Total folate and folic acid intakes from foods and dietary supplements

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Total folate and folic acid intakes from foods and dietary supplements of US children aged 1–13 y1–4 Regan L Bailey, Margaret A McDowell, Kevin W Dodd, Jaime J Gahche, Johanna T Dwyer, and Mary Frances Picciano ABSTRACT Background: Total folate intake includes naturally occurring food folate and folic acid from fortified foods and dietary supplements. Recent reports have focused on total folate intakes of persons aged 14 y. Information on total folate intakes of young children, however, is limited. Objective: The objective was to compute total folate and total folic acid intakes of US children aged 1–13 y by using a statistical method that adjusts for within-person variability and to compare these intakes with the Dietary Reference Intake guidelines for adequacy and excess. Design: Data from the 2003–2006 National Health and Nutrition Examination Survey, a nationally representative cross-sectional survey, were analyzed. Total folate intakes were derived by combining intakes of food folate (naturally occurring and folic acid from fortified foods) on the basis of 24-h dietary recall results and folic acid intakes from dietary supplements on the basis of a 30-d questionnaire. Results: More than 95% of US children consumed at least the Estimated Average Requirement (EAR) for folate from foods alone. More than one-third (35%) of US children aged 1–13 y used dietary supplements, and 28% used dietary supplements containing folic acid. Supplement users had significantly higher total folate and folic acid intakes than did nonusers. More than half (53%) of dietary supplement users exceeded the Tolerable Upper Intake Level (UL) for total folic acid (fortified food + supplements) as compared with 5% of nonusers. Conclusions: Total folate intakes of most US children aged 1–13 y meet the EAR. Children who used dietary supplements had significantly higher total folate intakes and exceeded the UL by .50%. Am J Clin Nutr 2010;92:353–8.

acid fortification of enriched cereal grain products to improve folate status, particularly among reproductive-aged females (6–8) and thereby reduce rates of neural tube defects. Folate status has been monitored for .2 decades, including the pre- and postfortification time periods. Several reports have documented the program’s success in terms of addressing a public health need and improving the blood and dietary folate status of children and adults (9, 10). Serum and RBC folate concentrations of children and adults increased significantly between 1988–1994 before mandatory fortification and 1999– 2004 after fortification (11). Despite these successes and improved folate adequacy, concerns have been raised about high folate and folic acid intakes of certain population subgroups, including young children (12, 13). The rationale for the concerns about high folate intakes was based in part on the hypothesis that epigenetic mechanisms, including DNA methylation processes that require methyl donors such as folate (14–16), might alter gene expression in offspring (3, 17). DNA methylation is also believed to play a role in the stability and plasticity of developing neuronal circuits that are a critical part of brain development during childhood (14). Until now, insufficient information has been available to assess the total folate and folic acid intakes of children despite the fact that monitoring total folate intake from food and dietary supplements is recommended (18, 19). This study was undertaken to examine data from the 2003– 2006 National Health and Nutrition Examination Surveys (NHANES). The data were analyzed to estimate dietary and supplemental contributors to total folate and folic acid intakes of 1

INTRODUCTION

Folate is the generic term for bioactive forms of the essential B vitamins, including naturally occurring food folate (pteroylpolyglutamates) and the monoglutamate folic acid form that is used in fortified foods and dietary supplements. Dietary folate therefore is a combination of food folate and folic acid from fortified foods. Total folate encompasses dietary folate and folic acid from dietary supplements (1). Folic acid plays a key role as a coenzyme for nucleic acid and amino acid metabolism. It is required for normal cell division and is critical during periods of growth and development (2, 3). Folic acid supplementation during the periconceptional period reduces the occurrence of neural tube defects (4, 5). For this reason, over a decade ago the US and Canadian governments implemented mandatory folic

From the Office of Dietary Supplements (RLB, JTD, and MFP), Division of Nutrition Research Coordination (MAM), and the National Cancer Institute (KWD), National Institutes of Health, Bethesda, MD, and the National Center for Health Statistics, Centers for Disease Control and Prevention, Hyattsville, MD (JJG). 2 The findings and conclusions in this report are those of the author(s) and do not necessarily represent the views of the Office of Dietary Supplements, the National Cancer Institute, the National Institutes of Health, the Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry, or any other entity of the US Government. 3 Supported by the National Institutes of Health, Office of Dietary Supplements. 4 Address reprint requests and correspondence to RL Bailey, 6100 Executive Boulevard, 2B03, Bethesda, MD 20892-7517. E-mail: baileyr@mail. nih.gov. Received April 9, 2010. Accepted for publication May 13, 2010. First published online June 9, 2010; doi: 10.3945/ajcn.2010.29652.

