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We used conventional and hierarchical logistic regression to examine the association of neural tube defects (NTDs) with intake of 26 nutrients that contribute to the mechanistic pathways of methylation, glycemic control, and oxidative stress, all of which have been implicated in NTD etiology. The hierarchical approach produces more plausible, more stable estimates than the conventional approach, while adjusting for potential confounding by other nutrients.Analyses included 386 cases and 408 nonmalformed controls with complete data on nutrients and potential confounders (race/ethnicity, education, obesity, and intake of vitamin supplements) from a population-based case-control study of deliveries in California from 1989 to 1991. Nutrients were specified as continuous, and their units were standardized to have a mean of zero and standard deviation (SD) of 1 for comparability of units across pathways. ORs reflect a 1-SD increase in the corresponding nutrient.Among women who took vitamin supplements, semi-Bayesian hierarchical modeling results suggested no associations between nutrient intake and NTDs. Among women who did not take supplements, both conventional and hierarchical models (HM) suggested an inverse association between lutein intake and NTD risk (HM odds ratio [OR] = 0.6; 95% confidence interval = 0.5–0.9) and a positive association with sucrose (HM OR 1.4; 1.1–1.8) and glycemic index (HM OR 1.3; 1.0–1.6).Our findings for lutein, glycemic index, and sucrose suggest that further study of NTDs and the glycemic control and oxidative stress pathways is warranted.