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Vitamin Metabolism and Aging Laboratory and Epidemiology Program, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111 and
The Framingham Heart Study, Boston University School of Medicine, Framingham, MA 01701
3To whom correspondence should be addressed. E-mail: jselhub{at}hnrc.tufts.edu.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • folate • folic acid • fortification • erythrocyte folate • nutritional status • humans
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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,2
). The proportion of women in the United States achieving this recommendation before conceiving was very small and a considerable proportion of all pregnancies were not planned (3
,4
). Consequently, the Food and Drug Administration (FDA) issued a regulation in March 1996 to take effect by January 1998 that all enriched cereal grain products (flour, rice, breads, rolls and buns, pasta, corn grits, corn meal, farina, macaroni and noodle products) be enriched with folic acid in addition to the iron, thiamin, riboflavin and niacin already added to these products. The amount of folic acid added to each product was to range from 95 to 309 µg folic acid/100 g of product. This range of fortification was selected on the basis of an overall fortification level of 140 µg folic acid/100 g of the cereal grain product (5
). Using dietary modeling, the projected average daily increase of folic acid intake in the general population was estimated to be 
100 µg (6
), or one quarter of the recommended amount.
Using plasma samples from the Framingham Offspring Cohort Study, our research group recently showed that the implementation of folic acid fortification resulted in the doubling of plasma folate concentrations and an 50% reduction in the prevalence of hyperhomocysteinemia among individuals who did not use B-vitamin supplements (7
). The present study was undertaken to assess the effect of folic acid fortification on RBC folate concentrations in the same cohort. RBC folate is believed to be a good measure of long-term tissue folate status (8
); it is the measure of folate status used by many investigators, particularly in research that addresses the protective effect of folic acid on NTD.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The Framingham Heart Study (FHS) is an epidemiologic study of heart disease established in Framingham, MA, between 1948 and 1950. This cohort originally included 5209 individuals and among them, 1644 husband and wife pairs. Their offspring and their spouses were recruited and invited to participate in the Framingham Offspring Study. Also, offspring who had only one parent participating in the FHS were invited to participate with their spouses in the Framingham Offspring Study if that parent had either abnormal lipoprotein patterns or coronary heart disease at the 1970 biennial examination of the FHS. The first examination of the offspring cohort was in 1971, and they have typically been examined every 3–4 y. The ethnicity of the participants is almost exclusively non-Hispanic Caucasian (9
).
Data from the 6th examination of the Framingham Offspring Cohort were used for this cross-sectional study. This examination started in January 1995, finished in August 1998, and 3532 individuals were examined. We focused our analyses on data from 872 individuals whose examination date preceded the implementation of folic acid fortification and from 626 individuals whose examination date was at least 2 mo after the implementation of this fortification. Details of the selection of both groups are explained elsewhere (7
). Briefly, the folic acid fortification regulation gave two years notice to food manufacturers to allow time to change the labels and product formulations. In New England, there were very few products fortified before September 1996, and most products were fortified by July 1997 (7
). Thus, participants of the Framingham Offspring Study whose 6th examination occurred between January 1995 and September 1996 were considered as the group that was examined before implementation of folic acid fortification (or group not exposed to fortification). Those who attended the 6th examination between September 1997 and August 1998 were considered as the group that was examined after implementation of folic acid fortification (or group exposed to fortification). Individuals whose examination was in between those dates (October 1996–August 1997) were not considered in the analysis. This study was approved by the Human Investigations Review Committee at New England Medical Center and by the Institutional Review Board for Human Research at Boston University Medical Center.
Biochemical measurements.
Individuals who participated in the 6th examination of the Framingham Offspring Cohort had a fasting blood sample taken in a supine position from an antecubital vein after a 12-h fast. Plasma was separated by centrifugation (800 x g for 10 min) and plasma and red cell aliquots were frozen at -70°C until analyzed. Frozen RBC samples were extracted by suspension in a buffer containing 12.5 g/L sodium ascorbate and heating for 15 min in a boiling water bath. After cooling on ice, samples were centrifuged and the supernatant fraction was used to measure RBC folate content by the microbial assay (Lactobacillus casei) with conjugase treatment (10
,11
). RBC folate was measured as ng of folate/g hemoglobin (Hb). Values were converted to µg folate/L packed cells using the mean cell Hb concentration as described by O’Broin et al. (12
).