Am J Clin Nutr 2010;92:353–8. Printed in USA. Ó 2010 American Society for Nutrition

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children aged 1–13 y, a group that has not been reported on previously. Therefore, the purpose of this analysis was to estimate total folate and folic acid intakes in children and adolescents in the United States. In addition, the percentage of children and adolescents meeting the Dietary Reference Intakes (DRIs) for adequacy and overconsumption are provided for the total population aged 1–13 y.

SUBJECTS AND METHODS

Survey description NHANES is a continuous (since 1999), nationally representative, cross-sectional survey of the civilian, noninstitutionalized, US household population conducted by the National Center for Health Statistics of the Centers for Disease Control and Prevention (20). Samples were drawn annually by using a complex, stratified, multistage probability cluster sampling design (20). Non-Hispanic blacks and Mexican Americans were among the population subgroups that were oversampled in 2003–2006 to improve the statistical reliability and precision of estimates for these groups. Survey participants were asked to complete an inperson home interview and a health examination, which was conducted in mobile examination centers (MECs), 3–6 wk after the home interview. Written informed consent and child assent was obtained, and the National Center for Health Statistics Ethics Review Board approved the survey protocol and materials. The NHANES data are publicly available. The data release files consist of 2-y data sets to reduce the risk of disclosure and achieve minimum sample size requirements for statistical analysis. The National Center for Health Statistics recommends that analysts combine 4 y of data to improve the reliability and stability of statistical estimates (21). This analysis was completed by using NHANES 2003–2004 and NHANES 2005–2006 data sets. The unweighted examination response rate was computed as the number of interviewed and examined persons divided by the total number sampled during each of the 2-y survey cycles. Examination response rates were 84–90% among 1–15-y-olds during 2003–2006 (22). A total of 6559 children aged 1–13 y were examined. Of these, 803 had unreliable or missing dietary-recall data and were excluded. Participants with satisfactory dietaryrecall data (denoted by the dietary-recall status variables DR1DRSTZ and DR2DRSTZ = 1) were included, which resulted in a final analytic sample of 5756 children. Dietary intake determined from 24-h recalls NHANES participants were asked to complete 2 dietary-recall interviews. The first dietary-recall interviews were collected inperson by highly trained dietary interviewers in the NHANES MEC. Proxy respondents provided dietary information for young children, and proxy-assisted interviews were used for 6–11-yolds. Telephone dietary interviews were collected 3–10 d after the MEC dietary interview but not on the same day of the week as the MEC interview. The US Department of Agriculture Automated Multiple-Pass Method dietary interview method was used to collect all of the dietary interview information (23, 24). Any participant with at least one 24-h recall was included in this analysis (n = 5756). Participants used measuring guides (inperson interviews) or a food model booklet (telephone inter-

views) to quantify the foods during the dietary-recall interviews. Folate and folic acid intakes from foods were based on the 24-h dietary-recall data. Dietary supplement use Detailed information on the use of dietary supplement products was collected during the household interview. The scope of the collection included all types of dietary supplements, including vitamins, minerals, herbs, and botanicals that were used during the past 30 d. Interviewers asked to see product containers when available. Information about product name, frequency of use, duration of product use, and dosage was recorded for each dietary supplements reported during the interview. The average daily intake of folic acid from dietary supplement products was derived for each participant based on the number of days the dietary supplements was used, the servings of product taken daily, and the folic acid content of the product per serving as listed on the product label. Missing or unknown dietary supplement information was replaced with default values or deleted. For this analysis, if the information on unit of reported intake was unknown (DSDUNIT = 21) the record was deleted (n = 2, 0.14%). However, if the serving unit was unknown or missing (DSD122U = 99 or DSD122U = .), it was replaced by the serving size unit (DSDSERVU); this occurred for ,2% of reports. If the missing or unknown information was the number of days the product was reported (DSD103), it was replaced withthe most common report of 30 d; the missing number of days was more common (3.0%) than the unknown number of days (0.19%). Finally, if the reported dosage was unknown or missing (DSD122Q = 999999 or DSD122Q = .) it was replaced by the labeled dosage (DSDSERVQ); this occurred for ,2% of reports. Folate bioequivalence The bioavailability of food folate is lower than that of folic acid added to fortified foods and dietary supplements. The Dietary Folate Equivalent (DFE) conversion was developed to account for this differential bioavailability (25). Total folate intakes Total folate intakes were computed by using food intake and dietary supplement information. First, the dietary folate intakes based on the 24-h dietary recalls were adjusted for within-person variability by using the bias-corrected best power method. Next, a set of intermediary values was produced reflecting the usual distribution of nutrient intake from foods (26, 27). Finally, the reported average daily dose of folic acid from DS was added to the intermediary value for each respondent to produce a final set of adjusted values that reflected the distribution of usual intake of folate (in DFE) and folic acid separately (lg) (27, 28). Complete details of the methods used to calculate total folate intakes are published elsewhere (1). Comparisons with the Dietary Reference Intakes The DRIs for folate are presented in 2 formats. Dietary and total nutrient intake estimates are presented as dietary and total folate expressed in DFEs, the unit used for the Estimated Average Requirement (EAR) of folate:

