Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification

Authors: MORRIS, MARTHA - HNRCA AT TUFTS; Jacques, Paul; Rosenberg, Irwin; Selhub, Jacob

Submitted to: The American Journal of Clinical Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/16/2006
Publication Date: 1/1/2007
Citation: Morris, M.S., Jacques, P., Rosenberg, I., Selhub, J. 2007. Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification. American Journal of Clinical Nutrition. 85(1):193-200.

Interpretive Summary: In 1998, the US Food and Drug Administration ordered folic-acid fortification of enriched grain products such as cereals and breads. The aim of the program was a reduction in the incidence of neural tube birth defects. It was feared, however, that the program might be harmful to some seniors. This possibility relates to an age-related decline in the ability to extract vitamin B12 from foods. In the 1940s and 1950s, people thought to lack folate, but who were actually suffering from a B12-deficiency disease, were treated with folic acid. Symptoms included low blood cell counts, or anemia, and various neurologic and psychiatric problems. The anemia appeared to improve after treatment, but the neurologic and psychiatric symptoms seemed to get much worse. Although the curing of a life-threatening anemia could be seen as a benefit, some feared that, without this symptom, cases of vitamin B12 deficiency would go unrecognized until the deficit was so severe that the neurologic and psychiatric problems would not respond to vitamin B12 replacement. Proponents of fortification have minimized this potential threat, because physicians have become increasingly aware that vitamin B12 deficiency may present with neurologic or psychiatric problems alone. The equally important idea that folic acid treatment can precipitate or exacerbate deficiency symptoms has also been questioned – particularly since many studies have reported beneficial effects of higher folate status, even among the elderly. We attempted to systematically study the hypothesis that high folate status is harmful to seniors with low vitamin B12 status using data collected on senior participants in the National Health and Nutrition Examination Survey (1999-2002). We used serum concentrations of vitamin B12 and methylmalonic acid to classify subjects according to vitamin B12 status. Then, we examined the association between high serum folate and anemia and cognitive impairment in each group. Cognitive impairment was defined as a low score on a cognitive function test administered to the seniors. In the group with normal vitamin B12 status, high serum folate was associated with protection from cognitive impairment. In the group with low vitamin B12 status, however, high serum folate was associated with more anemia and more cognitive impairment. Consequently, though the scenario was different from that expected based on reports from the 1940s and 1950s, our findings were consistent with the idea that high folate status is harmful to seniors with low vitamin B12 status. They were also consistent with the idea that higher folate status has health benefits for the majority of seniors.

Technical Abstract: Historic data on folic acid treatment of pernicious anemia suggested that high-level fortification would delay diagnosis or exacerbate effects of vitamin B12 deficiency, which affects many seniors. This idea is controversial, however, because observational data are few and inconclusive and experimental investigation is unethical. Our objective was to examine interrelations between serum folate and vitamin B12 status relative to anemia, macrocytosis, and cognitive impairment (i.e., Digit Symbol-Coding Score<34) in American seniors (n = 1,459). We analyzed data from the 1999-2002 National Health and Nutrition Examination Survey after exclusions for high serum creatinine and self-reported stroke, alcoholism, recent anemia therapy, or diseases of the liver, thyroid, or coronary arteries. We defined low B12 status as serum B12 <148 pmol/L or serum methylmalonic acid >210 nmol/L, the upper limit of the reference range for serum B12–replete participants with normal serum creatinine. After control for demographics, cancer, smoking, alcohol intake, and serum concentrations of ferritin and creatinine, odds ratios (OR) (95% CI) relating low B12 status to anemia, macrocytosis, and cognitive impairment were 2.7 (1.7-4.2), 1.8 (1.01-3.3), and 2.5 (1.6-3.8), respectively. ORs (95% CI) relating serum folate >59 nmol/L (80th percentile) to anemia and cognitive impairment were 3.1 (1.5-6.6) and 2.6 (1.1-6.1) for seniors with low B12 status, and 0.6 (0.1-2.4) and 0.4 (0.2-0.9) for the remainder (P interaction<0.05). Among seniors with low vitamin B12 status, high serum folate was associated with both anemia and cognitive impairment. Among seniors with normal vitamin B12 status, however, high serum folate was associated with protection from cognitive impairment.