Folate Status of Young Canadian Women after Folic Acid Fortification of Grain Products

Bringing clarity to the role of MTHFR variants in neural tube defect prevention

To the Editor: Low concentrations of folate are associated with an increased risk of neural tube defects, while preconception supplementation with folic acid attenuates that risk. 1 The government of Canada mandated that all flour and some corn and rice products be fortified with folic acid, a policy that was fully implemented by January 1998 [G. Carson, Grain Based Products, Robin Hood Multifoods, Inc., Canada, personal communication, 2001]. We studied the effect of this fortification program among women of reproductive age, age 18–42 years. Comparing data from before and after fortification, we considered all red blood cell (RBC) folate and serum vitamin B12 (Se B12) samples analyzed by MDS Laboratories (Toronto, Ontario, Canada), which provides diagnostic services to approximately one-third of community-based patients in the province of Ontario. These tests, paid for under Ontario’s publicly funded universal Ontario Health Insurance Plan, were ordered on clinical grounds, but the reasons were not available. Vitamin concentrations were determined by competitive protein binding (Bio-Rad Laboratories, Mississauga, Ontario, Canada), with a maximum reporting limit of 1,450 nmol/L for RBC folate and 1,600 pmol/L for Se B12. Identifiers were removed to protect patient confidentiality, and the Ethics Review Boards of Sunnybrook and Women’s College Health Sciences Centre and MDS Laboratories approved this study. A total of 8,408 consecutive, nonredundant samples were analyzed for the intervals of January 1, 1996 to December 31, 1997 (prefortification) and 30,061 samples for January 1, 1998 to December 31, 2000 (postfortification). The mean participant age was 31.8 years for both periods. The geometric mean RBC folate concentration rose from 527 nmol/L prefortification to 741 nmol/L after January 1, 1998 (mean difference 214 nmol/L) (Table 1 and Figure 1). The respective mean concentrations for Se B12 were 276 and 270 pmol/L (mean difference −6 pmol/L) (Table 1 and Figure 1). Similar trends were seen for the fifth-percentile concentrations of RBC folate and Se B12 (Table 1). Table 1: Red Blood Cell (RBC) -Folate and Serum Vitamin B12 (Se B12) Concentrations before and after Folic AcidFIGURE 1: Mean and 95% confidence interval concentrations of red blood cell (RBC) folate (upper curve) and serum vitamin B12 (Se B12; lower curve) after folic acid fortification (vertical line).We did not obtain information on the clinical indications for folate and cobalamin (vitamin B12) testing, which is a potential source of study bias. Furthermore, we did not account for use of folic acid supplements, which, in addition to lead-time compliance with folate fortification by the milling industry, could also explain the rise in RBC folate concentrations before January 1998. Because Se B12 levels have remained nearly constant over time, however, multivitamin supplement use could not account for more than a small portion of the rise in RBC folate. As in the U.S. general population, 2,3 Canada’s national folic acid fortification program has probably enhanced the folate status of women of reproductive age. Experimental data have demonstrated that withdrawal of dietary folic acid for as little as 12 weeks can significantly reduce RBC folate concentrations in women, 4 suggesting that an increase in RBC folate concentrations would be evident soon after the addition of folic acid to flour. We must highlight the fact that Se B12 concentrations have remained relatively constant since folic acid food fortification was introduced. Although cobalamin deficiency too has been implicated in the formation of neural tube defects, 5 its detection before and during pregnancy is a point of controversy. 6–8 Thus, with the rising popularity of ovo-lacto vegetarianism, 9 unrecognized vitamin B12 insufficiency may become an issue among women of reproductive age. 6 There is an urgent need to consider both the addition of synthetic vitamin B12 to current fortification programs 10 and the long-term health consequences of fortifying flour with folic acid but not cobalamin. 11 Joel G. Ray Marian J. Vermeulen Sheila C. Boss David E. C. Cole

Divergence between dietary folate intake and concentrations in the serum and red blood cells of aging males in the United States

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.Support or Funding InformationNo external support.

Focused Revision: Policy statement on folic acid and neural tube defects

Red blood cell (RBC) folate concentrations are a potential biomarker of folate-sensitive neural tube defect (NTD) risk in the population. The purpose of this analysis was to describe women in the U.S. population with RBC folate concentrations below those associated with optimal NTD prevention. We used data from the 2007 to 2012 National Health and Nutrition Examination Survey (NHANES) to assess the RBC folate status of U.S. women of childbearing age relative to risk categories for NTD risk based on RBC folate concentrations. We defined suboptimal RBC folate concentrations as those associated with a prevalence of ≥9 NTDs per 10,000 live births. Among nonpregnant women age 12 to 49 years, 22.8% (95% Confidence Interval: 21.1, 24.6) had suboptimal RBC folate concentrations. Women had greater odds of having a suboptimal RBC folate concentration if they did not use dietary supplements containing folic acid; had mandatorily fortified enriched cereal grain products as their only source of folic acid; were non-Hispanic black or Hispanic; or were current smokers. Based on RBC folate concentrations, we would predict that the majority of U.S. women of reproductive age are not at increased risk for folate sensitive NTDs in the presence of mandatory folic acid fortification. Prevention policies and programs can be aimed at population subgroups identified as having higher predicted risk for folate-sensitive NTDs based on RBC folate concentrations.

