Effect of high dose folic acid supplementation in pregnancy on pre-eclampsia (FACT): double blind, phase III, randomised controlled, international, multicentre trial
What this study found
High-dose folic acid did not prevent pre-eclampsia or improve maternal or neonatal outcomes in this high-risk pregnancy population. Pre-eclampsia occurred in 169/1144 (14.8%) in the folic acid group versus 156/1157 (13.5%) in the placebo group (relative risk 1.10, 95% CI 0.90 to 1.34; P=0.37). Other key outcomes were also not improved, including severe pre-eclampsia (2.10% vs 1.4%; RR 1.52, 0.81 to 2.84), perinatal mortality (1.7% vs 2.7%; RR 0.63, 0.37 to 1.05), and NICU admission (22% vs 20%; RR 1.08, 0.91 to 1.28). The authors concluded that 4.0 mg daily folic acid from early second…
- Study & population
- Double-blind, phase III, randomized controlled international multicentre trial in pregnant women at high risk for pre-eclampsia, including those with pre-existing hypertension, prepregnancy diabetes, twin pregnancy, prior pre-eclampsia, or BMI ≥35 kg/m2.
- Intervention
- Pregnant women at high risk for pre-eclampsia were assigned to oral folic acid 4.0 mg daily, given as four 1.0 mg tablets, from 8 to 16 completed weeks of gestation until delivery.
- Key limitation
- The trial allowed background prenatal vitamins or low-dose folic acid, and more than 80% of participants reported prior folic acid or folic acid-containing vitamin use, which may have reduced contrast between groups.
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Open PDFOriginal abstract
Abstract 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.