Progesterone to prevent miscarriage in women with early pregnancy bleeding: the PRISM RCT
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 vagina...
Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
NIHR Journals Library
2020-06-01
|
Series: | Health Technology Assessment |
Subjects: | |
Online Access: | https://doi.org/10.3310/hta24330 |
id |
doaj-fe61cf1f562741ef87202fb0e97784c9 |
---|---|
record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 |
spellingShingle |
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 Progesterone to prevent miscarriage in women with early pregnancy bleeding: the PRISM RCT Health Technology Assessment threatened miscarriage progesterone live birth early pregnancy vaginal bleeding first trimester randomised controlled trial |
author_facet |
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 |
author_sort |
Arri Coomarasamy |
title |
Progesterone to prevent miscarriage in women with early pregnancy bleeding: the PRISM RCT |
title_short |
Progesterone to prevent miscarriage in women with early pregnancy bleeding: the PRISM RCT |
title_full |
Progesterone to prevent miscarriage in women with early pregnancy bleeding: the PRISM RCT |
title_fullStr |
Progesterone to prevent miscarriage in women with early pregnancy bleeding: the PRISM RCT |
title_full_unstemmed |
Progesterone to prevent miscarriage in women with early pregnancy bleeding: the PRISM RCT |
title_sort |
progesterone to prevent miscarriage in women with early pregnancy bleeding: the prism rct |
publisher |
NIHR Journals Library |
series |
Health Technology Assessment |
issn |
1366-5278 2046-4924 |
publishDate |
2020-06-01 |
description |
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. |
topic |
threatened miscarriage progesterone live birth early pregnancy vaginal bleeding first trimester randomised controlled trial |
url |
https://doi.org/10.3310/hta24330 |
work_keys_str_mv |
AT arricoomarasamy progesteronetopreventmiscarriageinwomenwithearlypregnancybleedingtheprismrct AT hodamharb progesteronetopreventmiscarriageinwomenwithearlypregnancybleedingtheprismrct AT adamjdevall progesteronetopreventmiscarriageinwomenwithearlypregnancybleedingtheprismrct AT vershacheed progesteronetopreventmiscarriageinwomenwithearlypregnancybleedingtheprismrct AT tracyeroberts progesteronetopreventmiscarriageinwomenwithearlypregnancybleedingtheprismrct AT iliasgoranitis progesteronetopreventmiscarriageinwomenwithearlypregnancybleedingtheprismrct AT chidubembogwulu progesteronetopreventmiscarriageinwomenwithearlypregnancybleedingtheprismrct AT helenmwilliams progesteronetopreventmiscarriageinwomenwithearlypregnancybleedingtheprismrct AT ioannisdgallos progesteronetopreventmiscarriageinwomenwithearlypregnancybleedingtheprismrct AT abeyeapen progesteronetopreventmiscarriageinwomenwithearlypregnancybleedingtheprismrct AT janepdaniels progesteronetopreventmiscarriageinwomenwithearlypregnancybleedingtheprismrct AT amnaahmed progesteronetopreventmiscarriageinwomenwithearlypregnancybleedingtheprismrct AT ruthbenderatik progesteronetopreventmiscarriageinwomenwithearlypregnancybleedingtheprismrct AT kalsangbhatia progesteronetopreventmiscarriageinwomenwithearlypregnancybleedingtheprismrct AT ceciliabottomley progesteronetopreventmiscarriageinwomenwithearlypregnancybleedingtheprismrct AT janebrewin progesteronetopreventmiscarriageinwomenwithearlypregnancybleedingtheprismrct AT meenakshichoudhary progesteronetopreventmiscarriageinwomenwithearlypregnancybleedingtheprismrct AT fionacrosfill progesteronetopreventmiscarriageinwomenwithearlypregnancybleedingtheprismrct AT shilpadeb progesteronetopreventmiscarriageinwomenwithearlypregnancybleedingtheprismrct AT wcolinduncan progesteronetopreventmiscarriageinwomenwithearlypregnancybleedingtheprismrct AT andrewewer progesteronetopreventmiscarriageinwomenwithearlypregnancybleedingtheprismrct AT kimhinshaw progesteronetopreventmiscarriageinwomenwithearlypregnancybleedingtheprismrct AT thomasholland progesteronetopreventmiscarriageinwomenwithearlypregnancybleedingtheprismrct AT ferasizzat progesteronetopreventmiscarriageinwomenwithearlypregnancybleedingtheprismrct AT jemmajohns progesteronetopreventmiscarriageinwomenwithearlypregnancybleedingtheprismrct AT maryannlumsden progesteronetopreventmiscarriageinwomenwithearlypregnancybleedingtheprismrct AT padmamanda progesteronetopreventmiscarriageinwomenwithearlypregnancybleedingtheprismrct AT janeenorman progesteronetopreventmiscarriageinwomenwithearlypregnancybleedingtheprismrct AT natalienunes progesteronetopreventmiscarriageinwomenwithearlypregnancybleedingtheprismrct AT carolineeoverton progesteronetopreventmiscarriageinwomenwithearlypregnancybleedingtheprismrct AT kathiuskakriedt progesteronetopreventmiscarriageinwomenwithearlypregnancybleedingtheprismrct AT siobhanquenby progesteronetopreventmiscarriageinwomenwithearlypregnancybleedingtheprismrct AT sandhyarao progesteronetopreventmiscarriageinwomenwithearlypregnancybleedingtheprismrct AT jackieross progesteronetopreventmiscarriageinwomenwithearlypregnancybleedingtheprismrct AT anupamashahid progesteronetopreventmiscarriageinwomenwithearlypregnancybleedingtheprismrct AT martynunderwood progesteronetopreventmiscarriageinwomenwithearlypregnancybleedingtheprismrct AT nirmalavaithilingham progesteronetopreventmiscarriageinwomenwithearlypregnancybleedingtheprismrct AT lindawatkins progesteronetopreventmiscarriageinwomenwithearlypregnancybleedingtheprismrct AT catherinewykes progesteronetopreventmiscarriageinwomenwithearlypregnancybleedingtheprismrct AT andrewwhorne progesteronetopreventmiscarriageinwomenwithearlypregnancybleedingtheprismrct AT davorjurkovic progesteronetopreventmiscarriageinwomenwithearlypregnancybleedingtheprismrct AT leejmiddleton progesteronetopreventmiscarriageinwomenwithearlypregnancybleedingtheprismrct |
