Enriched Cereal Grain Products Research Articles

Folate and vitamin B12 usual intake and biomarker status by intake source in United States adults aged ≥19 y: NHANES 2007–2018

BackgroundFolate and vitamin B12 are important biomarkers of nutritional status of populations. ObjectivesThis study aims to estimate folate and vitamin B12 usual intakes among United States adults and examine folate and vitamin B12 biomarker status by intake source. MethodsWe analyzed data for United States adults aged ≥19 y from National Health and Nutrition Examination Survey 2007–2018 (n = 31,128), during which time voluntary corn masa flour (CMF) fortification was started. Usual intake was estimated using the National Cancer Institute method. Folate intake included folate from natural foods and folic acid from 4 sources: enriched cereal grain products (ECGPs), CMF, ready-to-eat cereals (RTEs), and folic acid–containing supplements (SUP). Vitamin B12 intake was mainly from food and supplements. ResultsThe median natural food folate intake (222 μg dietary folate equivalents (DFE)/d) was below the estimated average requirement (EAR) of 320 μg DFE/d. The proportions of those who consumed folic acid from ECGP/CMF only, ECGP/CMF + RTE, ECGP/CMF + SUP, and ECGP/CMF + RTE + SUP were 50%, 18%, 22%, and 10%, respectively. Median usual folic acid intakes (μg/d) were 236 (IQR: 152, 439) overall and 134, 313, 496, and 695 in the ECGP/CMF only, ECGP/CMF + RTE, ECGP/CMF + SUP, and ECGP/CMF + RTE + SUP folic acid consumption groups, respectively. Overall, 2.0% (95% CI: 1.7%, 2.3%) of adults, all of whom used folic acid supplements, consumed greater than the tolerable upper intake level (UL) of 1000 μg/d folic acid. The median usual vitamin B12 intake (μg/d) was 5.2 for vitamin B12 supplement nonusers and 21.8 for users. Consumption of RTE and/or supplements with folic acid was associated with higher serum and red blood cell folate concentrations. Vitamin B12 supplement users had significantly higher serum vitamin B12 concentrations. ConclusionsFolic acid fortification plays a critical role in helping United States adults meet the folate EAR. At current fortification levels, United States adults who do not consume supplements do not have the usual folic acid intake exceeding the UL.

Folate and Vitamin B12 Usual Intake and Biomarker Status in U.S. Adults: National Health and Nutrition Examination Survey (NHANES) 2007–2018

Abstract Objectives There are 3 major folic acid intake sources in the US—enriched cereal grain products (ECGP), ready-to-eat cereals (RTE), and folic acid containing supplements (SUP), generating 4 mutually exclusive consumption groups. This study aims to describe the contribution of these sources to folic acid intakes above the tolerable upper intake level (UL, 1000 mg/d), and their impact on red blood cell (RBC) folate and serum vitamin B12 concentrations. Methods We used data for nonpregnant US adults (≥19 y) from the National Health and Nutrition Examination Survey (NHANES) 2007–2018 (n = 31,128); serum vitamin B12 data were only available for 2011–2014 (n = 9,298). Median usual intake was estimated from two 24-h dietary recalls using the National Cancer Institute (NCI) method. Statistical analyses accounted for complex survey design using appropriate weights. Results The proportions of those who consumed folic acid from ECGP only, ECGP +RTE, ECGP +SUP, and ECGP +RTE +SUP were 50%, 18%, 22%, and 10%, and the median modelled usual folic acid intakes (mg/d) were 126 (interquartile range (IQR): 92,168), 308 (IQR: 267, 360), 490 (IQR: 347, 586), and 687 (IQR: 577, 767), respectively. Overall, 1.97% (95% CI: 1.96%, 1.98%) of adults consumed >UL. Adults who did not consume SUP did not have intakes >UL. The median usual vitamin B12 intake was 6.4 (IQR: 4.1, 11.7) mg/d. Consumption of RTE and/or SUP was associated with higher RBC folate concentrations (nmol/L) (ECGP only: 976 [95% CI: 963, 989], ECGP +RTE: 1130 [95% CI: 1110, 1150], ECGP +SUP: 1307 [95% CI: 1283, 1332], ECGP +RTE +SUP: 1467 [95% CI: 1439, 1495]). Serum vitamin B12 concentrations (pmol/L) were 350 (95% CI: 343, 356; ECGP only), 380 (95% CI: 366, 393; ECGP +RTE), 456 (95% CI: 440, 473; ECGP +SUP), and 485 (95% CI: 462, 509; ECGP +RTE +SUP). RBC folate deficiency (<305 nmol/L) was < 2% and vitamin B12 deficiency (<148 pmol/L) was < 6% across all folic acid consumption groups. Conclusions Folate and vitamin B12 deficiencies are low in the US population. At current fortification levels, US adults who do not consume supplements do not have usual folic acid intake exceeding the UL. Vitamin B12 intake among most US adults meets the recommended daily allowance (2.4 mg/d). Funding Sources This project was conducted with no specific support..

