Periconceptual use of folic acid supplements by women is effective in preventing neural tube defects in the fetus. Folic acid supplements also may prevent atherosclerosis and some malignant neoplasms. Nevertheless, safety concerns have delayed recommendations to increase folic acid consumption by the general population. Among the potential safety issues of folic acid supplementation are (1) difficulty identifying cobalamin deficiency, precipitation of neurologic complications of cobalamin deficiency, and lowering of cobalamin levels; (2) folate neurotoxicity; (3) antagonism of drugs that inhibit folate metabolism; (4) reduced zinc absorption; (5) association with malignant neoplasms; (6) hypersensitivity reactions; and (7) increased susceptibility to malaria. The data that suggest that folic acid supplements are unsafe are weak and consist predominantly of case series and reports. Nevertheless, greater difficulty diagnosing cobalamin deficiency due to "masking" of hematologic abnormalities by folic acid is a potential risk. Strict vegetarians need to be informed that they are at risk of cobalamin deficiency. Physicians need to be aware that routine hematologic indexes have a low sensitivity for cobalamin deficiency, especially in patients who are receiving folic acid supplements. Because no high-quality data exclude specific adverse effects, physicians should be vigilant in identifying detrimental effects when patients increase their consumption of folic acid.
Arch Intern Med. 1996;156:1638-1644