title: PROMISE: first-trimester progesterone therapy in women with a history of unexplained recurrent miscarriages - a randomised, double-blind, placebo-controlled, international multicentre trial and economic evaluation.
abstract: Progesterone is essential to maintain a healthy pregnancy. Guidance from the Royal College of Obstetricians and Gynaecologists and a Cochrane review called for a definitive trial to test whether or not progesterone therapy in the first trimester could reduce the risk of miscarriage in women with a history of unexplained recurrent miscarriage (RM). The PROMISE trial was conducted to answer this question. A concurrent cost-effectiveness analysis was conducted.
  
  
  
  A randomised, double-blind, placebo-controlled, international multicentre study, with economic evaluation, conducted in hospital settings across the UK (36 sites) and in the Netherlands (nine sites).
  
  
  
  Women with unexplained RM (three or more first-trimester losses), aged between 18 and 39 years at randomisation, conceiving naturally and giving informed consent, received either micronised progesterone (Utrogestan(®), Besins Healthcare) at a dose of 400 mg (two vaginal capsules of 200 mg) or placebo vaginal capsules twice daily, administered vaginally from soon after a positive urinary pregnancy test (and no later than 6 weeks of gestation) until 12 completed weeks of gestation (or earlier if the pregnancy ended before 12 weeks).
  
  
  
  Live birth beyond 24 completed weeks of gestation (primary outcome), clinical pregnancy at 6-8 weeks, ongoing pregnancy at 12 weeks, miscarriage, gestation at delivery, neonatal survival at 28 days of life, congenital abnormalities and resource use.
  
  
  
  Participants were randomised after confirmation of pregnancy. Randomisation was performed online via a secure internet facility. Data were collected on four occasions of outcome assessment after randomisation, up to 28 days after birth.
  
  
  
  A total of 1568 participants were screened for eligibility. Of the 836 women randomised between 2010 and 2013, 404 received progesterone and 432 received placebo. The baseline data (age, body mass index, maternal ethnicity, smoking status and parity) of the participants were comparable in the two arms of the trial. The follow-up rate to primary outcome was 826 out of 836 (98.8%). The live birth rate in the progesterone group was 65.8% (262/398) and in the placebo group it was 63.3% (271/428), giving a relative risk of 1.04 (95% confidence interval 0.94 to 1.15; p = 0.45). There was no evidence of a significant difference between the groups for any of the secondary outcomes. Economic analysis suggested a favourable incremental cost-effectiveness ratio for decision-making but wide confidence intervals indicated a high level of uncertainty in the health benefits. Additional sensitivity analysis suggested the probability that progesterone would fall within the National Institute for Health and Care Excellence's threshold of £20,000-30,000 per quality-adjusted life-year as between 0.7145 and 0.7341.
  
  
  
  There is no evidence that first-trimester progesterone therapy improves outcomes in women with a history of unexplained RM.
  
  
  
  This study did not explore the effect of treatment with other progesterone preparations or treatment during the luteal phase of the menstrual cycle.
  
  
  
  Future research could explore the efficacy of progesterone supplementation administered during the luteal phase of the menstrual cycle in women attempting natural conception despite a history of RM.
  
  
  
  Current Controlled Trials ISRCTN92644181; EudraCT 2009-011208-42; Research Ethics Committee 09/H1208/44.
  
  
  