Impact of Voluntary Folic Acid Fortification of Corn Masa Flour on RBC Folate Concentrations in the U.S. (NHANES 2011–2018)

ObjectivesSurveillance data have highlighted continued disparities in neural tube defects (NTDs) among infants of Hispanic women of reproductive age (HWRA) in the United States. Starting in 2017, the US Food and Drug Administration implemented voluntary folic acid fortification of corn masa flour to reduce the risk of NTDs. We assessed folate status, using red blood cell (RBC) folate concentrations, in HWRA (aged 12–49 y) before (2011–2016) and after (2017–2018) voluntary fortification of corn masa, stratified by acculturation factors (i.e., primary language spoken at home, length of time residing in the US). MethodsCross-sectional data from the National Health and Nutrition Examination Survey (NHANES) 2011–2018 with available RBC folate concentrations for HWRA were analyzed. Additional analyses were conducted among HWRA whose only folic acid source was fortified foods (enriched cereal grain products (ECGP) only), including usual intake and NTD prevalence estimations based on previously published models. ResultsOverall, RBC folate concentrations (adjusted geometric means) among HWRA remained similar from 2011–2016 to 2017–2018, though RBC folate significantly increased in 2017–2018 among lesser acculturated HWRA consuming ECGP only. Concentrations for those who were born outside the US and resided in the US < 15 y increased from 894 nmol/L (95% CI: 844–946) in 2011–2016 to 1018 nmol/L (95% CI: 982–1162; p < 0.001) in 2017–2018. Primarily Spanish speaking HWRA who consumed ECGP only increased from 941 nmol/L (95% CI: 895–990) in 2011–2016 to 1034 nmol/L (95% CI: 966–1107; p = 0.03) in 2017–2018. We observed no significant changes in the proportion at risk of NTD (<748 nmol/L) and no changes in Bayesian model-based estimated NTD rates. ConclusionsThis early analysis following voluntary corn masa fortification found an increase in RBC folate concentrations in lesser acculturated groups relying on fortified foods as their primary folic acid source, though HWRA overall had no significant increase in folate concentrations. These early data suggests that there is remaining risk among Hispanics for folate sensitive NTDs; continued monitoring of folate status with NHANES will help assess the long-term efficacy of voluntary fortification. Funding SourcesNo funding sources outside of salaries.

Impact of Voluntary Folic Acid Fortification of Corn Masa Flour on RBC Folate Concentrations in the U.S. (NHANES 2011-2018).

