Based on animal studies, epidemiologic studies and intervention trials, maternal folic acid is known to be protective for neural tube defects (NTD), primarily spina bifida and anencephalus. To reduce the risk of NTD, the U.S. Food and Drug Administration mandated that all enriched cereal grain products be fortified with folic acid as of January 1998. Recent data demonstrate that this public health action is associated with increased folate blood levels among U.S. women of childbearing age and that the national rate of spina bifida has decreased by 20%. Rates of anencephaly appear not to have declined. Epidemiologic data on use of folate and folate antagonists have also implicated folic acid in prevention of other birth defects such as facial clefts and cardiac and limb defects. Dietary folic acid is likely to be inadequate for maximal protection against NTD. Because about half of pregnancies in the U.S. are unplanned, according to the March of Dimes, birth defect prevention includes a recommended daily dose of 400 micro g synthetic folic acid for women of childbearing age. Uniform compliance is estimated to decrease the incidence of NTD by up to 70%. This could reduce the overall incidence from 2 to 0.6 per 1000 pregnancies and prevent disease in approximately 2000 babies per year in the U.S. Four thousand micrograms of folic acid per day is recommended for women with previous pregnancies affected by NTD.