Effect of high dose folic acid supplementation in pregnancy on pre-eclampsia (FACT): Double blind, phase III, randomised controlled, international, multicentre trial

Shi Wu Wen, Ruth Rennicks White, Natalie Rybak, Laura M. Gaudet, Stephen Robson, William Hague, Donnette Simms-Stewart, Guillermo Carroli, Graeme Smith, William D. Fraser, George Wells, Sandra T. Davidge, John Kingdom, Doug Coyle, Dean Fergusson, Daniel J. Corsi, Josee Champagne, Elham Sabri, Tim Ramsay, Ben Willem J. MolMartijn A. Oudijk, Mark C. Walker*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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Objective To 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. Design Randomised, phase III, double blinded international, multicentre clinical trial. Setting 70 obstetrical centres in five countries (Argentina, Australia, Canada, Jamaica, and UK). Participants 2464 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. Intervention Eligible 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 measure The 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). Results Pre-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. Conclusion Supplementation 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 registration Current Controlled Trials ISRCTN23781770 and ClinicalTrials.gov NCT01355159.

Original languageEnglish
Article numberk3478
Pages (from-to)1-8
Number of pages8
JournalBMJ (Online)
Issue number8167
Early online date11 Jul 2018
Publication statusPublished - 15 Sept 2018

Bibliographical note

This study was sponsored by the Ottawa Hospital Research Institute, and funded by the Canadian Institutes of Health Research (grants 198801 and 98030). FACT was conceived, designed, and coordinated independently of the funding source. The funder did not act as sponsor for the trial and had no role in analysis, interpretation of the data, writing of the report, or decision to submit for publication.

Data Availability Statement

The authors of this trial commit to making data available upon reasonable request. Requests for access to data from FACT should be addressed to the corresponding author.

Supplementary information: Supplemental appendix
with tables S1-S4

Supplementary information: Members of the FACT
Collaborating Group


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