Surveillance data have highlighted continued disparities in neural tube defects (NTDs) by race-ethnicity in the United States. Starting in 2016, the Food and Drug Administration (FDA) authorized voluntary folic acid fortification of corn masa flour to reduce the risk of neural tube defects (NTDs) among infants of Hispanic women of reproductive age. To assess the impact of voluntary corn masa fortification, cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) 2011–2018 for Hispanic women of reproductive age with available red blood cell (RBC) folate concentrations were analyzed, with additional analyses conducted among Hispanic women whose sole source of folic acid intake was fortified foods (enriched cereal grain products (ECGP) only), excluding ready-to-eat cereals and supplements. RBC folate concentration (adjusted geometric mean) among Hispanic women of reproductive age did not differ between 2011–2016 and 2017–2018, though RBC folate concentration increased significantly among lesser acculturated Hispanic women consuming ECGP only. Concentrations of RBC folate for those born outside the U.S and residing in the U.S <15 years increased from 894 nmol/L (95% CI: 844–946) in 2011–2016 to 1018 nmol/L (95% CI: 982–1162; p < 0.001) in 2017–2018. Primarily Spanish-speaking Hispanic women of reproductive age who only consumed ECGP saw an increase from 941 nmol/L (95% CI: 895–990) in 2011–2016 to 1034 nmol/L (95% CI: 966–1107; p = 0.03) in 2017–2018. By subpopulation, we observed no significant changes in the proportion at risk of NTDs (<748 nmol/L) and no changes in the model-based estimated NTD rates following voluntary corn masa fortification. This analysis suggests that there is a remaining risk among Hispanics for folate sensitive NTDs, though continued monitoring of folate status in future NHANES data cycles will help inform the long-term efficacy of voluntary fortification of corn masa flour.

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?

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. 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. 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. 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. 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.

Characteristics of U.S. Adults with Usual Daily Folic Acid Intake above the Tolerable Upper Intake Level: National Health and Nutrition Examination Survey, 2003-2010.

The Food and Drug Administration mandated that by 1998, all enriched cereal grain products (ECGP) be fortified with folic acid in order to prevent the occurrence of neural tube defects. The Institute of Medicine established the tolerable upper intake level (UL) for folic acid (1000 µg/day for adults) in 1998. We characterized U.S. adults with usual daily folic acid intake exceeding the UL. Using NHANES 2003–2010 data, we estimated the percentage of 18,321 non-pregnant adults with usual daily folic acid intake exceeding the UL, and among them, we calculated the weighted percentage by sex, age, race/ethnicity, sources of folic acid intake, supplement use and median usual daily folic acid intakes. Overall, 2.7% (standard error 0.6%) of participants had usual daily intake exceeding the UL for folic acid; 62.2% were women; 86.3% were non-Hispanic whites; and 98.5% took supplements containing folic acid. When stratified by sex and age groups among those with usual daily folic acid intake exceeding the UL, 20.8% were women aged 19–39 years. Those with usual daily intake exceeding the folic acid UL were more likely to be female, non-Hispanic white, supplement users or to have at least one chronic medical condition compared to those not exceeding the folic acid UL. Among those with usual daily folic acid intake exceeding the UL who also took supplements, 86.6% took on average >400 µg of folic acid/day from supplements. Everyone with usual daily folic acid intake exceeding the UL consumed folic acid from multiple sources. No one in our study population had usual daily folic acid intake exceeding the UL through consumption of mandatorily-fortified enriched cereal grain products alone. Voluntary consumption of supplements containing folic acid is the main factor associated with usual daily intake exceeding the folic acid UL.

Intake and Biomarkers of Folate and Risk of Cancer Morbidity in Older Adults, NHANES 1999-2002 with Medicare Linkage.

BackgroundAfter the 1998 mandatory folic acid fortification of enriched cereal-grain products in the U.S., safety concerns were raised that excess consumption of folic acid and high blood folate biomarkers detected in adults may increase the risk of certain types of cancer.MethodsBaseline data from about 1400 participants in the National Health and Nutrition Examination Survey (NHANES) 1999–2002, aged ≥ 57 years were linked to Medicare and mortality files through December 31, 2007. Using cox proportional hazards regression models, we assessed associations between dietary folate equivalents, folate biomarkers, the presence of unmetabolized folic acid and, overall cancer incidence.ResultsWith 8,114 person-years of follow-up (median follow-up, 6.3 years), about 125 cancer cases were identified. After adjusting for confounders, the hazard ratios of the highest quartile versus the second quartile of RBC folate and dietary folate equivalents were 0.54 (95% CI: 0.31–0.93) and 0.54 (95% CI: 0.30–0.95), respectively. Additionally, serum and RBC folate as continuous variables were inversely and significantly associated with cancer incidence (p<0.01). No significant associations were observed between the presence of unmetabolized folic acid, intake of naturally-occurring food folate or folic acid separately, and cancer incidence.ConclusionsHigh total folate intake and biomarkers in older adults appear to be protective against cancer in post-folic acid fortification years. This study does not show a negative impact of current level of folic acid fortification on cancer risk. As this is one of the few studies to examine the association between unmetabolized folic acid and cancer outcome, a study including a larger nationwide representative sample of the U.S. population is needed.