  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. 20, No. 41. See the NIHR Journals Library website for further project information.
authors.affiliation: College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Arri
authors.initials: A
authors.lastname: Coomarasamy
authors.affiliation: College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Williams
authors.affiliation: College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Ewa
authors.initials: E
authors.lastname: Truchanowicz
authors.affiliation: Department of Women's Health, King's College London and King's Health Partners, St Thomas' Hospital, London, UK.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Seed
authors.affiliation: Birmingham Heartlands Hospital, Heart of England NHS Foundation Trust, Birmingham, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Small
authors.affiliation: Biomedical Research Unit in Reproductive Health, University of Warwick, Coventry, UK.
authors.forename: Siobhan
authors.initials: S
authors.lastname: Quenby
authors.affiliation: Birmingham Heartlands Hospital, Heart of England NHS Foundation Trust, Birmingham, UK.
authors.forename: Pratima
authors.initials: P
authors.lastname: Gupta
authors.affiliation: Liverpool Women's Hospital, Liverpool Women's NHS Foundation Trust, Liverpool, UK.
authors.forename: Feroza
authors.initials: F
authors.lastname: Dawood
authors.affiliation: Department of Reproductive Medicine, University Medical Centre Utrecht, Utrecht, the Netherlands.
authors.forename: Yvonne E
authors.initials: YE
authors.lastname: Koot
authors.affiliation: The Miscarriage Association, Wakefield, UK.
authors.forename: Ruth Bender
authors.initials: RB
authors.lastname: Atik
authors.affiliation: Department of Obstetrics, Leiden University Medical Centre, Leiden, the Netherlands.
authors.forename: Kitty Wm
authors.initials: KW
authors.lastname: Bloemenkamp
authors.affiliation: Women's Health Research Centre, Imperial College at St Mary's Hospital Campus, London, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Brady
authors.affiliation: Department of Women's Health, King's Health Partners, St Thomas' Hospital, London, UK.
authors.forename: Annette
authors.initials: A
authors.lastname: Briley
authors.affiliation: Women's Health Research Centre, Imperial College at St Mary's Hospital Campus, London, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Cavallaro
authors.affiliation: University of Southampton Faculty of Medicine, Princess Anne Hospital, Southampton University Hospital NHS Trust, Southampton, UK.
authors.forename: Ying C
authors.initials: YC
authors.lastname: Cheong
authors.affiliation: College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Justin
authors.initials: J
authors.lastname: Chu
authors.affiliation: College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Abey
authors.initials: A
authors.lastname: Eapen
authors.affiliation: Department of Health Sciences, University of York, York, UK.
authors.forename: Holly
authors.initials: H
authors.lastname: Essex
authors.affiliation: Birmingham City Hospital, Sandwell and West Birmingham Hospitals NHS Teaching Trust, Birmingham, UK.
authors.forename: Ayman
authors.initials: A
authors.lastname: Ewies
authors.affiliation: Department of Reproductive Medicine and Gynaecology, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Annemieke
authors.initials: A
authors.lastname: Hoek
authors.affiliation: Department of Obstetrics and Gynaecology, Onze Lieve Vrouwe Gasthuis, Amsterdam, the Netherlands.
authors.forename: Eugenie M
authors.initials: EM
authors.lastname: Kaaijk
authors.affiliation: Department of Obstetrics and Gynaecology, Maxima Medical Centre Veldhoven, Veldhoven, the Netherlands.
authors.forename: Carolien A
authors.initials: CA
authors.lastname: Koks
authors.affiliation: Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.
authors.forename: Tin-Chiu
authors.initials: TC
authors.lastname: Li
authors.affiliation: Ayrshire Maternity Unit, University Hospital of Crosshouse, Kilmarnock, UK.
authors.forename: Marjory
authors.initials: M
authors.lastname: MacLean
authors.affiliation: The Robinson Institute, School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Ben W
authors.initials: BW
authors.lastname: Mol
authors.affiliation: Department of Obstetrics and Gynaecology, Nottingham University Hospitals NHS Trust, Nottingham, UK.
authors.forename: Judith
authors.initials: J
authors.lastname: Moore
authors.affiliation: Department of Health Sciences, University of York, York, UK.
authors.forename: Steve
authors.initials: S
authors.lastname: Parrott
authors.affiliation: Early Pregnancy and Gynaecology Assessment Unit, King's College Hospital NHS Foundation Trust, London, UK.
authors.forename: Jackie A
authors.initials: JA
authors.lastname: Ross
authors.affiliation: Women's Health Research Centre, Imperial College at St Mary's Hospital Campus, London, UK.
authors.forename: Lisa
authors.initials: L
authors.lastname: Sharpe
authors.affiliation: Royal Victoria Infirmary, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Stewart
authors.affiliation: Department of Health Sciences, University of York, York, UK.
authors.forename: Dominic
authors.initials: D
authors.lastname: Trépel
authors.affiliation: Queen Alexandra Hospital, Portsmouth Hospitals NHS Trust, Portsmouth, UK.
authors.forename: Nirmala
authors.initials: N
authors.lastname: Vaithilingam
authors.affiliation: Liverpool Women's Hospital, Liverpool Women's NHS Foundation Trust, Liverpool, UK.
authors.forename: Roy G
authors.initials: RG
authors.lastname: Farquharson
authors.affiliation: Centre for Women's and Children's Health, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Mark David
authors.initials: MD
authors.lastname: Kilby
authors.affiliation: Assisted Conception Unit, Guy's and St Thomas' NHS Foundation Trust, London, UK.
authors.forename: Yacoub
authors.initials: Y
authors.lastname: Khalaf
authors.affiliation: Department of Obstetrics and Gynaecology, Centre for Reproductive Medicine, Academic Medical Centre, Amsterdam, the Netherlands.
authors.forename: Mariëtte
authors.initials: M
authors.lastname: Goddijn
authors.affiliation: Women's Health Research Centre, Imperial College at St Mary's Hospital Campus, London, UK.
authors.forename: Lesley
authors.initials: L
authors.lastname: Regan
authors.affiliation: Women's Health Research Centre, Imperial College at St Mary's Hospital Campus, London, UK.
authors.forename: Rajendra
authors.initials: R
authors.lastname: Rai
mesh_terms: D000026:Abortion, Habitual / Q000188:drug therapy*; D000282:Administration, Intravaginal; D000293:Adolescent; D000328:Adult; D000013:Congenital Abnormalities / Q000453:epidemiology; D003362:Cost-Benefit Analysis; D004311:Double-Blind Method; D005260:Female; D005865:Gestational Age; D006801:Humans; D007223:Infant; D007226:Infant Mortality; D009426:Netherlands; D011247:Pregnancy; D011256:Pregnancy Outcome / Q000453:epidemiology*; D011261:Pregnancy Trimester, First; D011374:Progesterone / Q000008:administration & dosage / Q000009:adverse effects / Q000191:economics* / Q000627:therapeutic use*; D019057:Quality-Adjusted Life Years; D006113:United Kingdom; D055815:Young Adult
chemical_list: D011374:Progesterone