Are We Done? Predicting the Impact of Supplement Use and Mandatory and Voluntary Folic Acid Fortification on the Risk of Neural Tube Defects in the United States
Authors: Crider Krista Stimson , Devine Owen , Qi Yan Ping , Tinker Sarah C. , Berry Robert J 
Published: November 2023

The risk of a neural tube defect (NTD)‐affected pregnancy increases about 10 fold as red blood cell (RBC) folate status decreases from a sufficient status to a deficient status (<340 nmol/L), with the optimal RBC folate concentration for the prevention of NTD having been recently defined as >906 nmol/L by the World Health Organization. Since the implementation of mandatory folic acid fortification in the U.S. population, RBC folate concentrations have increased and NTD prevalence has decreased about35%. There are three primary sources of folic acid in the U.S. diet: folic acid supplements (typically 400 μg ‐ 1,000 μg per dose), ready‐to‐eat breakfast cereals (allowed but not required to include 400 μg per serving) and cerealgrain flour labeled as enriched (140 μg per 100g; resulted in ~140 μg increase in daily average usual intake). It is critical to determine if this demonstrated effective intervention has reached its full potential. To determine if women in the U.S. were still at risk of folate sensitive NTDs even in the presence of folic acid fortification we used RBC folate concentration distributions from the 2007–2012 National Health and Nutrition Examination Survey (NHANES) among U.S. women of childbearing age (12–49 years) to estimate NTD prevalence by source of folic acid intake. We applied a prediction model developed using Bayesian methods to estimate the risk of NTD‐affected pregnancies at specific RBC folate concentrations. The overall predicted NTD risk was 6.9 per 10,000 births (95%uncertainty interval [UI] 5.0–9.0) based on a median RBC folate concentration of 1220 nmol/L (log of the variance σ =0.400). RBC folate concentrations were higher for supplement users compared to non‐users, however, there was no difference in their predicted NTD risk. This is consistent with the NTD risk observed between folic acid supplement users and non‐users among existing epidemiological studies. However, women whose only reported source of folicacid was cereal grain products labeled as enriched had RBC concentrations (median1075 nmol/L) that suggest significantly elevated predicted NTD risks (8.8 NTD sper 10,000; 6.7–11.1 95% uncertainty interval) compared to women who consumed additional sources of folic acid (i.e. ready‐to‐eat cereal and/or supplements)in their diet (median NTD prevalence: 4–6 per 10,000 births). Population level estimated NTD prevalence was driven by slight shifts in distribution at the lower RBC folate concentration because NTD risk increases very rapidly with decreasing folate concentrations. Additional analyses are underway to determine usual folic acid intake among women with optimal RBC folate concentrations. Folate‐sensitive NTD prevention interventions could be considered to target U.S. women of reproductive age consuming cereal grain products labeled as enriched as their only source of folic acid.

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