Unmetabolized Folic Acid by Sources of Folic Acid Intake Among US Adults in the National Health and Nutrition Examination Survey 2007‐2008

Circulating unmetabolized folic acid (UMFA) has generated great interest; however, its biological effects are unclear. The prevalence of UMFA by all sources of folic acid intake from foods and supplements has not been assessed among a nationally representative sample of US adults. Using cross‐sectional data from the National Health and Nutrition Examination Survey (NHANES) 2007‐2008, we examined the prevalence of any detectable circulating UMFA and UMFA &gt;1 nmol/L among US adults &gt;19 years (n=1,496), categorized into mutually exclusive groups according to sources of folic acid consumption: enriched cereal grain products (ECGP) only, ECGP + ready‐to‐eat cereals (RTE), ECGP + supplements (SUP), and ECGP+RTE+SUP. Intake was self‐reported and assessed using 2‐24 hour dietary recalls. We used chi‐square tests in SUDAAN to compare the prevalence across different exposure groups adjusting for sex, age, and race/ethnicity. Compared to those consuming ECGP only, the consumption of RTEs and/or supplements with folic acid was positively associated with detectable circulating UMFA and UMFA &gt;1 nmol/L. The proportion of adults with detectable UMFA among ECGP only, ECGP+RTE, ECGP+SUP, and ECGP+RTE+SUP was 95%, 97%, 96%, and 99%, respectively (p=0.0447). The proportion of adults with UMFA &gt;1 nmol/L among these same groups was 18%, 32%, 50%, and 62%, respectively (p&lt;0.0001). Among adults who consumed supplements containing folic acid, the prevalence of UMFA &gt;1 nmol/L was 47% and 68% among those consuming &lt;400 and &gt;400 µg folic acid/day from supplements, respectively (p=0.0014). These analyses indicate that the prevalence of circulating UMFA was high among US adults post‐folic acid fortification.

Usual folic acid intakes: a modelling exercise assessing changes in the amount of folic acid in foods and supplements, National Health and Nutrition Examination Survey, 2003–2008

The USA currently fortifies enriched cereal grain products (ECGP) with folic acid at 140 μg/100 g. In addition, folic acid can be voluntarily added to ready-to-eat cereals (RTEC) up to 400 μg/serving and it is found in many dietary supplements, most often at a dose of 400 μg. We sought to model folic acid intake under various fortification and supplementation scenarios. The National Health and Nutrition Examination Survey is a population-based cross-sectional survey representative of the non-institutionalized, civilian US population. Information on folic acid intake is collected in two 24 h dietary recalls and survey questions on dietary supplement use, which allows estimation of usual total folic acid intake. We modelled five different levels of folic acid fortification in ECGP, while varying the amounts in RTEC and dietary supplements. United States. US adults (n 14 353) aged ≥19 years; non-pregnant women of childbearing age (n 4272). The percentage of adults with usual daily folic acid intake above the tolerable upper intake level of 1000 μg was influenced more by the typical amount in supplements, while the median intake was influenced more by the ECGP fortification level. By manipulating the amount in at least two sources, it was possible to shift the distribution such that more women of childbearing age consumed the recommended intake of 400 μg of folic acid without increasing the percentage of adults with intake above the tolerable upper intake level. The results varied among population subgroups. Our results suggest that combined strategies are required to meet population recommendations for folic acid intake.