Red blood cell folate concentrations increase more after supplementation with [6 S]-5-methyltetrahydrofolate than with folic acid in women of childbearing age

BackgroundA recent study reported that 22.8% of U.S. women of childbearing age have folate insufficiency, defined as red blood cell (RBC) folate below optimal concentrations needed for neural tube defect (NTD) prevention per guidelines established by the World Health Organization. Clinical trials have shown that consuming 400 μg of folic acid daily prevents NTDs.ObjectiveWe assessed the daily usual total folic acid intake and RBC folate status of women of childbearing age. We estimated the proportion of women consuming ≥400 μg folic acid/day, the daily amount recommended for NTD prevention for all women capable of becoming pregnant.MethodsWe used 2007–2012 data on non‐pregnant women aged 12–49 years (n = 4783) from the National Health and Nutrition Examination Survey (NHANES) and estimated daily usual total folic acid intake from all fortified foods and dietary supplements. Folate insufficiency was defined as an RBC folate concentration of <748 nmol/L using the NHANES microbiologic assay, which is associated with prevalence of NTDs of ≥9 cases per 10,000 live births.ResultsAmong all women in our study, 21.2% (95% confidence interval [CI]: 18.0, 24.3) had an average total folic acid intake of ≥400 μg /day from fortified foods and supplements. The prevalence of folate insufficiency was 22.5% (95% CI: 20.3, 24.9). Among the subgroup of women with folate insufficiency (n = 1196), only 3.9% (95% CI: 2.0, 5.7) achieved the recommended daily intake of folic acid. Among all women in our study, median usual daily total folic acid intake was highest among non‐Hispanic Whites (264 μg) and lowest among non‐Hispanic Blacks (185 μg). However, among women with folate insufficiency, the median usual daily total folic acid intake did not differ by race/ethnicity. Among women with folate insufficiency, 69.7% (95%CI: 64.8, 74.1) had mandatorily fortified foods (i.e., enriched cereal grain products) as their only source of folic acid; 12.6% (95% CI: 9.7, 16.1) reported taking supplements containing folic acid in the previous 30 days. Among folate‐insufficient women who did not use supplements, less than 1% had usual total folic acid intake ≥400 μg/day.ConclusionsThe majority of U.S. women of childbearing age with RBC folate below the optimal concentration do not consume the amount of folic acid recommended for NTD prevention. Targeted programs and guidance might increase folic acid intake among groups of women at higher risks for folate insufficiency.Support or Funding InformationThis work was supported by the CDC.

Folic acid: a public-health challenge

BackgroundIn 1998, the United States (US) implemented mandatory folic acid fortification of enriched cereal grain products (ECGP) to prevent neural tube defects (NTD) in newborns. NTD rates remained highest among Hispanic births. Voluntary fortification of corn masa flour was approved in 2016, without improvement in NTD rates. This review aims to understand folic acid consumption among Hispanic women in the US before and after voluntary fortification.MethodsA systematic search was conducted in PubMed, Embase, and Scopus from inception to September 2024 using the keywords folic acid, Hispanic Americans, and fortification. Study designs included descriptive, cross-sectional, and observational cohort. Studies in any language reporting the consumption of folic acid fortified foods among Hispanic women of reproductive age in the US were eligible. Study variables were compared to non-Hispanic White (NHW) women when available. Findings were summarized descriptively.ResultsOf 446 publications, eight studies (n = 20,123) met inclusion criteria. All studies reported on folic acid fortified foods, four characterized folic acid intake and acculturation factors, three quantified red blood cell (RBC) folate concentrations, and two described NTD rates. Hispanic women consumed grains, cereals, bread, flour, pasta, and corn masa flour. Most Hispanic women obtained folic acid from ECGP only. Hispanic women consumed more dietary folic acid than NHW women pre-voluntary fortification (406–456 µg (mcg) versus 349 mcg daily, p < 0.001) but less total folic acid when supplements were included (244 mcg versus 332 mcg daily, p < 0.05). Monolingual Spanish-speakers had the lowest total intake (224 mcg daily, p < 0.05). RBC folate concentrations were lower among Hispanic women compared to NHW women pre-voluntary fortification (963 nmol per liter (nmol/L) versus 1043 nmol/L) but showed no improvement post-fortification. Voluntary fortification did not significantly increase folic acid intake or reduce the proportion with inadequate intake; however, monolingual Spanish-speakers demonstrated higher intake and RBC folate concentrations. NTD rates remained similar between Hispanic (7.5/10,000 live births) and NHW women (7.1/10,000 live births) post-fortification. The certainty of evidence, assessed using the Grading of Recommendations, Assessment, Development, and Evaluations framework, ranged from low to very low across outcomes.ConclusionsThere is a paucity of literature to describe the rate, influencing factors, and prevalence disparities in NTD among Hispanic women living in the US despite its public health importance. This review provides a current summary on the disparities in folic acid intake and NTD rates between Hispanic and NHW women, and the effectiveness of voluntary fortification targeting populations at higher risk. Research initiatives investigating the factors influencing these disparities and future targeted interventions are necessary.

Four Years After Enhanced Folic Acid Fortification of the Canadian Food Supply — How Are We Doing?

Steady state folate concentrations achieved with 5 compared with 1.1 mg folic acid supplementation among women of childbearing age

Folic acid supplementation and malaria susceptibility and severity among people taking antifolate antimalarial drugs in endemic areas.

Fortification of bakery and corn masa–based foods in Mexico and dietary intake of folic acid and folate in Mexican national survey data

MTHFR 677C→T genotype is associated with folate and homocysteine concentrations in a large, population-based, double-blind trial of folic acid supplementation