Though folic acid supplementation is recommended during preconception and early pregnancy, high doses do not benefit women who are at high risk of developing pre-eclampsia after the first trimester, according to a study published in The BMJ.

Investigators for the Folic Acid Clinical Trial (FACT) Collaborating Group conducted a phase 3, randomized, double-blind, international, multicenter clinical analysis to study whether high-dose folic acid supplementation would prevent pre-eclampsia in women with at least 1 of the following risk factors: pre-existing hypertension, prepregnancy diabetes, twin pregnancy, pre-eclampsia in a previous pregnancy, or body mass index ≥35.

The researchers invited pregnant women between 8 and 16 weeks of gestation with at least one of the risk factors for pre-eclampsia listed above to receive either high-dose folic acid 1 mg 4 times daily or placebo until delivery.

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The primary outcome was pre-eclampsia, which was defined as hypertension occurring later than 20 weeks’ gestation with major proteinuria or HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome. Secondary outcomes included maternal mortality, severe pre-eclampsia, placental abruption, preterm delivery, perinatal mortality, neonatal mortality, stillbirth, and neonatal morbidity.

Of the 6499 women screened for the analysis, 2464 were enrolled in the trial and randomly assigned to receive either folic acid supplements (n = 1228) or placebo (n = 1236). A total of 1144 women in the folic acid group and 1157 in the placebo group completed the study and were analyzed for main outcome.

Both groups had similar pregnancy characteristics, and 80% of women in both groups self-reported taking folic acid (supplementation or folic acid containing vitamins).

A total of 169 (14.8%) women receiving folic acid developed pre-eclampsia compared with 156 (13.5%) in the placebo group (relative risk, 1.10). No significant differences were observed in secondary outcomes.

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The authors reported that serum folate was significantly higher in blood samples from women who took folic acid supplements than in women who took placebo (average, 260.1 vs 77.8 nmol/L). In addition, erythrocyte folate levels were similar between both groups (2700 vs 2680 nmol/L). There were no significant differences in adverse events (reported or severe) between the 2 groups.

“Our well powered trial did not find benefit for high dose folic acid supplementation beyond the first trimester for the prevention of pre-eclampsia or related maternal and neonatal adverse outcomes,” the authors wrote. “The trial deals with an important public health issue: the lack of demonstrated benefit of high dose folic acid supplementation beyond the first trimester for women at high risk of developing pre-eclampsia indicates that high dose recommendation should now cease, and the search for an effective and acceptable strategy to prevent pre-eclampsia must continue.”


Wen SW, White RR, Rybak N, et al; for the FACT Collaborating Group. Effect of high dose folic acid supplementation in pregnancy on pre-eclampsia (FACT): double blind, phase III, randomized controlled, international, multicenter trial. BMJ. 2018;362:k3478.