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1DFE ¼ 1lg food folate ¼ 0:6 lg folic acid from supplements and fortified foods ð1Þ Folic acid found in fortified foods can be converted to DFEs and the resulting intakes used to examine folate adequacy, such as percentage of the population with intakes below the EAR. The second format is used to assess high folate intakes. The Tolerable Upper Intake Level (UL) is expressed as lg folic acid from synthetic folic acid sources only and excludes folate that naturally occurs in foods (25). Statistical analysis SAS (version 9; SAS Institute Inc, Cary, NC) was used for the statistical analysis. All analyses were weighted by using the appropriate NHANES sample weights to account for the complex survey design (including oversampling) and survey nonresponse and are poststratified to Census Bureau population estimates (21). Estimates of mean dietary (from all foods including folic acid from fortified foods) and total folate (from foods, including fortified foods, and dietary supplements) intakes expressed in DFEs and dietary (from fortified foods) and total folic acid (from fortified foods and dietary supplements) intakes in lg were produced. Mean dietary and total folate intakes were compared with EARs, and mean dietary and total folic acid intakes were compared with the UL (25, 29). SEs for all means and proportions with usual intake below or above the EAR or UL, and contrasts were approximated with Fay’s Modified Balanced Repeated Replication technique (30, 31) by using 32 sets of replicate weights constructed with an initial perturbation factor of 0.7. Each set of replicate weights was poststratified to control totals computed from the initial sample weights. Contrasts were constructed to test for statistical differences in the percentage achieving the EAR and exceeding the UL for age, race-ethnicity, and supplement-use groups. For the contrasts, a t statistic was computed by dividing the estimate of each contrast by its estimated SE. To account for multiple pairwise comparisons, a Bonferroni-adjusted P value of 0.016 was used to test for statistical significance at the P  0.05 level. No statistical testing was performed to compare dietary and total folate and folic acid intakes due to the variability in food energy intakes. RESULTS

Dietary supplement use was common among children. Approximately, 35% (60.9) of 1–13-y-olds used one or more supplements, and 28% reported use of products containing folic acid. Supplement use differed by age group: ’28% of 1–3-y-olds, 365 of 4–8-y-olds, and 21% of 9–13-y-olds had used dietary supplements during the previous 30 d. For both males and females, nonHispanic whites had significantly higher rates of folic acid dietary supplement use (33%) than did non-Hispanic blacks (17%) and Mexican Americans (20%) (Table 1). The overall mean (6SE) folic acid intake from dietary supplements was 260 6 12 lg for 1–13-y-olds. Mean dietary and total folate intakes and percentages with intakes below the EAR are shown for the total sample and by age and race-ethnicity within sex (Table 2). The percentages of children with total folate intakes below the EAR did not change

TABLE 1 Prevalence of use and daily contribution of supplemental folic acid in children and adolescents aged 1–13 y in the United States, 2003–20061

