Folic acid taken around the time of conception can prevent many neural-tube defects, Women with low-normal vitamin B-12 values may also be at increased risk. We considered whether homocysteine metabolism via the enzyme methionine synthase, which requires both folate and B-12, could be the critical defect in folate-related neural tube defects. Blood was obtained during pregnancies that produced 81 infants with neural-tube defects and 323 normal children, Samples were assayed for homocysteine, methylmalonic acid, plasma folate, red-cell folate, and B-12. Mothers of children with neural-tube defects had significantly higher homocysteine values (8.62 [SD 2.8] mu mol/L) than did B-12-matched controls (7.96 [2.5] mu mol/L, p=0.03). The difference was significant (p=0.004) in the lower half of the B-12 distribution after adjusting for plasma folate. Our study shows that an abnormality in homocysteine metabolism, apparently related to methionine synthase, is present in many women who give birth to children with neural-tube defects. Overcoming this abnormality is likely to be the mechanism by which folic acid prevents neural-tube defects. These findings suggest that the most effective periconceptional prophylaxis to prevent neural-tube defects may require B-12 as well as fotic acid.
