Modeling the Impact of Folic Acid Fortification and Supplementation on Red Blood Cell Folate Concentrations and Predicted Neural Tube Defect Risk in the United States: Have We Reached Optimal Prevention?

Am J Clin Nutr. 2018 Jun 1;107(6):1027-1034. doi: 10.1093/ajcn/nqy065.


Background: The US CDC and the Institute of Medicine recommend that women capable of becoming pregnant consume ≥400 µg synthetic folic acid/d to prevent neural tube defects (NTDs). The United States has 3 sources of folic acid: fortified enriched cereal grain products (ECGPs), fortified ready-to-eat (RTE) cereals, and dietary supplements.

Objective: Our objectives were as follows: 1) to estimate the usual daily folic acid intake and distributions of red blood cell (RBC) folate concentrations among women consuming folic acid from different sources; 2) to assess the usual daily total folic acid intake associated with optimal RBC folate concentrations for NTD prevention; 3) to predict NTD prevalence; and 4) to estimate the number of preventable folate-sensitive NTDs.

Design: NHANES data (2007-2012) for nonpregnant women of reproductive age (12-49 y) were used to estimate usual daily intakes of synthetic folic acid and natural food folate. We applied existing models of the relation between RBC folate concentrations and NTD risk to predict NTD prevalence.

Results: Based on the distribution of overall RBC folate concentrations (4783 women), the predicted NTD prevalence was 7.3/10,000 live births [95% uncertainty interval (UI): 5.5-9.4/10,000 live births]. Women consuming folic acid from ECGPs as their only source had lower usual daily total folic acid intakes (median: 115 µg/d; IQR: 79-156 µg/d), lower RBC folate concentrations (median: 881 nmol/L; IQR: 704-1108 nmol/L), and higher predicted NTD prevalence (8.5/10,000 live births; 95% UI: 6.4-10.8/10,000 live births) compared with women consuming additional folic acid from diet or supplements. If women who currently consume folic acid from ECGPs only (48% of women) consumed additional folic acid sources, 345 (95% UI: 0-821) to 701 (95% UI: 242-1189) additional NTDs/y could be prevented.

Conclusions: This analysis supports current recommendations and does not indicate any need for higher intakes of folic acid to achieve optimal NTD prevention. Ensuring 400 µg/d intake of folic acid prior to pregnancy has the potential to increase the number of babies born without an NTD.

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Computer Simulation
  • Erythrocytes / chemistry*
  • Erythrocytes / metabolism
  • Female
  • Folic Acid / administration & dosage*
  • Folic Acid / blood*
  • Folic Acid / chemistry
  • Folic Acid / pharmacology
  • Food Analysis
  • Humans
  • Middle Aged
  • Models, Biological
  • Neural Tube Defects / epidemiology
  • Neural Tube Defects / prevention & control*
  • Nutrition Surveys
  • Pregnancy
  • Prenatal Nutritional Physiological Phenomena
  • Risk Factors
  • United States / epidemiology
  • Young Adult


  • Folic Acid