Characteristic Age group All 1–3 y (n = 1507) 4–8 y (n = 1560) 9–13 y (n = 2659) Male 1–3 y (n = 758) 4–8 y (n = 809) 9–13 y (n = 1258) Female 1–3 y (n = 749) 4–8 y (n = 871) 9–13 y (n = 1311) Race-ethnicity All Non-Hispanic white (n = 1586) Non-Hispanic black (n = 1792) Mexican American (n = 1846) Male Non-Hispanic white (n = 792) Non-Hispanic black (n = 898) Mexican American (n = 882) Female Non-Hispanic white (n = 794) Non-Hispanic black (n = 894) Mexican American (n = 964)

Use of folic acid dietary supplement

Mean intake

%

lg

28 6 1a 36 6 2b 21 6 1c

250 6 31 262 6 16 264 6 15

27 6 2a 40 6 3b 20 6 2a

218 6 10 267 6 19 272 6 25

28 6 2a 32 6 2a,b 22 6 3a

283 6 61 256 6 22 256 6 15

33 6 2a 17 6 1b 20 6 2b

254 6 16a,b 348 6 44a 216 6 16b

33 6 2a 18 6 2b 20 6 2b

248 6 14a,b 396 6 69a 228 6 30b

32 6 3a 16 6 2b 20 6 3b

262 6 26a,b 292 6 30a 205 6 11b

All values are means or percentages 6 SEs. SEs were calculated by using Fay’s Modified Balanced Repeated Replication technique. Values in a subgroup with different superscript letters are significantly different, P  0.05 (Bonferroni-adjusted). 1

appreciably when all folate sources were included. Only a small percentage of 1–8-y-olds (,1%) and of 9–13-y-olds (’3%) failed to achieve the EAR from foods alone. The mean intakes of folic acid from the diet (ie, fortified foods) and from all sources (ie, fortified foods and dietary supplements) were examined separately (Table 3). Mean folic acid intakes increased when the contribution from dietary supplements was included, as did the prevalence of intakes exceeding the UL. Among males, 4–8-y-olds had the highest prevalence of intakes above the UL (33%), whereas 9–13-y-old males and females had the lowest prevalence of intakes above the UL (7%). With respect to the race-ethnicity comparisons, the prevalence of total folic acid intakes exceeding the UL was significantly higher among non-Hispanic whites than among non-Hispanic blacks and Mexican Americans. Within age and race-ethnicity groups, dietary supplement users had higher rates of folic acid intake above the UL than did nonusers (Figure 1). DISCUSSION

Estimates of the total folate intakes of US children aged 1–13 y were derived by combining individual dietary supplements and adjusted dietary folate intake estimates. These population estimates contribute current information regarding total folate and

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TABLE 2 Dietary folate and total folate intakes of children 1–13 y of age in dietary folate equivalents (DFEs) and comparisons with the Estimated Average Requirement (EAR) by sex, age group, and race-ethnicity group: United States, 2003–20061

Age group All 1–3 y (n = 1507) 4–8 y (n = 1560) 9–13 y (n = 2659) Male 1–3 y (n = 758) 4–8 y (n = 809) 9–13 y (n = 1258) Female 1–3 y (n = 749) 4–8 y (n = 871) 9–13 y (n = 1311) Race-ethnicity All Non-Hispanic white (n = 1586) Non-Hispanic black (n = 1792) Mexican American (n = 1846) Male Non-Hispanic white (n = 792) Non-Hispanic black (n = 898) Mexican American (n = 882) Female Non-Hispanic white (n = 794) Non-Hispanic black (n = 894) Mexican American (n = 964)

