Effects and Safety of Periconceptional Folate Supplementation for Preventing Birth Defects

Use folic acid before conception and up to 12 weeks of pregnancy for preventing neural tube defects.

A Cochrane review [Abstract] 1 included 5 studies with a total of 7391 women (2033 with a history of a pregnancy affected by a neural tube defect (NTD) and 5358 with no history of NTDs. 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 0.31, 95% CI 0.17 to 0.58; 5 trials, n=6708). 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.

A systematic review 2 included 24 studies with a total over 58 860participants. In 1 RCT from Hungary incidence of NTD for folic acid supplementation compared with trace element supplementation was 0% vs 0.25% (Peto odds ratio [OR], 0.13, 95% CI 0.03 to 0.65; n=4862). Cohort studies beneficial associations (ORs ranged from 0.11 to 0.27, n=19 982). 3 of 4 case-control studies reported ORs ranging from 0.6 to 0.7 (n over 7121). Evidence of benefit led to food fortification in the United States beginning in 1998, after which no new prospective studies have been conducted. More recent case-control studies drawing from data collected after 1998 have not demonstrated a protective association consistently with folic acid supplementation.

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.

References

• De-Regil LM, Peña-Rosas JP, Fernández-Gaxiola AC et al. Effects and safety of periconceptional oral folate supplementation for preventing birth defects. Cochrane Database Syst Rev 2015;(12):CD007950. [PubMed]
• Viswanathan M, Treiman KA, Kish-Doto J et al. Folic Acid Supplementation for the Prevention of Neural Tube Defects: An Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA 2017;317(2):190-203. [PubMed]