Canadian researchers add that while taking these supplements in later pregnancy (beyond the first trimester) has no significant effect, a low dose before and during early pregnancy does prevent birth defects, such as spina bifida, and as such is still recommended for all women.
“A high daily dose (4.0 milligrams (mg)) of folic acid might be needed for these women because they may have placental, endothelial, and metabolic defects (including those of folate metabolism) leading to an increased risk of developing pre-eclampsia,” said the team, led by Dr Shi Wu Wen, professor of clinical epidemiology at the Ottawa Hospital Research Institute in Canada.
The results provide clarification to the generally inconsistent body of studies that look into folic acid’s effect on pre-eclampsia in women susceptible to the condition.
Observational studies have pointed to link between folic acid supplementation and a lower risk of other pregnancy complications such as pre-eclampsia.
However, an ongoing challenge in studies of this nature is the influence of various dietary and lifestyle factors, which make firm conclusions difficult to pin down.
Other approaches, like antioxidant supplements, have been equally biologically plausible but have failed to translate into clinical benefits.
What the researchers stress though is folic acid’s effectiveness in preventing neural tube defects that is accompanied by reliable supporting evidence.
The randomised controlled trial - the Folic Acid Clinical Trial (FACT) – enrolled 2,301 pregnant women who were between 8 and 16 weeks' pregnant at the beginning of the study and had at least one risk factor for pre-eclampsia.
Women were randomly placed into one of two groups to receive either a daily high dose (4mg) of folic acid or a placebo in addition to up to 1.1mg of folic acid throughout pregnancy.
After taking account of factors that could have affected the results, they found that pre-eclampsia occurred in 169 out of 1,144 (14.8%) women in the folic acid group and 156 out of 1,157 (13.5%) in the placebo group.
The research team found no evidence of differences between the groups for any other adverse outcomes.
‘An important public health issue’
In trying to explain their observations, the team said that their 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 trial deals with an important public health issue,” they added. “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.”
Commenting on the study in an accompanying editorial, Lucy Chappell, NIHR research professor in obstetrics at King’s College London, UK alongside colleagues said the results were "another disappointment in the long search for a more effective measure to prevent pre-eclampsia".
“Recommendation of low dose folic acid supplementation before pregnancy and in the first trimester must continue for prevention of neural tube defects,” they added.
“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.”
Published online: doi.org/10.1136/bmj.k3478
“Effect of high dose folic acid supplementation in pregnancy on pre-eclampsia (FACT): double blind, phase III, randomised controlled, international, multicentre trial.”
Authors: Shi Wu Wen et al.