Diet2

Less than the EAR

Total2

Less than the EAR

lg DFEs

%

lg DFEs

%

385 6 8 534 6 11 559 6 11

0.5 6 0.2a,3 0.1 6 0.08a,3 3.0 6 0.7b

489 6 14 692 6 18 656 6 17

0.5 6 0.2a,3 0.1 6 0.08a,3 2.7 6 0.6b

382 6 10 564 6 15 595 6 14

0.1 6 0.07a,3 0.1 6 0.07a,3 3.0 6 0.9a,3

469 6 16 746 6 27 684 6 24

0a 0a 3.0 6 0.9b

388 6 12 505 6 16 519 6 17

1.1 6 0.5a,4 0.2 6 0.1a,4 3.2 6 1.0b,3

511 6 29 639 6 22 626 6 26

1.1 6 0.5a,4 0.2 6 0.1a,4 2.7 6 0.9a,3

519 6 11 497 6 16 510 6 11

1.7 6 0.5a 3.5 6 0.8b 1.5 6 0.5a,3

661 6 17 578 6 20 592 6 18

1.5 6 0.4a 3.3 6 0.8b 1.5 6 0.5a,3

545 6 13 531 6 21 537 6 15

1.3 6 0.6a 3.0 6 1.0b,3 1.1 6 0.5a,4

683 6 22 616 6 24 619 6 21

1.2 6 0.6a 3.0 6 1.0b 1.1 6 0.5a

491 6 16 462 6 17 483 6 13

2.0 6 0.7a,4 4.1 6 1.2b,3 2.0 6 0.7a,3

637 6 25 541 6 27 564 6 25

1.7 6 0.6a 3.8 6 1.2b 1.9 6 0.7a

All values are means or percentages 6 SEs. SEs were calculated by using Fay’s Modified Balanced Repeated Replication technique. Different sample sizes were available for the age groups and race-ethnicity groups by sex because the “All” racial category is included in the age group analysis. Dietary folate includes naturally occurring folate and folic acid from fortified foods; total folate includes dietary folate plus folic acid from dietary supplements. EARs are as follows: 120 lg DFEs at age 1–3 y, 160 lg DFEs at age 4–8 y, and 250 lg DFEs at age 9–13 y. Values in a subgroup with different superscript letters are significantly different, P  0.05 (Bonferroni-adjusted). 2 Not compared statistically because of differences in caloric intake. 3 The relative SE is .30% and ,40%. 4 The relative SE is .40%; this estimate is unreliable. 1

folic acid intake from foods, fortified foods, and dietary supplements. A significant percentage of children 1–8 y (’5%) exceeded the UL based on folate intake from food alone, and even higher percentages of dietary supplement users exceeded the UL (range: 30–66% depending on age group). The rates of intakes above the UL were higher among children and young adolescents than among persons aged 14 y (1). Earlier published estimates of food and total folate intakes among US children reflected pre- and postfortification periods. Food folate intake estimates were similar for children aged 1–11 y based on NHANES III (1988–1994) and US Department of Agriculture Continuing Survey of Food Intakes by Individuals (CSFII 1994–1996)—2 nationally representative surveys conducted before mandatory fortification enactment (9, 10). Mean folate intakes of children aged 1–2 y were 177 and 189 lg and those of 3–5 y olds were 215 and 228 lg based on CSFII and NHANES III, respectively. The sex-specific mean intakes reported in CSFII 1994–1996 and NHANES III for 6–11-y-olds were 283 and 279 lg for boys and 232 and 238 lg for girls, respectively. National estimates of total usual folate from foods and dietary supplements following the enactment of the folate-fortification

policy were based on a national sample of 3022 infants and toddlers aged 4–24 mo who participated in the 2002 Feeding Infants and Toddlers Study (FITS) (32). Unlike NHANES, the estimated contribution of dietary supplement products to total nutrient intakes in FITS reflected intakes from the previous 24 h; dietary supplement intake information was ascertained after a 24-h recall of foods and beverages was completed. The closest FITS age group for comparison with the present study was the toddler group aged 12–24 mo. The prevalence of dietary supplement use among the FITS toddlers was 31%, compared with 28% of the NHANES sample aged 12–36 mo. The mean (6SEM) usual intake of folate in the FITS sample was 443 6 16.3 lg for dietary supplement users and 276 6 3.5 lg for nonusers. Similar to the findings presented in our current NHANES analysis, very low percentages of FITS participants (,1%) consumed less than the EAR of folate. However, the percentage of children aged 12–24 mo with folate intakes exceeding the UL was ,1% among dietary supplement nonusers and 18% among dietary supplement users (32). Our results indicate a higher prevalence of intakes exceeding the UL than does the FITS study. The methodologic adjustments used in this analysis assume that the nutrient intake estimates from food sources on any given

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TOTAL FOLATE AND FOLIC ACID INTAKES OF US CHILDREN TABLE 3 Dietary folic acid and total folic acid intakes of children 1–13 y of age by sex, age group, race-ethnicity, and supplement-use group: United States, 2003–20061

Age group All 1–3 y (n = 1507) 4–8 y (n = 1560) 9–13 y (n = 2659) Male 1–3 y (n = 758) 4–8 y (n = 809) 9–13 y (n = 1258) Female 1–3 y (n = 749) 4–8 y (n = 871) 9–13 y (n = 1311) Race-ethnicity All Non-Hispanic white (n = 1586) Non-Hispanic black (n = 1792) Mexican American (n = 1846) Male Non-Hispanic white (n = 792) Non-Hispanic black (n = 898) Mexican American (n = 882) Female Non-Hispanic white (n = 794) Non-Hispanic black (n = 894) Mexican American (n = 964)

