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High-dose folic acid doesn’t prevent pre-eclampsia

But women should still take supplements before and in early pregnancy to prevent neural tube defects

Louise Prime

Thursday, 13 September 2018

High-dose folic acid supplementation beyond the first trimester of pregnancy is of no benefit in preventing pre-eclampsia in at-risk women, according to new research. But commentators on the international study*, published today in the BMJ, stressed that all women must still be recommended to take low-dose folic acid supplements before and during early pregnancy to help prevent neural tube defects.

Previous observational studies had suggested that folic acid might reduce the risk of pre-eclampsia in women with identified risk factors, and a dose-response effect. However, a large randomised controlled trial had not been done until now.

An international research team led from Ottawa, Canada, recruited women from 70 obstetrical centres in Argentina, Australia, Canada, Jamaica, and the UK, who had at least one high risk factor for pre-eclampsia (pre-existing hypertension, pre-pregnancy diabetes (type 1 or 2), twin pregnancy, pre-eclampsia in a previous pregnancy, or body mass index ≥35). They randomised 2,464 women to receive either daily high-dose folic acid (four 1.0mg oral tablets) or placebo, from randomisation (at 8-16 completed weeks of gestation) until delivery. Participants could continue taking prenatal vitamins or low-dose folic acid supplements containing up to 1.1mg of folic acid.

The primary outcome of pre-eclampsia – defined as hypertension presenting after 20 weeks’ gestation with major proteinuria or HELLP syndrome (haemolysis, elevated liver enzymes, low platelets) – occurred in 169/1144 (14.8%) women in the folic acid group, compared with 156/1157 (13.5%) in the placebo group (relative risk 1.10, and not a statistically significant difference). The study authors also reported that there was no evidence of differences between the groups for any other adverse maternal or neonatal outcomes.

They concluded: “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.”

They added: “However, folic acid supplementation remains indicated in preconception and early pregnancy but there is a need to define when to discontinue supplementation as current clinical practice guidelines do not provide clear guidance beyond the first trimester.”

In their linked editorial**, UK experts commented: “Recommendation of low dose folic acid supplementation before pregnancy and in the first trimester must continue for prevention of neural tube defects. But Wen and colleagues’ trial does not support higher dose folic acid supplements for the prevention of pre-eclampsia. All pregnant women and their families hope for a healthy pregnancy and a happy outcome; until we find additional ways to prevent pre-eclampsia, thousands of women each year will not achieve this goal.”


*Wen SW, White R, Rybak N, et al. Effect of high dose folic acid supplementation in pregnancy on pre-eclampsia (FACT): double blind, phase III, randomised controlled, international, multicentre trial. BMJ 2018; 362: k3478 doi: 10.1136/bmj.k3478.
** Myers JE, Green M, Chappell LC. Why is the search for pre-eclampsia prevention so elusive? BMJ 2018; 362: k3536 doi: 10.1136/bmj.k3536.

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