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Randomized Controlled Trial
. 2020 Jun;24(33):1-70.
doi: 10.3310/hta24330.

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

Arri Coomarasamy  1 , Hoda M Harb  1 , Adam J Devall  1 , Versha Cheed  2 , Tracy E Roberts  2 , Ilias Goranitis  3 , Chidubem B Ogwulu  2 , Helen M Williams  1 , Ioannis D Gallos  1 , Abey Eapen  4 , Jane P Daniels  5 , Amna Ahmed  6 , Ruth Bender-Atik  7 , Kalsang Bhatia  8 , Cecilia Bottomley  9 , Jane Brewin  10 , Meenakshi Choudhary  11 , Fiona Crosfill  12 , Shilpa Deb  13 , W Colin Duncan  14 , Andrew Ewer  1 , Kim Hinshaw  6 , Thomas Holland  15 , Feras Izzat  16 , Jemma Johns  17 , Mary-Ann Lumsden  18 , Padma Manda  19 , Jane E Norman  14 , Natalie Nunes  20 , Caroline E Overton  21 , Kathiuska Kriedt  9 , Siobhan Quenby  22 , Sandhya Rao  23 , Jackie Ross  17 , Anupama Shahid  24 , Martyn Underwood  25 , Nirmala Vaithilingham  26 , Linda Watkins  27 , Catherine Wykes  28 , Andrew W Horne  14 , Davor Jurkovic  9 , Lee J Middleton  2
Affiliations
Randomized Controlled Trial

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

Arri Coomarasamy et al. Health Technol Assess. 2020 Jun.

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.

Keywords: EARLY PREGNANCY VAGINAL BLEEDING; FIRST TRIMESTER; LIVE BIRTH; PROGESTERONE; RANDOMISED CONTROLLED TRIAL; THREATENED MISCARRIAGE.

Plain language summary

Miscarriage is a common complication of pregnancy that affects one in five pregnancies. Several small studies have suggested that progesterone, a hormone essential for maintaining a pregnancy, may reduce the risk of miscarriage in women presenting with early pregnancy bleeding. This research was undertaken to test whether or not progesterone given to pregnant women with early pregnancy bleeding would increase the number of live births when compared with placebo (dummy treatment). The women participating in the study had an equal chance of receiving progesterone or placebo, as determined by a computer; one group received progesterone (400 mg twice daily as vaginal pessaries) and the other group received placebo with an identical appearance. Treatment began when women presented with vaginal bleeding, were < 12 weeks of gestation and were found to have at least a pregnancy sac on an ultrasound scan. Treatment was stopped at 16 weeks of gestation, or earlier if the pregnancy ended before 16 weeks. Neither the participants nor their health-care professionals knew which treatment was being received. In total, 23,775 women were screened and 4153 women were randomised to receive either progesterone or placebo pessaries. Altogether, 2972 participants had a live birth after at least 34 weeks of gestation. Overall, the live birth rate in the progesterone group was 75% (1513 out of 2025 participants), compared with 72% (1459 out of 2013 participants) in the placebo group. Although the live birth rate was 3% higher in the progesterone group than in the placebo group, there was statistical uncertainty about this finding. However, it was observed that women with a history of one or more previous miscarriages and vaginal bleeding in their current pregnancy may benefit from progesterone. For women with no previous miscarriages, our analysis showed that the live birth rate was 74% (824 out of 1111 participants) in the progesterone group compared with 75% (840 out of 1127 participants) in the placebo group. For women with one or more previous miscarriages, the live birth rate was 75% (689 out of 914 participants) in the progesterone group compared with 70% (619 out of 886 participants) in the placebo group. The potential benefit appeared to be most strong for women with three or more previous miscarriages, who had a live birth rate of 72% (98 out of 137 participants) in the progesterone group compared with 57% (85 out of 148 participants) in the placebo group. Treatment with progesterone did not appear to have any negative effects.

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Conflict of interest statement

Jane P Daniels declares membership of the Clinical Trials Unit Standing Advisory Committee. Meenakshi Choudhary declares membership of Health Technology Assessment (HTA) Maternal, Newborn and Child Health (MNCH) Panel and the HTA Prioritisation Committee. Jane E Norman declares membership of the HTA MNCH Panel, that she currently receives funding from the National Institute for Health Research Efficacy and Mechanism Evaluation (EME) programme, that she participates in a Data Monitoring and Ethics Committee for GlaxoSmithKline plc (Brentford, UK) and that she is a paid consultant for Dilafor AB (Solna, Sweden). She was a member of the HTA and EME Editorial Board from 2012 to 2014. Caroline Overton declares that she was a Mylan clinical educator for general practitioner education about hormone replacement therapy and incorporated private practice in April 2017 (now called Bristol Women’s Clinic Ltd).

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