Diet2

More than the UL

Total2

More than the UL

lg

%

lg

%

156 6 5 236 6 7 243 6 7

5 6 1a 4 6 1a 1 6 0.3b,3

217 6 8 329 6 11 300 6 10

20 6 2a 27 6 2b 7 6 1c

151 6 6 251 6 10 264 6 8

4 6 1a 6 6 2a,3 2 6 1b,4

202 6 9 358 6 17 316 6 15

18 6 2a 33 6 3b 7 6 2c

162 6 7 222 6 10 222 6 10

6 6 2a,3 3 6 1a,b,3 0.1 6 0.01b

234 6 18 300 6 13 284 6 15

23 6 3a 21 6 3a 7 6 1b

242 6 7 220 6 10 208 6 6

3 6 0.07 561 3 6 0.1

310 6 10 268 6 13 256 6 10

20 6 2a 13 6 1b 12 6 2b

323 6 14 288 6 15 220 6 10

21 6 2a 15 6 2b 12 6 2 b

297 6 14 249 6 18 245 6 13

18 6 2a 12 6 2b 11 6 2b

242 6 7 238 6 14 220 6 10 212 6 10 203 6 13 198 6 6

3.5 6 1 762 461 2 6 0.94 461 2 6 14

All values are means or percentages 6 SEs. SEs were calculated by using Fay’s Modified Balanced Repeated Replication technique. Different sample sizes were available for the age groups and race-ethnicity groups by sex because the “All” racial category is included in the age group analysis. Dietary folic acid is from fortified foods. Total folic acid is from fortified foods combined with folic acid from dietary supplements. Tolerable Upper Intake Levels (UL) are 300 lg synthetic folic acid at age 1–3 y, 400 lg at age 4–8 y, and 600 lg at age 9–13 y. Values in a subgroup with different superscript letters are significantly different, P  0.05 (Bonferroni-adjusted). 2 Not compared statistically because of differences in caloric intake. 3 The relative SE is .30% and ,40%. 4 The relative SE is .40%; this estimate is unreliable. 1

recall day are unbiased and that the self-reported intakes from dietary supplement products reflect true long-term dietary supplement intake. The estimates of folate and folic acid in foods are based on label declarations rather than on values from chemical analysis, which may underestimate intakes (33). Similarly, the folic acid content of dietary supplements reflects product label values rather than chemical analysis values. Recent chemical analysis reports of dietary supplement products showed that folic acid label values often exceed the analytic values for adult dietary supplements (34, 35). For folic acid, the average deviation in a weighted national sample was 12–14% above the label level (for supplements containing 50–400 lg) (36). Dietary intake and biomarker data collected before mandatory cereal grain fortification indicated that many US children did not consume adequate amounts of folate. This analysis of NHANES 2003–2006 dietary intake and dietary supplement data and earlier reports documenting improved dietary and blood folate status suggest that the folate status of children and adolescents has improved dramatically. However, certain subgroups of children often exceed UL values for folate. The potential risk of high folate intakes, possibly underestimated here because of underreported food intake and the known limitations of food and dietary supplement composition data deficiencies, requires further

review. These folate and folic acid intakes are needed to evaluate the folate DRIs for US children and adolescents given that the current folate requirements for persons aged 1–18 y are based on extrapolations from studies conducted with adults (25). Clearly, continued monitoring of folate biomarkers and dietary and

FIGURE 1. Prevalence (percentage 6 SE) of folic acid intakes exceeding the Tolerable Upper Intake Level by dietary supplement use categories. *Significantly different from nonusers, P  0.05 (Bonferroni-adjusted). NHW, non-Hispanic white; NHB, non-Hispanic black; MA, Mexican American.

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supplemental exposure to folic acid are necessary to ensure the adequate and safe level of folic acid fortification in the United States (39, 40). The authors’ responsibilities were as follows—RLB, MAM, JTD, and MFP: contributed to the concept development and manuscript preparation; and KWD and JJG: contributed to the methodologic and statistical aspects of the work and the manuscript review. None of the authors had a personal or financial conflict of interest.

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