Statistics.
We performed separate analyses according to the use of B-vitamin supplements. RBC folate data were positively skewed; therefore these values were log-transformed before analysis. To determine the effect of folic acid fortification on RBC folate, we compared RBC folate geometric means in individuals exposed and not exposed to folic acid fortification using SAS PROC GLM program (13
) with adjustment for age and number of cigarettes smoked per day. We also adjusted for folate intake calculated using the food composition database not modified to reflect folic acid fortification of enriched cereal grain products. In this way, we adjusted RBC folate values for dietary patterns related to folate intake (to ensure that any differences seen in RBC folate were due to fortification and not to differences in dietary patterns of folate or folic acid–containing foods). We also calculated the prevalence of deficient and acceptable RBC folate values in the group exposed and in the group not exposed to folic acid fortification. Deficient RBC folate values were defined as values <160 µg/L packed cells (<362.6 nmol/L) and acceptable RBC folate as values > 200 µg/L packed cells (>453.2 nmol/L) (14
).
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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. In this cohort, we measured RBC folate in a group of 872 individuals not exposed and in another group of 626 individuals exposed to folic acid fortification. We categorized them according to their B-vitamin supplement use. The mean age in each group was between 58 and 60 y old and the proportion of women within nonusers and users of B-vitamin supplements was similar between those exposed and not exposed to fortification, although women were more likely to use B-vitamin supplements. Red blood cell folate geometric means are reported; means and prevalences were adjusted by age, number of cigarettes smoked per day and folate-related dietary patterns. Sex and body mass index were not significant predictors of RBC folate and were not included in the final model.
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In individuals who used B-vitamin supplements, RBC folate concentrations were 24% higher in the group that was exposed to folic acid fortification (P < 0.001). The prevalence of individuals with deficient RBC folate concentrations was 1.6% in the group not exposed to fortification and 0% in the group exposed to fortification (P < 0.05). The prevalence of individuals with acceptable RBC folate concentrations was 97.2% in the group not exposed to fortification and 99.2% in the group exposed to fortification (P = 0.08).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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). The present results confirm our earlier work using RBC folate, which is considered to be a good measure of tissue folate status and was chosen as the main indicator of folate nutritional status and folate sufficiency to establish the new Dietary Reference Intakes (DRI) (15
,16
).
We defined folate deficiency as RBC folate concentrations <160 µg/L (362.6 nmol/L) and folate adequacy as RBC folate concentrations > 200 µg/L (453.2 nmol/L) (14
). However, there is no accepted standard for folate deficiency or inadequacy based on RBC folate concentrations. The new DRI suggests a cut-off point of 140 µg/L (317.2 nmol/L) of RBC folate to assess folate deficiency and adequacy (16
). Even by our more conservative definitions, folate deficiency was uncommon in this cohort among those who did not take B-vitamin supplements (1.9%) and among those who took B-vitamins supplements (0%) after implementation of folic acid fortification. The prevalence of individuals with acceptable RBC folate status after implementation of folic acid fortification was very high, 96.1% in those who did not take B-vitamin supplements and 99.2% in B-vitamin supplements users.
It is possible that the observed differences in RBC folate status stemmed from variations in folate intake that were unrelated to fortification. However, we adjusted RBC values for consumption of folate and folic acid–rich foods in the groups exposed and not exposed to fortification, and therefore we are confident that the changes seen in RBC folate status can be ascribed to folic acid fortification.
Because this study sample included only seven women 
45 y old who were exposed to fortification and who did not take B-vitamin supplements, we could not assess the effect of folic acid fortification in women of childbearing age for which this fortification was targeted. This analysis was recently carried out by the CDC using data from the third National Health and Nutrition Examination Survey (NHANES III; 1988–1994) and NHANES 1999 (17
). Among women of childbearing age (15–44 y old) who did not use supplements, mean plasma folate was 4.7 µg/L (10.7 nmol/L) in women not exposed to fortification vs. 12.6 µg/L (28.6 nmol/L) in women exposed to fortification. Among supplement users, mean plasma folate was 8.4 µg/L (19.0 nmol/L) in women not exposed to fortification vs. 20.0 µg/L (45.3 nmol/L) in women exposed to fortification. Mean RBC folate from all women was 181 µg/L (410.1 nmol/L) compared with 315 µg/L (713.8 nmol/L) in women not exposed and exposed to fortification, respectively (17
). However, the benefits of higher folate intake may extend beyond protection against NTD. Mild folate deficiency has been associated with increased concentrations of plasma homocysteine, which is an independent risk factor for vascular disease (18
,19
). It has also been associated with increased risk of certain cancers (20
) and increased risk of cognitive impairment in the elderly (21
).
