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

Preeclampsia is a serious medical condition, affecting approximately 3% to 5% of pregnancies, accounting for more than 35,000 maternal deaths annually worldwide and an important factor in maternal morbidity. Preeclampsia affects multiple organ systems and leads to an increased risk of other severe maternal and neonatal complications in pregnancy. Since delivery of the placenta is the only known cure, preeclampsia is a leading cause of indicated preterm delivery, perinatal morbidity, mortality, and long term disability. Epidemiological studies of the association between folic acid supplementation and the incidence of preeclampsia have shown a potential protective effect, although findings have been inconsistent. The current study, the Folic Acid Clinical Trial, was designed and conducted to evaluate the effect of daily supplementation with 4.0 mg folic acid beyond the first trimester on the risk of developing preeclampsia among pregnant women at high risk of this condition.

The researchers performed a randomized, double-blind, placebo-controlled, phase III international multicenter trial carried out at 70 high-risk obstetric referral centers covering diverse populations in Canada, Argentina, Australia, Jamaica, and the United Kingdom. Pregnant women eligible for participation in the trial included those between 8 and 16 completed weeks of gestation with a confirmed viable fetus and at least one of the following risk factors for preeclampsia: preexisting hypertension, prepregnancy diabetes (type 1 or 2), twin pregnancy, preeclampsia in a previous pregnancy, or body mass index greater than 35 kg/m2. Documentation of body mass index measured (height and weight) between 3 months before pregnancy and up to the time of randomization was required as part of study eligibility. We excluded women if they had a known fetal anomaly or fetal death, a history of maternal medical complications (including renal disease with altered renal function), epilepsy, cancer, or current use of folic acid antagonists, illicit drug or alcohol misuse (>2 drinks daily) during current pregnancy, known hypersensitivity to folic acid, multiple pregnancy, previous participation in this trial, or a history or presence of any important disease or condition that would preclude the use of high-dose (up to 5.1 mg daily) folic acid.

The primary outcome was preeclampsia, defined as hypertension presenting after 20 weeks' gestation with major proteinuria or HELLP syndrome (hemolysis, elevated liver enzymes, low platelets). There were 2464 pregnant women with at least 1 high-risk factor for preeclampsia randomized 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. Preeclampsia occurred in 169/1144 (14.8%) women in the folic acid group and 156/1157 (13.5%) in the placebo group (relative risk [RR], 1.10; 95% confidence interval [CI], 0.90–1.34; P = 0.37). There was no evidence of differences between the groups for any other adverse maternal or neonatal outcomes.

The researchers concluded that supplementation with 4.0 mg/d folic acid beyond the first trimester does not prevent preeclampsia in women at high risk of this condition.