Contributions of enriched cereal-grain products, ready-to-eat cereals, and supplements to folic acid and vitamin B-12 usual intake and folate and vitamin B-12 status in US children: National Health and Nutrition Examination Survey (NHANES), 2003–2006

US children consume folic acid from multiple sources. These sources may contribute differently to usual intakes above the age-specific tolerable upper intake level (UL) for folic acid and to folate and vitamin B-12 status. We estimated usual daily folic acid intakes above the UL and adjusted serum and red blood cell folate, serum vitamin B-12, homocysteine, and methylmalonic acid (MMA) concentrations in US children by age group and by the following 3 major folic acid intake sources: enriched cereal-grain products (ECGP), ready-to-eat cereals (RTE), and supplements containing folic acid (SUP). We analyzed data in 4 groups of children aged 1-3, 4-8, 9-13, and 14-18 y from the National Health and Nutrition Examination Survey (NHANES), 2003-2006 (n = 7161). A total of 19-48% of children consumed folic acid from ECGP only. Intakes above the UL varied from 0-0.1% of children who consumed ECGP only to 15-78% of children who consumed ECGP+RTE+SUP. In children aged 1-8 y, 99-100% of those who consumed ≥ 200 μg folic acid/d from supplements exceeded their UL. Although < 0.5% of children had folate deficiency or low vitamin B-12 status, the consumption of RTE or SUP with folic acid was associated with higher mean folate and vitamin B-12 concentrations and, in some older children, with lower homocysteine and MMA concentrations. Our data suggest that the majority of US children consume more than one source of folic acid. Postfortification, the consumption of RTE or SUP increases usual daily intakes and blood concentrations of folate and vitamin B-12.

Folic acid source, usual intake, and serum folate concentrations in US children, the National Health and Nutrition Examination Survey (NHANES) 2003–2006

Our objective was to estimate among US children usual folic acid intake above the tolerable upper intake levels (UL) established for that age group and folate concentrations by three major folic acid sources: enriched cereal grain products (ECGP), ready‐to‐eat cereals (RTE), and supplements (SUP). We analyzed data from 7397 children aged 1–18 years (y) in NHANES 2003–2006. Among children aged 1–3 y, 4–8 y, 9–13 y, and 14–18 y, 21%, 18%, 34%, and 47%, respectively, reported consumption of folic acid from ECGP only. Fifty‐two percent, 45%, 44% and 36%, respectively, reported consumption from ECGP+RTE. Eight to nine percent reported consumption from ECGP+SUP. Eighteen percent, 28%, 13%, and 9%, respectively, reported consumption from ECGP+RTE+SUP. Among all age groups, 0% of the children who consumed folic acid from ECGP only exceeded the UL for their age group. The proportion above the UL for their age group was greater with consumption of RTE and SUP. Compared with consumption of ECGP only, the adjusted geometric mean folate concentrations were progressively higher among those who consumed ECGP + RTE, ECGP + SUP, and ECGP+SUP+RTE in all age groups except children aged 4–8 y. Post‐fortification, US children who consume ECGP only are unlikely to exceed the UL for their age group and the majority of children consume folic acid from either RTE or SUP. Research funded by CDC.

Use of the affinity/HPLC method for quantitative estimation of folic acid in enriched cereal-grain products.

In 1998, the United States introduced mandatory fortification of enriched cereal-grain products with folic acid to reduce the incidence of neural tube defects. As a consequence, substantial amounts of folic acid, the synthetic form of folate, were added to the American diet, and the ability to assess folic acid intake took on greater importance. The purpose of the current study was to separate and quantify folic acid and 5-methyltetrahydrofolate, the most prominent naturally occurring folate in fortified foods, with a reliable and robust method. Folates were heat-extracted from food samples. A trienzyme treatment (alpha-amylase, rat plasma conjugase, and protease) was applied to the extracts followed by purification by affinity chromatography. Folic acid and 5-methyltetrahydrofolate were separated and quantified by reversed-phase HPLC with fluorescence and UV detection. A gradient elution with phosphate buffer and acetonitrile was used to separate the different forms of folates. The method gave a linear response in a range of 0.1-3 mumol/L and 0.0125-0.25 mumol/L for folic acid and 5-methyltetrahydrofolate, respectively. These ranges were similar to the expected levels in the samples. The CV of the peak areas of folic acid and 5-methyltetrahydrofolate for 5 commercial wheat flour samples extracted and run separately on the same day was 2.0 and 5.7% and, run over 5 consecutive days, was 7.2 and 7.3%, respectively. Total folate values in 45 samples of fortified food measured by HPLC and by the traditional microbiological assay demonstrated a high correlation (r(2) = 0.986).

