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US Preventive Services Task Force
Evidence Report
January 10, 2017

Folic Acid Supplementation for the Prevention of Neural Tube DefectsAn Updated Evidence Report and Systematic Review for the US Preventive Services Task Force

Author Affiliations
  • 1RTI International, Evidence-based Practice Center, University of North Carolina at Chapel Hill
  • 2RTI International, Research Triangle Park, North Carolina
  • 3Cecil G. Sheps Center for Health Services Research, University of North Carolina at Chapel Hill
  • 4Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill
JAMA. 2017;317(2):190-203. doi:10.1001/jama.2016.19193
Abstract

Importance  Neural tube defects are among the most common congenital anomalies in the United States. Periconceptional folic acid supplementation is a primary care–relevant preventive intervention.

Objective  To review the evidence on folic acid supplementation for preventing neural tube defects to inform the US Preventive Services Task Force for an updated Recommendation Statement.

Data Sources  MEDLINE, Cochrane Library, EMBASE, and trial registries through January 28, 2016, with ongoing surveillance through November 11, 2016; references; experts.

Study Selection  English-language studies of folic acid supplementation in women. Excluded were poor-quality studies; studies of prepubertal girls, men, women without the potential for childbearing, and neural tube defect recurrence; and studies conducted in developing countries.

Data Extraction and Synthesis  Two investigators independently reviewed abstracts, full-text articles, and risk of bias of included studies. One investigator extracted data and a second checked accuracy. Because of heterogeneity, data were not pooled.

Main Outcomes and Measures  Neural tube defects, harms of treatment (twinning, respiratory outcomes).

Results  A total of 24 studies (N > 58 860) were included. In 1 randomized clinical trial from Hungary initiated in 1984, incidence of neural tube defects for folic acid supplementation compared with trace element supplementation was 0% vs 0.25% (Peto odds ratio [OR], 0.13 [95% CI, 0.03-0.65]; n = 4862). Odds ratios from cohort studies recruiting participants between 1984 and 1996 demonstrated beneficial associations and ranged from 0.11 to 0.27 (n = 19 982). Three of 4 case-control studies with data from 1976 through 1998 reported ORs ranging from 0.6 to 0.7 (n > 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, with ORs ranging from 0.93 to 1.4 and confidence intervals spanning the null (n > 13 990). Regarding harms, 1 trial (OR, 1.40 [95% CI, 0.89-2.21]; n = 4767) and 1 cohort study (OR, 1.04 [95% CI, 0.91-1.18]; n = 2620) found no statistically significant increased risk of twinning. Three systematic reviews found no consistent evidence of increased risk of asthma (OR, 1.06 [95% CI, 0.99-1.14]; n = 14 438), wheezing, or allergy.

Conclusions and Relevance  In studies conducted before the initiation of food fortification in the United States in 1998, folic acid supplementation provided protection against neural tube defects. Newer postfortification studies have not demonstrated a protective association but have the potential for misclassification and recall bias, which can attenuate the measured association of folic acid supplementation with neural tube defects.

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