1 OMNI Research Group, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada2 School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, Ottawa, Ontario, Canada3 Department of Obstetrics, Gynecology & Newborn Care, University of Ottawa, Ottawa, Ontario, Canada4 Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne, UK5 Obstetric Medicine, Robinson Research Institute, University of Adelaide, South Australia, Australia6 Women's and Children's Hospital, Adelaide, South Australia, Australia7 Department of Obstetrics and Gynaecology, Faculty of Medical Sciences, The University of the West Indies, Mona, Kingston, Jamaica8 Centro Rosarino de Estudios Perinatales (CREP), Rosario, Santa Fé, Argentina9 Queen's Perinatal Research Unit, Kingston General Hospital, Department of Obstetrics and Gynecology, Queens University, Kingston, Ontario, Canada10 Mother & Child Axis, Centre de recherche du Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada11 Centre de Recherche, Universite de Sherbrooke, Sherbrooke, Quebec, Canada12 Department of Obstetrics and Gynecology, Faculty of Medicine and Health Sciences, Centre de recherche du CHUS, University of Sherbrooke, Sherbrooke, Quebec, Canada;13 Cardiovascular Research Methods Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada14 Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada15 Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada16 Women and Children's Health Research Institute, University of Alberta, Edmonton, Alberta, Canada17 Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Alberta, Canada18 Department of Physiology, University of Alberta, Edmonton, Alberta, Canada19 Maternal-Fetal Medicine Division, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada20 Departments of Medicine, School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, Ottawa, Ontario, Canada21 Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia22 Department of Obstetrics, University Medical Center, Utrecht, Utrecht, Netherlands23 Department of Obstetrics, Academic Medical Center, Amsterdam, Netherlands
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ObjectiveTo determine the efficacy of high dose folic acid supplementation for prevention of pre-eclampsia in women with at least one risk factor: pre-existing hypertension, prepregnancy diabetes (type 1 or 2), twin pregnancy, pre-eclampsia in a previous pregnancy, or body mass index ≥35.DesignRandomised, phase III, double blinded international, multicentre clinical trial.Setting70 obstetrical centres in five countries (Argentina, Australia, Canada, Jamaica, and UK).Participants2464 pregnant women with at least one high risk factor for pre-eclampsia were randomised between 2011 and 2015 (1144 to the folic acid group and 1157 to the placebo group); 2301 were included in the intention to treat analyses.InterventionEligible women were randomised to receive either daily high dose folic acid (four 1.0 mg oral tablets) or placebo from eight weeks of gestation to the end of week 16 of gestation until delivery. Clinicians, participants, adjudicators, and study staff were masked to study treatment allocation.Main outcome measureThe primary outcome was pre-eclampsia, defined as hypertension presenting after 20 weeks' gestation with major proteinuria or HELLP syndrome (haemolysis, elevated liver enzymes, low platelets).ResultsPre-eclampsia occurred in 169/1144 (14.8%) women in the folic acid group and 156/1157 (13.5%) in the placebo group (relative risk 1.10, 95% confidence interval 0.90 to 1.34; P=0.37). There was no evidence of differences between the groups for any other adverse maternal or neonatal outcomes.ConclusionSupplementation with 4.0 mg/day folic acid beyond the first trimester does not prevent pre-eclampsia in women at high risk for this condition.Trial registrationCurrent Controlled Trials ISRCTN23781770 and ClinicalTrials.gov NCT01355159.