title: Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised, double-blind trial.
abstract: Progesterone administration has been shown to reduce the risk of preterm birth and neonatal morbidity in women at high risk, but there is uncertainty about longer term effects on the child.
  
  
  
  We did a double-blind, randomised, placebo-controlled trial of vaginal progesterone, 200 mg daily taken from 22-24 to 34 weeks of gestation, on pregnancy and infant outcomes in women at risk of preterm birth (because of previous spontaneous birth at ≤34 weeks and 0 days of gestation, or a cervical length ≤25 mm, or because of a positive fetal fibronectin test combined with other clinical risk factors for preterm birth [any one of a history in a previous pregnancy of preterm birth, second trimester loss, preterm premature fetal membrane rupture, or a history of a cervical procedure to treat abnormal smears]). The objective of the study was to determine whether vaginal progesterone prophylaxis given to reduce the risk of preterm birth affects neonatal and childhood outcomes. We defined three primary outcomes: fetal death or birth before 34 weeks and 0 days gestation (obstetric), a composite of death, brain injury, or bronchopulmonary dysplasia (neonatal), and a standardised cognitive score at 2 years of age (childhood), imputing values for deaths. Randomisation was done through a web portal, with participants, investigators, and others involved in giving the intervention, assessing outcomes, or analysing data masked to treatment allocation until the end of the study. Analysis was by intention to treat. This trial is registered at ISRCTN.com, number ISRCTN14568373.
  
  
  
  Between Feb 2, 2009, and April 12, 2013, we randomly assigned 1228 women to the placebo group (n=610) and the progesterone group (n=618). In the placebo group, data from 597, 587, and 439 women or babies were available for analysis of obstetric, neonatal, and childhood outcomes, respectively; in the progesterone group the corresponding numbers were 600, 589, and 430. After correction for multiple outcomes, progesterone had no significant effect on the primary obstetric outcome (odds ratio adjusted for multiple comparisons [OR] 0·86, 95% CI 0·61-1·22) or neonatal outcome (OR 0·62, 0·38-1·03), nor on the childhood outcome (cognitive score, progesterone group vs placebo group, 97·3 [SD 17·9] vs 97·7 [17·5]; difference in means -0·48, 95% CI -2·77 to 1·81). Maternal or child serious adverse events were reported in 70 (11%) of 610 patients in the placebo group and 59 (10%) of 616 patients in the progesterone group (p=0·27).
  
  
  
  Vaginal progesterone was not associated with reduced risk of preterm birth or composite neonatal adverse outcomes, and had no long-term benefit or harm on outcomes in children at 2 years of age.
  
  
  
  Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership. The EME Programme is funded by the MRC and NIHR, with contributions from the Chief Scientist Office in Scotland and National Institute for Social Care and Research in Wales.
authors.affiliation: Tommy's Centre for Maternal and Fetal Health, MRC Centre for Maternal and Fetal Health, University of Edinburgh, Edinburgh, UK. Electronic address: jane.norman@ed.ac.uk.
authors.forename: Jane Elizabeth
authors.initials: JE
authors.lastname: Norman
authors.affiliation: University College London, London, UK.
authors.forename: Neil
authors.initials: N
authors.lastname: Marlow
authors.affiliation: Robertson Centre for Biostatistics, Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK.
authors.forename: Claudia-Martina
authors.initials: CM
authors.lastname: Messow
authors.affiliation: Women's Health Academic Centre, King's College London, London, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Shennan
authors.affiliation: Imperial College London, London, UK.
authors.forename: Phillip R
authors.initials: PR
authors.lastname: Bennett
authors.affiliation: Queen Mary University of London, London, UK.
authors.forename: Steven
authors.initials: S
authors.lastname: Thornton
authors.affiliation: Medical School, University of Newcastle, Newcastle, UK.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Robson
authors.affiliation: Robertson Centre for Biostatistics, Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK.
authors.forename: Alex
authors.initials: A
authors.lastname: McConnachie
authors.affiliation: Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK.
authors.forename: Stavros
authors.initials: S
authors.lastname: Petrou
authors.affiliation: University College London, London, UK.
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Sebire
authors.affiliation: University of Manchester School of Nursing, University of Manchester, Manchester, UK.
authors.forename: Tina
authors.initials: T
authors.lastname: Lavender
authors.affiliation: Tommy's Centre for Maternal and Fetal Health, MRC Centre for Maternal and Fetal Health, University of Edinburgh, Edinburgh, UK.
authors.forename: Sonia
authors.initials: S
authors.lastname: Whyte
authors.affiliation: Centre for Healthcare Randomised Trials, Health Services Research Unit, University of Aberdeen, Aberdeen, UK.
authors.forename: John
authors.initials: J
authors.lastname: Norrie
mesh_terms: D000282:Administration, Intravaginal; D000328:Adult; D001930:Brain Injuries / Q000453:epidemiology; D002675:Child, Preschool; D004311:Double-Blind Method; D005260:Female; D005313:Fetal Death; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D011247:Pregnancy; D011256:Pregnancy Outcome; D018566:Pregnancy, High-Risk; D047928:Premature Birth / Q000517:prevention & control*; D011374:Progesterone / Q000627:therapeutic use*; D011372:Progestins / Q000627:therapeutic use*; D012307:Risk Factors; D013548:Sweden / Q000453:epidemiology; D016896:Treatment Outcome; D006113:United Kingdom / Q000453:epidemiology
chemical_list: D011372:Progestins; D011374:Progesterone