥ 34 weeks. In addition, a within-trial cost-effectiveness analysis was conducted from an NHS and NHS/Personal Social Services perspective. Results: A total of 4153 women from 48 hospitals in the UK received either progesterone (n = 2079) or placebo (n = 2074). The follow-up rate for the primary outcome was 97.2% (4038 out of 4153 participants). The live birth rate was 75% (1513 out of 2025 participants) in the progesterone group and 72% (1459 out of 2013 participants) in the placebo group (relative rate 1.03, 95% confidence interval 1.00 to 1.07; p = 0.08). A significant subgroup effect (interaction test p = 0.007) was identified for prespecified subgroups by the number of previous miscarriages: none (74% in the progesterone group vs. 75% in the placebo group; relative rate 0.99, 95% confidence interval 0.95 to 1.04; p = 0.72); one or two (76% in the progesterone group vs. 72% in the placebo group; relative rate 1.05, 95% confidence interval 1.00 to 1.12; p = 0.07); and three or more (72% in the progesterone group vs. 57% in the placebo group; relative rate 1.28, 95% confidence interval 1.08 to 1.51; p = 0.004). A significant post hoc subgroup effect (interaction test p = 0.01) was identified in the subgroup of participants with early pregnancy bleeding and any number of previous miscarriage(s) (75% in the progesterone group vs. 70% in the placebo group; relative rate 1.09, 95% confidence interval 1.03 to 1.15; p = 0.003). There were no significant differences in the rate of adverse events between the groups. The results of the health economics analysis show that progesterone was more costly than placebo (£7655 vs. £7572), with a mean cost difference of £83 (adjusted mean difference £76, 95% confidence interval –£559 to £711) between the two arms. Thus, the incremental cost-effectiveness ratio of progesterone compared with placebo was estimated as £3305 per additional live birth at ≥ 34 weeks of gestation. Conclusions: Progesterone therapy in the first trimester of pregnancy did not result in a significantly higher rate of live births among women with threatened miscarriage overall, but an important subgroup effect was identified. A conclusion on the cost-effectiveness of the PRISM trial would depend on the amount that society is willing to pay to increase the chances of an additional live birth at ≥ 34 weeks. For future work, we plan to conduct an individual participant data meta-analysis using all existing data sets.

Bibliographic note

Funding Information: The research reported in this issue of the journal was funded by the HTA programme as project number 12/167/26. The contractual start date was in October 2014. The draft report began editorial review in October 2018 and was accepted for publication in May 2019. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report. Funding Information: This report presents independent research funded by the National Institute for Health Research (NIHR). The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Health and Social Care. If there are verbatim quotations included in this publication the views and opinions expressed by the interviewees are those of the interviewees and do not necessarily reflect those of the authors, those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Health and Social Care. Funding Information: Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 33. See the NIHR Journals Library website for further project information. Funding Information: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 33. See the NIHR Journals Library website for further project information. Funding Information: l The study is supported by the Miscarriage Association (a patient support organisation), The Scottish Early Pregnancy Network, INVOLVE (a national advisory group that supports greater public involvement in health research), PRIME (Public and Researchers Involvement in Maternity and Early Pregnancy), CHARM (Charity for Research into Miscarriage) and Tommy’s charity. Publisher Copyright: © Queen’s Printer and Controller of HMSO 2020. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

Details

Original languageEnglish
Pages (from-to)1-70
Number of pages70
JournalHealth Technology Assessment
Volume24
Issue number33
Publication statusPublished - Jun 2020

ASJC Scopus subject areas