Serum unmetabolized folic acid in a nationally representative sample of adults ≥60 years in the United States, 2001–2002

Vitamin Supplement

Serum unmetabolized folic acid in a nationally representative sample of adults ≥60 years in the United States, 2001–2002

Regan L. Bailey1*, James L. Mills2, Elizabeth A. Yetley1, Jaime J. Gahche3, Christine M. Pfeiffer4, Johanna T. Dwyer1, Kevin W. Dodd5, Christopher T. Sempos1, Joseph M. Betz1 and Mary Frances Picciano1

1National Institutes of Health, Office of Dietary Supplements, Bethesda, MD, USA; 2National Institutes of Health, Eunice Kennedy Shriver National Institute of Child and Human Development, Division of Epidemiology, Statistics, and Prevention Research, Bethesda, MD, USA; 3National Center for Health Statistics, Centers for Disease Control and Prevention, Hyattsville, MD, USA; 4National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA, USA; 5National Institutes of Health, National Cancer Institute, Bethesda, MD, USA

Keywords: folic acid; folate; NHANES; folic acid fortification

Published: 2 April 2012

Food & Nutrition Research 2012. © 2012 Regan L. Bailey et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 3.0 Unported License (, permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Citation: Food & Nutrition Research 2012. 56 5616 - DOI: 10.3402/fnr.v56i0.5616


Folic acid is a compound that does not occur naturally in food but is added as a fortificant and dietary supplement. When it is ingested it is converted into forms of reduced folate that are identical to those arising from ingestion of naturally occurring folate in foods; however, some folic acid may appear unmetabolized in the serum (1, 2). Very little is known about its metabolism and biological effects. Folic acid fortification increased dietary intakes of folic acid (3) and blood folate levels in the United States (4). Some (59) but not all (1012) research suggests that high folic acid intakes may promote the growth of pre-existing cancers or malignant lesions.

Material and methods

The National Health and Nutrition Examination Survey (NHANES) is a nationally representative, cross-sectional survey of the US population. During 2001–2002, UMFA and 5-methyltetrahydrofolic acid (5-methylTHF), the major circulating folate form in serum, were assayed in participants who fasted a mean of 8 hours (n = 1121 individuals, ≥60 years) using a revised affinity/HPLC method with electrochemical (coulometric) detection (13, 14). Other biochemical parameters measured were serum folate, red blood cell (RBC) folate, serum vitamin B12, and plasma homocysteine and methylmalonic acid (MMA).


Unmetabolized folic acid (UMFA) was detected in 38% of the population (15), with a mean concentration of 4.4±0.6 nmol/L (median 1.2±0.2 nmol/L). The group with detectable UMFA (+UMFA) included a significantly higher proportion of folic acid supplement users than those without it (−UMFA; 60 vs. 41%). The +UMFA males and females had higher supplemental and total (food+supplements) folic acid intakes than their −UMFA counterparts. Serum folate, 5-methylTHF, and vitamin B12 concentrations were also higher in the +UMFA group, while there was no differences in RBC folate, homocysteine, or MMA concentrations. The distribution of the −UMFA group was approximately equal across quartiles of 5-methylTHF concentrations. However, the distribution of +UMFA in their serum increased with increasing quartile of 5-methylTHF concentrations (Fig. 1A). A similar trend was observed in total folic acid intake quartiles (Fig. 1B).

Fig 1
Fig. 1.  The percentage of US adults (≥60 years) without (−UMFA) and with (+UMFA) detectable concentrations of unmetabolized serum folic acid by quartiles of serum 5-methyltetrahydrofolate (5-methylTHF) concentrations (A), quartiles of total folic acid intake (B).


Folic acid intakes do not entirely explain the variability in the presence or persistence of UMFA in this US population, suggesting that genetic differences in its metabolism may also be involved. More research is needed to determine the factors associated with circulating UMFA in folic acid fortified-populations. Given the possibility that excessive folic acid exposure may be associated with adverse effects such as promoting progression of certain cancers and its possible associations with anemia, macrocytosis, and cognition (16), understanding the association between folic acid intake (dietary and supplemental) and serum UMFA is important. Monitoring of UMFA may therefore be warranted.


The authors of this Extended Abstract acknowledge the reproduction of essential information from ‘Unmetabolized serum folic acid and its relation to folic acid intake from diet and supplements in a nationally representative sample of adults aged ≥60 years in the United States’ by Bailey RL, Mills JL, Yetley EA, Gahche JJ, Pfeiffer CM, Dwyer JT, et al. (Ref. 15). Thanks are due to American Journal of Clinical Nutrition for giving us permission to reproduce parts of this article.


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, Centers for Disease Control, Prevention/the Agency for Toxic Substances and Disease Registry, or any other entity of the US Government.

Conflict of interest and funding

The authors have not received any funding or benefits from industry or elsewhere to conduct this study.


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*Regan Lucas Bailey, PhD
RD Office of Dietary Supplements National Institutes of Health 6100
Executive Blvd., Rm. 3B01 Bethesda, MD 20892-7517
Tel: 301-496-0187
Fax: 301-480-1845

About The Authors

Regan L. Bailey
National Insitutes of Health
United States

James L. Mills
National Institutes of Health
United States

Elizabeth A. Yetley
National Institutes of Health
United States

Jaime J. Gahche
National Center for Health Statistics
United States

Chrisitne M. Pfeiffer
Centers for Disease Control and Prevention
United States

Johanna T. Dwyer
National Institutes of Health
United States

Kevin W. Dodd
National Institutes of Health
United States

Christopher T. Sempos
National Institutes of Health
United States

Joseph M. Beth
National Institutes of Health
United States

Mary Frances Picciano
National Institutes of Health
United States

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