Results of this study and others (7
,17
) suggest that American adults have reached unprecedented levels of folic acid intake and that folate deficiency has essentially been eliminated in the general U.S. population. Nevertheless, some suggest that higher fortification levels are required to optimally prevent NTD (22
–25
). Before any changes in the levels of fortification are made, it is essential to evaluate the effect of the current levels of fortification on NTD rates (26
). The difference in mean RBC folate levels between nonsupplement users not exposed to fortification and those exposed (325 vs. 450 µg/L) was comparable to the change in RBC folate observed by Daly et al. (27
) in women who received 200 µg of folic acid/d for 6 mo (from 311 to 475 µg/L). In the latter study, a reduction in NTD risk of 41% was estimated among those women (27
). A recently published study reported a 19% decrease in NTD birth prevalence in the United States after implementation of folic acid fortification (28
). However, another aspect that should be considered in evaluating the effect of folic acid fortification is the effect (positive and negative) of the current levels of fortification on the health of sectors of the population that were not targeted for this fortification, mainly children and the elderly (26
). The current levels of fortification may expose a large proportion of American children to daily amounts of folic acid that surpass their Tolerable Upper Intake Levels for folic acid (29
). Similarly, a large proportion of older Americans may be at risk because high levels of folic acid may mask the anemia associated with vitamin B-12 deficiency which, if left untreated, can cause irreversible neurologic damage. It has also been proposed that folic acid may induce or increase the rate and severity of neuropsychiatric disorders caused by B-12 deficiency (30
,31
). Changes in the current fortification levels should await the necessary data to assess and balance the potential benefits and risks of increased folic acid intakes.
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FOOTNOTES |
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2 Supported in part by the U.S. Department of Agriculture under agreement no. 58–1950-9–001, by the National Heart, Lung and Blood Institute’s Framingham Heart Study contract N01-HC-38038 and by National Institutes of Health grant 1R01 DK 56105–01.
4 Abbreviations used: CDC, Centers for Disease Control and Prevention; DRI, Dietary Reference Intakes; FDA, Food and Drug Administration; FHS, Framingham Heart Study; Hb, hemoglobin; NHANES, National Health and Nutrition Examination Survey; NTD, neural tube defects.
Manuscript received July 19, 2001. Initial review completed August 8, 2001. Revision accepted September 18, 2001.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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1. Center for Disease Control (1992) Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. Morb. Mortal. Wkly. Rep. 41:1-7.
2. Scott, J. M., Weir, D. G. & Kirke, P. N. (1995) Folate and neural tube defects. Bailey, L. B. eds. Folate in Health and Disease 1995:329-360 Marcel Dekker New York, NY. .
3.
From the Centers for Disease Control and Prevention (1999) Knowledge and use of folic acid by women of childbearing age—United States, 1995 and 1998. J. Am. Med. Assoc. 281:1883-1884.
4. From the Centers for Disease Control and Prevention (1995) Knowledge and use of folic acid by women of childbearing age—United States, 1995. Morb. Mortal. Wkly. Rep. 44:716-718.[Medline]
5. Food standards: amendment of the standards of identity for enriched grain products to require addition of folic acid. Final rule. Federal Register 61:8781-8797.
6. Food labeling: health claims and label statements; folate and neural tube defects. Federal Register 58:53254-53295.
7.
Jacques, P. F., Selhub, J., Bostom, A. G., Wilson, P. W. & Rosenberg, I. H. (1999) The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N. Engl. J. Med. 340:1449-1454.
8. Shane, B. (1995) Folate chemistry and metabolism. Bailey, L. B. eds. Folate in Health and Disease 1995:1-22 Marcel Dekker New York, NY. .
9. Kannel, W. B., Feinleib, M., McNamara, P. M., Garrison, R. J. & Castelli, W. P. (1979) An investigation of coronary heart disease in families. The Framingham Offspring Study. Am. J. Epidemiol. 110:281-290.
10.
