Randomized clinical trial to evaluate the efficacy of high dose folic acid to prevent the occurrence of congenital malformations: a further opportunity to promote preconceptional care.

Strong evidence shows that a supplementation of folic acid (FA) during the periconceptional period reduces the risk of neural tube defects (NTD). Secondary analysis of the Hungarian randomized trial as well as some observational studies suggest that this supplementation can also reduce the risk of other congenital malformations (including congenital heart defects and perhaps Down Syndrome) as well as other adverse reproductive outcomes (including prematurity). Some observational studies suggest that, compared to the standard dose of 0.4 mg daily, the higher dose of FA (4.0 mg/day), recommended uniformly to prevent NTD recurrence, could also reduce further the risk of NTD occurrence and possibly reduce the risk for other birth defects. To evaluate this hypothesis, a randomized clinical trial (RCT) of FA vs. placebo is not feasible because of ethical considerations and the need for huge sample size. The present study evaluates the overall rate of CM (the primary outcome) and that of selected CM, miscarriage, recurrent abortion, pre-eclampsia, abruptio placentae, small-for-gestational age, preterm birth and twinning (the secondary outcomes) in a group of women intending to get pregnant.