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

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. For the folic acid arm, 1144 participants were randomized and for the placebo arm 1157 were randomized; 2301 participants were included in intention-to-treat analyses. The trial was conducted at 70 obstetrical centres in Argentina, Australia, Canada, Jamaica, and the United Kingdom.

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. Placebo was the comparator, and prenatal vitamins or low-dose folic acid supplements containing up to 1.1 mg folic acid were allowed.

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 trimester until delivery should not be used for pre-eclampsia prevention.

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. Outcome denominators varied across endpoints, and some secondary neonatal outcomes were infrequent, limiting precision. Baseline folate status was not fully characterized for the whole cohort.