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

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.

TRIAL REGISTRATION:

Current Controlled Trials ISRCTN14163439, EudraCT 2014-002348-42 and Integrated Research Application System (IRAS) 158326.

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.

• Authors: Arri Coomarasamy, Hoda M Harb, Adam J Devall, Versha Cheed, Tracy E Roberts, Ilias Goranitis, Chidubem B Ogwulu, Helen M Williams, Ioannis D Gallos, Abey Eapen, Jane P 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 J Middleton
• Journal: Health technology assessment (Winchester, England) (Health Technol Assess) Vol. 24 Issue 33 Pg. 1-70 (06 2020) ISSN: 2046-4924 [Electronic] England
• PMID: 32609084 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Suppositories
• Progesterone

Topics

• Abortion, Spontaneous (prevention & control)
• Adolescent
• Adult
• Cost-Benefit Analysis (economics)
• Double-Blind Method
• Female
• Humans
• Parturition
• Pregnancy
• Pregnancy Trimester, First
• Progesterone (administration & dosage)
• Suppositories (administration & dosage)
• United Kingdom
• Uterine Hemorrhage (drug therapy, etiology)
• Young Adult