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Contributions of Total Daily Intake of Folic Acid to Serum Folate Concentrations
To the Editor: Recent literature has associated potential adverse effects with daily use of folic acid supplements (1000 µg),1 high concentrations of serum folate (26.5 ng/mL or greater [to convert to nmol/L, multiply by 2.266]),2 or high folic acid intake,3 but researchers have not adequately considered the source of folic acid. We examined the relative contribution of different sources of folic acid to serum folate concentrations among US adults.
Methods
Data were obtained from a single 24-hour dietary recall from the National Health and Nutrition Examination Survey (NHANES) 2001 through 2004 for 8655 nonpregnant participants aged 19 years and older who also had serum folate concentrations measured. The 24-hour dietary recall in NHANES underestimates energy intake by 11% among adults.4 Daily folic acid intake from individual fortified foods was calculated.5 Average daily intake of folic acid from supplements over the prior 30 days was calculated.6 The 3 main sources of dietary folic acid are enriched cereal-grain products (ECGPs) fortified at 140 µg of folic acid per 100 grams of flour, ready-to-eat cereals (RTEs) such as breakfast cereals with up to 400 µg of folic acid per serving, and supplements containing folic acid.
Serum folate concentration was log-transformed because the distribution was not Gaussian. For each serum folate quintile, the adjusted geometric means for serum folate concentration and adjusted mean daily intake of folic acid from ECGPs, RTEs, and supplements containing folic acid were estimated using multiple regression models. Daily intake of folic acid from ECGPs only was estimated by subtracting the intake of folic acid from RTEs from the intake of folic acid from all foods.6 The proportion of participants who reported using a supplement containing folic acid in the past month was estimated using a logistic regression model.
Differences across serum folate quintiles for each intake source and for proportion of supplement users were tested using Satterthwaite adjusted F statistic. All analyses were weighted, taking into account the complex sampling design of NHANES, using SUDAAN version 9.0 (RTI, Research Triangle Park, North Carolina), and adjusted for age, sex, and race/ethnicity. In NHANES, race/ethnicity is designated by the participant through a series of multiple-choice questions and an "other" write-in response. Statistical hypotheses were tested at a 2-tailed  = .05 level of significance.
Results
Participants in the highest serum folate quintile were more likely to be older, female, and non-Hispanic white (P < .001 for each comparison) (Table). Across the serum folate quintiles, the daily intake of folic acid from ECGPs was about 140 µg per day and showed a statistically significant but small variation (P = .01) (Figure). However, from the first to the fifth quintile, daily intake from RTEs varied from 14 to 107 µg per day (P < .001) and daily intake from supplements varied from 42 to 392 µg per day (P < .001). The adjusted proportion of ECGP-only users varied from 82.1% to 13.9% (P < .001) and supplement users varied from 10.9% to 74.6% (P < .001), respectively (Table).
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Table. Characteristics of Participants Aged 19 Years or Older, National Health and Nutrition Examination Survey, 2001 – 2004
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Figure. Estimated Daily Intake of Folic Acid by Serum Folate Quintile
Data were obtained from the National Health and Nutrition Examination Survey (NHANES) 2001-2004 for 8655 nonpregnant adults aged 19 years and older. For ready-to-eat cereals, P < .001; for enriched cereal-grain products, P = .01; and for supplements, P < .001 (Satterthwaite adjusted F statistic). All analyses were adjusted for age, sex, and race/ethnicity. Error bars indicate 95% confidence intervals. Refer to Table for quintile ranges.
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In the highest quintile, the total adjusted mean folic acid intake was 643 µg per day and the mean serum folate was 24.3 ng/mL. Of these participants, 75% used supplements containing folic acid, which on average contributed 61% of the total daily folic acid intake. Enriched cereal-grain products contributed 22% of total daily intake. Refer to Table for quintile ranges.
Comment
High serum folate concentrations were primarily associated with the use of supplements containing folic acid. Folic acid fortification of ECGPs appears unlikely to produce the high serum folate concentrations reported in recent studies to be associated with potential adverse effects.1-3 Researchers should differentiate folic acid intake contributed by voluntary consumption of supplements and RTEs from folic acid intake due to mandatory fortification of ECGPs before attributing research findings to a particular source of folic acid. Current and planned public health prevention strategies to fortify food with folic acid should be based on information about appropriate dietary sources.
Author Contributions: Dr Yang had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Yeung, Yang, Berry.
Acquisition of data: Yang.
Analysis and interpretation of data: Yeung, Yang, Berry.
Drafting of the manuscript: Yeung, Berry.
Critical revision of the manuscript for important intellectual content: Yeung, Yang, Berry.
Statistical analysis: Yeung, Yang.
Obtained funding: Berry.
Administrative, technical, or material support: Yeung, Berry.
Study supervision: Berry.
Financial Disclosures: None reported.
Funding/Support: This study was supported by the Centers for Disease Control and Prevention.
Role of the Sponsor: Employees of the Centers for Disease Control and Prevention supervised the design and conduct of the study; the collection, management, analysis, and interpretation of the data; and the preparation, review, and approval of the manuscript.
Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.
Additional Contributions: Mary E. Cogswell, PhD, Centers for Disease Control and Prevention, provided expert advice. No compensation was received.
Lorraine Yeung, MD, MPH
Division of Birth Defects and Developmental Disabilities
National Center on Birth Defects and Developmental Disabilities
Quanhe Yang, PhD
National Office of Public Health Genomics
R. J. Berry, MD, MPHTM
rjberry{at}cdc.gov
Division of Birth Defects and Developmental Disabilities
National Center on Birth Defects and Developmental Disabilities
Centers for Disease Control and Prevention
Atlanta, Georgia
1. Cole BF, Baron JA, Sandler RS; et al. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA. 2007;297(21):2351-2359.
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2. Morris MS, Jacques PF, Rosenberg IH, Selhub J. Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification. Am J Clin Nutr. 2007;85(1):193-200.
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3. Morris MC, Evans DA, Bienias JL; et al. Dietary folate and vitamin B12 intake and cognitive decline among community-dwelling older persons. Arch Neurol. 2005;62(4):641-645.
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4. Moshfegh AJ, Cleveland LE, Baer DJ, Sebastian RS, Rhodes DG, Perloff BP. Accuracy of Americans reporting dietary intakes: results from cohort 1 of the USDA Doubly Labeled Water Study. J Am Diet Assoc. 2003;103(9):A-23.
5. National Health and Nutrition Examination Survey. Centers for Disease Control and Prevention Web site. http://www.cdc.gov/nchs/about/major/nhanes/nhanes01-02.htm. Accessed September 26, 2008.6. Yang QH, Carter HK, Mulinare J; et al. Race-ethnicity differences in folic acid intake in women of childbearing age in the United States after folic acid fortification: findings from the National Health and Nutrition Examination Survey, 2001-2002. Am J Clin Nutr. 2007;85(5):1409-1416.
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Letters Section Editor: Robert M. Golub, MD, Senior Editor.
JAMA. 2008;300(21):2486-2487.
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