The repeating history of objections to the fortification of bread and alcohol: from iron filings to folic acid

The recent viewpoint by Kamien is timely, given Food Standards Australia New Zealand is currently advocating for the mandatory fortification of all bread-making flour with folic acid (80–180μg per 100g of bread). The proposal is now before the Australia and New Zealand Food Regulation Ministerial Council, and a decision is imminent. In 1991, the Medical Research Council Vitamin Study Research Group reported a randomised double-blind trial conducted at 33 centres in seven countries. Periconceptual folic acid supplementation had a 72% protective effect against neural tube defects (relative risk, 0.28; 95% CI, 0.12– 0.71). Because folic acid supplementation is ineffective when started after the pregnancy is confirmed, fortification of staple foods such as bread remains best practice. The United States started mandatory fortification of enriched cereal-grain products a decade ago. As expected, there has been an increase in the population geometric mean concentrations of serum folate and red blood cell folate, and a corresponding reduction in the number of babies born with debilitating neural tube defects. The benefits are clear and the risks are vague. Historical concerns that folic acid supplementation could mask pernicious anaemia and cause cancer have not been substantiated by international experience in more than 50 countries. Australian health professionals have a brief window of opportunity to join Maberly and Stanley and advocate for mandatory fortification in spite of commercial objections, which are based on marketshare concerns for existing “designer” products. If we educate and inform our patients and the community at large, the decisionmakers should finally get the message and this cheap, safe and effective public health policy would be implemented — a decade overdue.

The repeating history of objections to the fortification of bread and alcohol: from iron filings to folic acid

The recent viewpoint by Kamien is timely, given Food Standards Australia New Zealand is currently advocating for the mandatory fortification of all bread-making flour with folic acid (80–180μg per 100g of bread). The proposal is now before the Australia and New Zealand Food Regulation Ministerial Council, and a decision is imminent. In 1991, the Medical Research Council Vitamin Study Research Group reported a randomised double-blind trial conducted at 33 centres in seven countries. Periconceptual folic acid supplementation had a 72% protective effect against neural tube defects (relative risk, 0.28; 95% CI, 0.12– 0.71). Because folic acid supplementation is ineffective when started after the pregnancy is confirmed, fortification of staple foods such as bread remains best practice. The United States started mandatory fortification of enriched cereal-grain products a decade ago. As expected, there has been an increase in the population geometric mean concentrations of serum folate and red blood cell folate, and a corresponding reduction in the number of babies born with debilitating neural tube defects. The benefits are clear and the risks are vague. Historical concerns that folic acid supplementation could mask pernicious anaemia and cause cancer have not been substantiated by international experience in more than 50 countries. Australian health professionals have a brief window of opportunity to join Maberly and Stanley and advocate for mandatory fortification in spite of commercial objections, which are based on marketshare concerns for existing “designer” products. If we educate and inform our patients and the community at large, the decisionmakers should finally get the message and this cheap, safe and effective public health policy would be implemented — a decade overdue.

Prevalence of Neural Tube Defects, Folate Status, and Folate Fortification of Enriched Cereal-Grain Products in the United States

In their recent report, Williams et al1 examined data from 21 population-based birth defect surveillance systems for trends in prevalence of spina bifida and anencephaly for specific racial/ethnic groups from 1995 to 2002. Data were stratified into pre-, optional, and mandatory fortification intervals, coincident with the authorization of folate fortification of enriched cereal-grain products by the Food and Drug Administration (FDA) in 1996. Williams et al1 found prevalence values per 10000 births for spina bifida for Hispanic, non-Hispanic white, and non-Hispanic black women of 4.18, 3.37, and 2.90, respectively, for the mandatory fortification interval versus corresponding values for the same groups of 6.49, 5.13, and 3.57, respectively, for the prefortification interval. These results suggested that folate fortification was associated with significant decreases in the prevalence of spina bifida among non-Hispanic white and Hispanic births (34% and 36% decreases, respectively). The 19% decline in the prevalence of spina bifida among non-Hispanic black births was borderline statistically significant.1 This failure to find a statistically significant decline among non-Hispanic black births may have been attributable to smaller samples examined (total cases were 515 for non-Hispanic black births, 2672 for non-Hispanic white births, and 1281 for Hispanic births). In their editorial on the article by Williams et al,1 Brent and Oakley2 argued that folic acid fortification levels in the United States are too low. They have inappropriately generalized the data of Williams et al1 into a broad criticism of the current folic acid fortification program and a call for increased fortification. This warrants our response. Consideration of whether increases in fortification are warranted depends a number of complex issues. For example, are the residual neural tube defects (NTDs) in all racial/ethnic groups folate sensitive? If so, then would increasing the levels of folic acid in enriched cereal-grain products … Address correspondence to Jeanne I. Rader, PhD, Division of Research & Applied Technology, Office of Nutritional Products, Labeling and Dietary Supplements, Center for Food Safety and Applied Nutrition, Food and Drug Administration, 5100 Paint Branch Pkwy, College Park, MD 20740. E-mail: Jeanne.Rader{at}cfsan.fda.gov

