To the Editor: Will Increasing Folic Acid in Fortified Grain Products Further Reduce Neural Tube Defects without Causing Harm? Consideration of the Evidence. In the January issue of this journal, Johnston (1) includes our group's recent analysis of data from 1999 to 2002 National Health and Nutrition Examination Survey (2) among studies providing data inconsistent with those linking higher folate status to protection from cognitive dysfunction. Our work is also cited as evidence against the idea that the anemia of vitamin B12 deficiency is cured by high folic acid intake. In fact, our study showed that high folate status was associated with good cognition in seniors with normal vitamin B12 status. However, approximately 4% of seniors who had high folate status combined with low vitamin B12 status, which represented ¾ to one million Americans, experienced significantly more anemia and cognitive dysfunction than other seniors, including seniors with low vitamin B12 status alone. Furthermore, although Johnston cites reduction of hyperhomocysteinemia and associated health outcomes as a potential benefit of fortification, a more recent analysis of data collected on vitamin B12-deficient adult participants in the same survey revealed positive associations between serum folate concentrations and circulating levels of homocysteine and methylmalonic acid (2). Although emphasizing the evidence against masking, the importance of which is questionable given the infrequency of anemia in clinically significant vitamin B12 deficiency (3) and the availability of biochemical assays, Johnston ignores a potential adverse effect of high folic acid intake that our data seem to support; namely, exacerbation of the consequences of vitamin B12 deficiency. Serum folate concentrations ≥45.4 nmol/L were observed in 43% of survey participants, compared with only 7% of participants in the prefortification National Health and Nutrition Examination Survey III (4). It is thus reasonable to conclude that fortification contributed to the relations we reported.

As noted in our 2005 editorial (5), an evidence-based answer to the question posed in the title to Johnston's paper will require a balance of risks and benefits based on a fair representation of all the evidence.

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