Periconceptional folic acid and risk for neural tube defects among higher risk pregnancies

Birth Defects Res. 2019 Nov 15;111(19):1501-1512. doi: 10.1002/bdr2.1579. Epub 2019 Aug 21.


Background: Women with a previous neural tube defect (NTD)-affected pregnancy are recommended to consume 4,000 μg daily folic acid (FA) for prevention (10 times the general-population recommendation). Protection from doses between 400 and 4,000 μg for this and other higher risk groups is unclear.

Methods: In the case-control Slone Birth Defects Study (1988-2015), we examined the associations between periconceptional FA doses and NTDs among four higher risk groups: NTD family history, periconceptional antiepileptic drug exposure (AED), pregestational diabetes, and prepregnancy obesity. Mothers completed standardized interviews about pregnancy events and exposures. FA categorizations were based on (a) supplements only and (b) supplements and diet ("total folate"). We estimated odds ratios (ORs) and 95% confidence intervals (CIs) (adjusted for age and study center) using logistic regression.

Results: Cases and controls included: 45 and 119 with family history, 25 and 108 with AED exposure, 12 and 63 with pregestational diabetes, 111 and 1,243 with obesity. Daily FA supplementation was associated with lower NTD risk compared to no supplementation (adjusted ORs were 0.33 [95% CI 0.13, 0.76] for family history, 0.31 [0.09, 0.95] for AED exposure, 0.25 [0.04, 1.05] for pregestational diabetes, 0.65 [0.40, 1.04] for obesity). Though estimates were imprecise, as total folate increased stronger point estimates were observed, notably among family history. No mothers with a prior NTD-affected pregnancy supplemented with 4,000 μg.

Conclusions: Our findings reinforce that all women of childbearing potential should consume at least 400 μg FA/day to protect against NTDs. Higher risk groups may benefit from higher doses.

Keywords: folic acid; neural tube defects; obesity; prevention; recurrence.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Case-Control Studies
  • Diabetes, Gestational
  • Dietary Supplements
  • Female
  • Folic Acid / metabolism*
  • Folic Acid / therapeutic use*
  • Humans
  • Logistic Models
  • Mothers
  • Neural Tube Defects / etiology
  • Neural Tube Defects / prevention & control*
  • Obesity
  • Odds Ratio
  • Pregnancy
  • Risk Factors
  • Young Adult


  • Folic Acid