A differential assay of folic acid and total folate in foods containing enriched cereal-grain products to calculate μg dietary folate equivalents (μg DFE)

A method was developed to differentiate folic acid from total folate in enriched cereal products. By elimination of the protease and conjugase digestion steps from the trienzyme digestion used to measure total folate, folic acid can be directly quantified by the microbiological assay using Lactobacillus casei ( ssp. rhamnosus) ATCC 7469. Determination of total folate by the trienzyme digestion together with assay of folic acid by the procedure reported here allows calculation of food folate and μg dietary folate equivalents (μg DFE). Recovery studies conducted at five concentration levels in a non-fortified wheat flour gave a mean recovery of 95.5 (RSD% 9.7) for folic acid and 98.5 (RSD% 5.0) for total folate. Recoveries from a variety of enriched cereal foods ranged from 88% to 99% for the folic acid extraction and 90% to 96% for the trienzyme digestion. Analysis of SRM 1846 Infant Formula ( n = 11 ) gave means± s.d. of 123.5±6.9 μg/100 g of folic acid and 136.6±6.7 μg/100 g of total folate (reference concentration value=129±28 μg/100 g). Intermediate precision determined as intra-laboratory reproducibility( r) gave RSDr % values of 4.32 for the folic acid assay and 3.15 for the total folate assay. Microgram DFE values were determined for several enriched cereals by calculating food folate as the difference between total folate and folic acid and the formula μg DFE=μg food folate+(1.7×μg folic acid). The differential assay of folic acid and total folate is a simple and accurate procedure to determine μg DFE in enriched cereal-grains or foods containing enriched flour.

Reevaluating the benefits of folic acid fortification in the United States: economic analysis, regulation, and public health.

Before a 1996 US regulation requiring fortification of enriched cereal-grain products with folic acid, 3 economic evaluations projected net economic benefits or cost savings of folic acid fortification resulting from the prevention of pregnancies affected by a neural tube defect. Because the observed decline in neural tube defect rates is greater than was forecast before fortification, the economic gains are correspondingly larger. Applying both cost-benefit and cost-effectiveness analytic techniques, we estimated that folic acid fortification is associated with annual economic benefit of 312 million dollars to 425 million dollars. The cost savings (net reduction in direct costs) were estimated to be in the range of 88 million dollars to 145 million dollars per year.

The Effect of Folate Fortification of Cereal-Grain Products on Blood Folate Status, Dietary Folate Intake, and Dietary Folate Sources among Adult Non-Supplement Users in the United States

