A Cochrane review included 5 studies with a total of 5 6105 women. Daily folic acid supplementation (alone or in combination with other vitamins and minerals) prevented NTDs compared with no interventions/placebo or vitamins and minerals without folic acid (RR 0.28, 95% CI 0.15 to 0.52; 5 trials, n=6105). Only one study assessed the incidence of NTDs and the effect was not statistically significant (RR 0.08, 95% CI 0.00 to 1.33) although no events were found in the group that received folic acid. Folic acid had a significant protective effect for reoccurrence of NTD (RR 0.32, 95% CI 0.17 to 0.60; 4 trials, n=1949). Daily dose over 0.4 mg reduced NTDs clearly (RR 0.30, 95% CI 0.16 to 0.56; 4 trials, n=5741), however with dose of 0.36 mg the reduction was not significant (RR 0.12, 95% CI 0.01 to 2.29; 1 trial, n=364). There is no statistically significant evidence of prevention of cleft palate, cleft lip, congenital cardiovascular defects, miscarriages or any other birth defects.
Comment: The level of evidence is downgraded by study quality (unclear allocation concealment and blinding in some studies) and upgraded by large magnitude of effect.