ELEVATED MIDTRIMESTER SERUM METHYLMALONIC ACID LEVELS AS A RISK FACTOR FOR NEURAL-TUBE DEFECTS

The role of folic acid in the primary prevention of neural tube defect s (NTDs) is well established. However, questions related to the protec tive mechanism remain unanswered. To help answer these questions, we d esigned a case-control study to assess the role of folate- and cobalam in-related metabolites in the pathogenesis of NTDs. Concentrations of folate, cobalamin, and 14 other related metabolites were measured by g as chromatography/mass spectrometry in midtrimester serum specimens fr om 32 women with an NTD-affected pregnancy and from 132 control women, and in serum specimens from 46 nonpregnant women who had a history of NTD-affected pregnancy and from 43 nonpregnant control women. log-tra nsformed means of metabolites were compared between case and control w omen for both the midtrimester and nonpregnant groups. In the pregnant group, serum methylmalonic acid (MMA) concentrations were higher amon g case women than among control women (130 vs 105 nM). There was a str ong dose-response relationship between midtrimester serum MMA level an d the risk for an NTD-affected pregnancy, with the relative risk incre asing 13-fold for women with MMA levels > 90th percentile. In the nonp regnant group, there was no difference in serum MMA levels between cas e and control women (140 vs 140 nM). Thus, the serum MMA levels of wom en in the midtrimester of pregnancies unaffected by NTDs were signific antly lower than the levels of nonpregnant women, whereas the levels o f women whose pregnancies were affected by NTDs were similar to those of nonpregnant women. The finding of elevated MMA serum concentrations among women in the midtrimester of NTD-affected pregnancies suggests that cobalamin may be involved in the etiology of NTDs. The possible r ole of cobalamin in relation to the protective effect of folic acid ne eds further evaluation. (C) 1995 Wiley-Liss, Inc.