_version_ |
1724622799823175680 |
spelling |
doaj-fe61cf1f562741ef87202fb0e97784c92020-11-25T03:19:22ZengNIHR Journals LibraryHealth Technology Assessment1366-52782046-49242020-06-01243310.3310/hta2433012/167/26Progesterone to prevent miscarriage in women with early pregnancy bleeding: the PRISM RCTArri Coomarasamy0Hoda M Harb1Adam J Devall2Versha Cheed3Tracy E Roberts4Ilias Goranitis5Chidubem B Ogwulu6Helen M Williams7Ioannis D Gallos8Abey Eapen9Jane P Daniels10Amna Ahmed11Ruth Bender-Atik12Kalsang Bhatia13Cecilia Bottomley14Jane Brewin15Meenakshi Choudhary16Fiona Crosfill17Shilpa Deb18W Colin Duncan19Andrew Ewer20Kim Hinshaw21Thomas Holland22Feras Izzat23Jemma Johns24Mary-Ann Lumsden25Padma Manda26Jane E Norman27Natalie Nunes28Caroline E Overton29Kathiuska Kriedt30Siobhan Quenby31Sandhya Rao32Jackie Ross33Anupama Shahid34Martyn Underwood35Nirmala Vaithilingham36Linda Watkins37Catherine Wykes38Andrew W Horne39Davor Jurkovic40Lee J Middleton41Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UKInstitute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UKInstitute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UKInstitute of Applied Health Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UKInstitute of Applied Health Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UKMelbourne School of Population and Global Health, University of Melbourne, Melbourne, VIC, AustraliaInstitute of Applied Health Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UKInstitute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UKInstitute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UKCarver College of Medicine, University of Iowa Health Care, Iowa City, IA, USAFaculty of Medicine and Health Sciences, Queen’s Medical Centre, University of Nottingham, Nottingham, UKSunderland Royal Hospital, City Hospitals Sunderland NHS Foundation Trust, Sunderland, UKMiscarriage Association, Wakefield, UKBurnley General Hospital, East Lancashire Hospitals NHS Trust, Burnley, UKUniversity College Hospital, University College London Hospitals NHS Foundation Trust, London, UKTommy’s, London, UKRoyal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UKRoyal Preston Hospital, Lancashire Teaching Hospitals NHS Trust, Preston, UKQueen’s Medical Centre, Nottingham University Hospitals NHS Trust, Nottingham, UKMedical Research Council Centre for Reproductive Health, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UKInstitute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UKSunderland Royal Hospital, City Hospitals Sunderland NHS Foundation Trust, Sunderland, UKSt Thomas’ Hospital, Guy’s and St Thomas’ NHS Foundation Trust, London, UKUniversity Hospital Coventry, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UKKing’s College Hospital, King’s College Hospital NHS Foundation Trust, London, UKReproductive & Maternal Medicine, School of Medicine, Dentistry and Nursing, University of Glasgow, Glasgow, UKThe James Cook University Hospital, South Tees Hospitals NHS Foundation Trust, Middlesbrough, UKMedical Research Council Centre for Reproductive Health, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UKWest Middlesex University Hospital, Chelsea and Westminster Hospital NHS Foundation Trust, Isleworth, UKSt Michael’s Hospital, University Hospitals Bristol NHS Foundation Trust, Bristol, UKUniversity College Hospital, University College London Hospitals NHS Foundation Trust, London, UKBiomedical Research Unit in Reproductive Health, Warwick Medical School, University of Warwick, Coventry, UKWhiston Hospital, St Helen’s and Knowsley Teaching Hospitals NHS Trust, Prescot, UKKing’s College Hospital, King’s College Hospital NHS Foundation Trust, London, UKWhipps Cross Hospital, Barts Health NHS Trust, London, UKPrincess Royal Hospital, Shrewsbury and Telford Hospital NHS Trust, Telford, UKQueen Alexandra Hospital, Portsmouth Hospitals NHS Trust, Portsmouth, UKLiverpool Women’s Hospital, Liverpool Women’s NHS Foundation Trust, Liverpool, UKEast Surrey Hospital, Surrey and Sussex Healthcare NHS Trust, Redhill, UKMedical Research Council Centre for Reproductive Health, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UKUniversity College Hospital, University College London Hospitals NHS Foundation Trust, London, UKInstitute of Applied Health Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UKBackground: 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.https://doi.org/10.3310/hta24330threatened miscarriageprogesteronelive birthearly pregnancy vaginal bleedingfirst trimesterrandomised controlled trial |