Arri Coomarasamy1, Hoda M Harb1, Adam J Devall1, Versha Cheed2, Tracy E Roberts2, Ilias Goranitis3, Chidubem B Ogwulu2, Helen M Williams1, Ioannis D Gallos1, Abey Eapen4, Jane P Daniels5, Amna Ahmed6, Ruth Bender-Atik7, Kalsang Bhatia8, Cecilia Bottomley9, Jane Brewin10, Meenakshi Choudhary11, Fiona Crosfill12, Shilpa Deb13, W Colin Duncan14, Andrew Ewer1, Kim Hinshaw6, Thomas Holland15, Feras Izzat16, Jemma Johns17, Mary-Ann Lumsden18, Padma Manda19, Jane E Norman14, Natalie Nunes20, Caroline E Overton21, Kathiuska Kriedt9, Siobhan Quenby22, Sandhya Rao23, Jackie Ross17, Anupama Shahid24, Martyn Underwood25, Nirmala Vaithilingham26, Linda Watkins27, Catherine Wykes28, Andrew W Horne14, Davor Jurkovic9, Lee J Middleton2. 1. Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK. 2. Institute of Applied Health Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK. 3. Melbourne School of Population and Global Health, University of Melbourne, Melbourne, VIC, Australia. 4. Carver College of Medicine, University of Iowa Health Care, Iowa City, IA, USA. 5. Faculty of Medicine and Health Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, UK. 6. Sunderland Royal Hospital, City Hospitals Sunderland NHS Foundation Trust, Sunderland, UK. 7. Miscarriage Association, Wakefield, UK. 8. Burnley General Hospital, East Lancashire Hospitals NHS Trust, Burnley, UK. 9. University College Hospital, University College London Hospitals NHS Foundation Trust, London, UK. 10. Tommy's, London, UK. 11. Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK. 12. Royal Preston Hospital, Lancashire Teaching Hospitals NHS Trust, Preston, UK. 13. Queen's Medical Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK. 14. Medical Research Council Centre for Reproductive Health, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK. 15. St Thomas' Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK. 16. University Hospital Coventry, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK. 17. King's College Hospital, King's College Hospital NHS Foundation Trust, London, UK. 18. Reproductive & Maternal Medicine, School of Medicine, Dentistry and Nursing, University of Glasgow, Glasgow, UK. 19. The James Cook University Hospital, South Tees Hospitals NHS Foundation Trust, Middlesbrough, UK. 20. West Middlesex University Hospital, Chelsea and Westminster Hospital NHS Foundation Trust, Isleworth, UK. 21. St Michael's Hospital, University Hospitals Bristol NHS Foundation Trust, Bristol, UK. 22. Biomedical Research Unit in Reproductive Health, Warwick Medical School, University of Warwick, Coventry, UK. 23. Whiston Hospital, St Helen's and Knowsley Teaching Hospitals NHS Trust, Prescot, UK. 24. Whipps Cross Hospital, Barts Health NHS Trust, London, UK. 25. Princess Royal Hospital, Shrewsbury and Telford Hospital NHS Trust, Telford, UK. 26. Queen Alexandra Hospital, Portsmouth Hospitals NHS Trust, Portsmouth, UK. 27. Liverpool Women's Hospital, Liverpool Women's NHS Foundation Trust, Liverpool, UK. 28. East Surrey Hospital, Surrey and Sussex Healthcare NHS Trust, Redhill, UK.
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 eitherprogesterone (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.
RCT Entities:
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.
Entities:
Keywords:
EARLY PREGNANCY VAGINAL BLEEDING; FIRST TRIMESTER; LIVE BIRTH; PROGESTERONE; RANDOMISED CONTROLLED TRIAL; THREATENED MISCARRIAGE
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