title: Effect of metformin on maternal and fetal outcomes in obese pregnant women (EMPOWaR): a randomised, double-blind, placebo-controlled trial.
abstract: BACKGROUND
  Maternal obesity is associated with increased birthweight, and obesity and premature mortality in adult offspring. The mechanism by which maternal obesity leads to these outcomes is not well understood, but maternal hyperglycaemia and insulin resistance are both implicated. We aimed to establish whether the insulin sensitising drug metformin improves maternal and fetal outcomes in obese pregnant women without diabetes.
  
  
  METHODS
  We did this randomised, double-blind, placebo-controlled trial in antenatal clinics at 15 National Health Service hospitals in the UK. Pregnant women (aged ≥16 years) between 12 and 16 weeks' gestation who had a BMI of 30 kg/m(2) or more and normal glucose tolerance were randomly assigned (1:1), via a web-based computer-generated block randomisation procedure (block size of two to four), to receive oral metformin 500 mg (increasing to a maximum of 2500 mg) or matched placebo daily from between 12 and 16 weeks' gestation until delivery of the baby. Randomisation was stratified by study site and BMI band (30-39 vs ≥40 kg/m(2)). Participants, caregivers, and study personnel were masked to treatment assignment. The primary outcome was Z score corresponding to the gestational age, parity, and sex-standardised birthweight percentile of liveborn babies delivered at 24 weeks or more of gestation. We did analysis by modified intention to treat. This trial is registered, ISRCTN number 51279843.
  
  
  RESULTS
  Between Feb 3, 2011, and Jan 16, 2014, inclusive, we randomly assigned 449 women to either placebo (n=223) or metformin (n=226), of whom 434 (97%) were included in the final modified intention-to-treat analysis. Mean birthweight at delivery was 3463 g (SD 660) in the placebo group and 3462 g (548) in the metformin group. The estimated effect size of metformin on the primary outcome was non-significant (adjusted mean difference -0·029, 95% CI -0·217 to 0·158; p=0·7597). The difference in the number of women reporting the combined adverse outcome of miscarriage, termination of pregnancy, stillbirth, or neonatal death in the metformin group (n=7) versus the placebo group (n=2) was not significant (odds ratio 3·60, 95% CI 0·74-17·50; p=0·11).
  
  
  CONCLUSIONS
  Metformin has no significant effect on birthweight percentile in obese pregnant women. Further follow-up of babies born to mothers in the EMPOWaR study will identify longer-term outcomes of metformin in this population; in the meantime, metformin should not be used to improve pregnancy outcomes in obese women without diabetes.
  
  
  BACKGROUND
  The Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council and National Institute for Health Research partnership.
authors.affiliation: Tommy's Centre for Maternal and Fetal Health, Medical Research Council (MRC) Centre for Reproductive Health, Queen's Medical Research Institute, Edinburgh, UK.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Chiswick
authors.affiliation: British Heart Foundation Centre for Cardiovascular Science, Queen's Medical Research Institute, Edinburgh, UK.
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Reynolds
authors.affiliation: Tommy's Centre for Maternal and Fetal Health, Medical Research Council (MRC) Centre for Reproductive Health, Queen's Medical Research Institute, Edinburgh, UK.
authors.forename: Fiona
authors.initials: F
authors.lastname: Denison
authors.affiliation: British Heart Foundation Centre for Cardiovascular Science, Queen's Medical Research Institute, Edinburgh, UK.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Drake
authors.affiliation: British Heart Foundation Centre for Cardiovascular Science, Queen's Medical Research Institute, Edinburgh, UK.
authors.forename: Shareen
authors.initials: S
authors.lastname: Forbes
authors.affiliation: Chancellor's Building, Royal Infirmary of Edinburgh, Edinburgh, UK.
authors.forename: David E
authors.initials: DE
authors.lastname: Newby
authors.affiliation: British Heart Foundation Centre for Cardiovascular Science, Queen's Medical Research Institute, Edinburgh, UK.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Walker
authors.affiliation: Division of Reproductive Health, Warwick Medical School, University of Warwick, Coventry, UK.
authors.forename: Siobhan
authors.initials: S
authors.lastname: Quenby
authors.affiliation: Faculty of Health and Life Sciences, First Floor, Liverpool Women's Hospital, Liverpool, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Wray
authors.affiliation: Faculty of Health and Life Sciences, First Floor, Liverpool Women's Hospital, Liverpool, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Weeks
authors.affiliation: Academic Unit of Reproductive and Developmental Medicine, The Jessop Wing, Sheffield, UK.
authors.forename: Hany
authors.initials: H
authors.lastname: Lashen
authors.affiliation: Centre for Population Health Sciences, Teviot Place, Edinburgh, UK.
authors.forename: Aryelly
authors.initials: A
authors.lastname: Rodriguez
authors.affiliation: Centre for Population Health Sciences, Teviot Place, Edinburgh, UK.
authors.forename: Gordon
authors.initials: G
authors.lastname: Murray
authors.affiliation: Tommy's Centre for Maternal and Fetal Health, Medical Research Council (MRC) Centre for Reproductive Health, Queen's Medical Research Institute, Edinburgh, UK.
authors.forename: Sonia
authors.initials: S
authors.lastname: Whyte
authors.affiliation: Tommy's Centre for Maternal and Fetal Health, Medical Research Council (MRC) Centre for Reproductive Health, Queen's Medical Research Institute, Edinburgh, UK. Electronic address: jane.norman@ed.ac.uk.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Norman
mesh_terms: D000022:Abortion, Spontaneous / Q000453:epidemiology; D000328:Adult; D016640:Diabetes, Gestational / Q000453:epidemiology*; D004311:Double-Blind Method; D005260:Female; D005320:Fetal Macrosomia / Q000453:epidemiology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008687:Metformin / Q000627:therapeutic use*; D056128:Obesity, Abdominal / Q000188:drug therapy*; D011247:Pregnancy; D011248:Pregnancy Complications / Q000188:drug therapy*; D011256:Pregnancy Outcome / Q000453:epidemiology*; D050497:Stillbirth / Q000453:epidemiology; D055815:Young Adult
chemical_list: D007004:Hypoglycemic Agents; D008687:Metformin