Objective: Since January 1998, the Federal Drug Administration has required folic acid fortification of all enriched cereal-grain products in the U.S. This program intended to increase folic acid intake among women of childbearing age in order to decrease their risk of pregnancies affected by neural tube defects. The aim of this study was to explore the changes in serum and erythrocyte folate status of the adult U.S. population following folic acid fortification of enriched cereal-grain products and to explore accompanying changes in food sources and dietary total folate intake.Methods: We compared data from two National Health and Nutrition Examination Surveys (NHANES): NHANES III, conducted during 1988 to 1994, reflecting the time prior to folate fortification, and NHANES 1999–2000, reflecting the time period after fortification.Results: Mandatory folic acid fortification led to significant increases in both serum and erythrocyte folate concentrations in all sex and age groups. In the overall study population the mean serum folate concentration increased more than two-fold (136%), from 11.4 nmol/L to 26.9 nmol/L, and the mean erythrocyte folate concentration increased by 57 percent, from 375 nmol/L to 590 nmol/L. Less than 10% of women of childbearing age reached the recommended erythrocyte folate concentration of greater than 906 nmol/L that has been shown to be associated with a significant reduction in neural tube defect (NTD) risk. After fortification, the category “bread, rolls, and crackers” became the single largest contributor of total folate to the American diet, contributing 15.6% of total intake, surpassing vegetables, which were the number one folate food source prior to fortification. Dietary intake of total folate increased significantly in almost all sex and age groups, except in females over 60 years of age. The mean dietary total folate intake of the study population increased by 76 μg/d (28%), from 275 μg/d to 351 μg/d.Conclusions: The fortification of enriched cereal-grain products with folic acid lead to a significant improvement of blood folate status of the overall adult, non-supplement using, US population. However, women of childbearing age may take folic acid supplements to reach erythrocyte folate levels that have been associated with decreased risk of NTDs.

Microbiological Assay-Trienzyme Procedure for Total Folates in Cereals and Cereal Foods: Collaborative Study

In 1996, U.S. Food and Drug Administration regulations mandated the fortification of enriched cereal-grain products with folic acid, thereby emphasizing the need for validated methods for total folates in foods, particularly cereal products. The AOAC Official Methods (944.12, 960.46) currently used for the analysis of folate in foods for compliance purposes are microbiological methods. When the fortification regulations were finalized, no Official AOAC or Approved AACC methods for folate in cereal-grain products were in place. The AOAC Official Method (992.05) for folic acid in infant formula does not incorporate important improvements in the extraction procedure and was not considered suitable for the analysis of folates in foods in general. A microbiological assay protocol using a trienzyme extraction procedure was prepared and submitted for comments to 40 laboratories with recognized experience in folate analysis. On the basis of comments, the method was revised to have the conjugase (gamma-glutamyl-carboxy-peptidase) treatment follow a protease treatment, to include the use of cryoprotected inoculum, and to include the spectroscopic standardization of the standard and optional use of microtiter plates. Thirteen laboratories participated in a collaborative study of 10 required and 10 optional cereal-grain products, including flour, bread, cookies, baking mixes, and ready-to-eat breakfast cereals. The majority of the participating laboratories performed the assay by the standard test tube method; others used the microtiter plate modification for endpoint quantitation with equal success. For the required products, the relative standard deviation between laboratories (RSD(R)) ranged from 7.4 to 21.6% for 8 fortified (or enriched) products compared with expected (Horwitz equation-based) values of 11-20%. RSD(R) values were higher (22.7-52.9%) for 2 unfortified cereal-grain products. For the optional products, the RSD(R) ranged from 1.8 to 11.2% for 8 fortified products. RSD(R) values were higher (27.9-28.7%) for 2 unfortified cereal-grain products. Based on the results of the collaborative study, the microbiological assay with trienzyme extraction is recommended for adoption as Official First Action.

Should calcium and vitamin D be added to the current enrichment program for cereal-grain products?

Mean dietary intakes of calcium and vitamin D in the US adult population are far below the adequate intake (AI) values recommended by the Food and Nutrition Board, Institute of Medicine of the National Academy of Sciences, and thus substantial segments of the American population have inadequate intakes and elevated risks of osteoporosis and colon cancer. The current Code of Federal Regulations, Title 21, sets standards for the optional addition of moderate amounts of calcium and vitamin D in the enrichment of cereal-grain products, a provision that is essentially not used. We propose that the addition of calcium and vitamin D to currently enriched cereal-grain products be mandated in the United States: this would result in an increase in mean daily dietary intakes in the United States of approximately 400 mg Ca and > or =50 IU (or possibly >200 IU) vitamin D. The benefits would be a significant reduction in the incidences of osteoporosis and colon cancer over time and overall improvement in health, with little risk and a modest financial cost because of the ability to capitalize on existing technology. We suggest a full scientific review of cereal-grain enrichment with calcium and vitamin D.