Horne, D. W. & Patterson, D. (1988) Lactobacillus casei microbiological assay of folic acid derivatives in 96-well microtiter plates. Clin. Chem. 34:2357-2359.
11. Tamura, T., Freeberg, L. E. & Cornwell, P. E. (1990) Inhibition of EDTA of growth of Lactobacillus casei in the folate microbiological assay and its reversal by added manganese or iron. Clin. Chem. 36:1993.[Medline]
12.
O’Broin, S. D., Kelleher, B. P., Davoren, A. & Gunter, E. W. (1997) Field-study screening of blood folate concentrations: specimen stability and finger-stick sampling. Am. J. Clin. Nutr. 66:1398-1405.
13. SAS Institute, Inc. (1989) SAS/STAT User’s Guide, Version 6 1989 SAS Institute Cary, NC .
14. Sauberlich, H. E. (1995) Folate status of U.S. population groups. Bailey, L. B. eds. Folate in Health and Disease 1995:171-194 Marcel Dekker New York, NY. .
15.
Bailey, L. B. & Gregory, J. F., III (1999) Folate metabolism and requirements. J. Nutr. 129:779-782.
16. Food and Nutrition Board, Institute of Medicine (1998) Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. A Report of the Standing Committee on the Scientific Evaluation of Dietary References Intakes and Its Panel on Folate, Other B Vitamins and Choline and Subcommittee on Upper Reference Levels of Nutrients 1998 National Academy Press National Academy Press .
17. Folate status in women of childbearing age—United States, (1999) Morb. Mortal. Wkly. Rept. 49:962-965.
18. Selhub, J. (1999) Homocysteine metabolism. Annu. Rev. Nutr. 19:217-246.[Medline]
19. Refsum, H., Ueland, P. M., Nygard, O. & Vollset, S. E. (1998) Homocysteine and cardiovascular disease. Annu. Rev. Med. 49:31-62.[Medline]
20. Mason, J. B. & Levesque, T. (1996) Folate: effects on carcinogenesis and the potential for cancer chemoprevention. Oncology (Huntington) 10:1727-1743.[Medline]
21. Selhub, J., Bagley, L. C., Miller, J. & Rosenberg, I. H. (2000) B vitamins, homocysteine, and neurocognitive function in the elderly. Am. J. Clin. Nutr. 71(suppl.):614S-620S.
22. Folic acid and the prevention of neural tube defects (2000) Am. J. Public Health 90:465-466.
23. Wald, N. J., Law, M. & Jordan, R. (1998) Folic acid food fortification to prevent neural tube defects. Lancet 351:834.[Medline]
24.
Oakley, G. P., Jr (1998) Eat right and take a multivitamin. N. Engl. J. Med. 338:1060-1061.
25.
American Academy of Pediatrics. Committee on Genetics (1999) Folic acid for the prevention of neural tube defects. Pediatrics 104:325-327.
26.
Mills, J. L. (2000) Fortification of foods with folic acid—how much is enough?. N. Engl. J. Med 342:1442-1445.
27. Daly, S., Mills, J. L., Molloy, A. M., Conley, M., Lee, Y. J., Kirke, P. N., Weir, D. G. & Scott, J. M. (1997) Minimum effective dose of folic acid for food fortification to prevent neural-tube defects. Lancet 350:1666-1669.[Medline]
28.
Honein, M. A., Paulozzi, L. J., Mathews, T. J., Erickson, J. D. & Wong, L.Y.C. (2001) Impact of folic acid fortification of the US food supply on the occurrence of neural tube defects. J. Am. Med. Assoc. 285:2981-2986.
29.
Lewis, C. J., Crane, N. T., Wilson, D. B. & Yetley, E. A. (1999) Estimated folate intakes: data updated to reflect food fortification, increased bioavailability, and dietary supplement use. Am. J. Clin. Nutr. 70:198-207.
30. Savage, D. G. & Lindenbaum, J. (1995) Folate-cobalamin interactions. Bailey, L.B. eds. Folate in Health and Disease 1995:237-285 Marcel Dekker New York, NY. .
31. Tucker, K. L., Mahnken, B., Wilson, P. W., Jacques, P. & Selhub, J. (1996) Folic acid fortification of the food supply. Potential benefits and risks for the elderly population. J. Am. Med. Assoc. 276:1879-1885.[Abstract]
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