American Journal of Epidemiology Original Contribution Nitrosatable Drug Exposure during Early Pregnancy and Neural Tube Defects in Offspring National Birth Defects Prevention Study

Nitrosatable drugs, such as secondary or tertiary amines and amides, form N-nitroso compounds in the presence of nitrite. Various N-nitroso compounds have been associated with neural tube defects in animal models. Using data from the National Birth Defects Prevention Study, the authors examined nitrosatable drug exposure 1 month before and 1 month after conception in 1,223 case mothers with neural tube defect-affected pregnancies and 6,807 control mothers who delivered babies without major congenital anomalies from 1997 to 2005. Nitrite intakes were estimated from mothers' responses to a food frequency questionnaire. After adjustment for maternal race/ethnicity, educational level, and folic acid supplementation, case women were more likely than were control women to have taken tertiary amines (odds ratio ¼ 1.60, 95% confidence interval (CI): 1.31, 1.95). This association was strongest with anencephalic births (odds ratio ¼ 1.96, 95% CI: 1.40, 2.73); odds ratios associated with tertiary amines from the lowest tertile of nitrite intake to the highest tertile were 1.16 Odds ratios for anencephaly with nitrosatable drug exposure were reduced among women who also took daily vitamin supplements that contained vitamin C. Prenatal exposure to nitrosatable drugs may increase the risk of neural tube defects, especially in conjunction with a mother's higher dietary intake of nitrites, but vitamin C might modulate this association. Various N-nitroso compounds have been associated with neural tube defects (NTDs) in animal models (1, 2), and DNA alkylation of embryonic cells has been suggested as one of the mechanisms for teratogenicity (1). Extensive experimental evidence indicates that N-nitroso compounds can be formed in vivo by nitrosatable amines or amides reacting with nitro-sating agents, such as nitrite, in an acidic environment like that found in the stomach (3). Endogenous N-nitroso compound formation contributes 40%–75% of exposure to such compounds in humans (4), and a variety of drugs contribute nitrosatable amines or amides in the endogenous formation of N-nitrosamines and N-nitrosamides. In experiments with simulated gastric conditions (5–7), the combination of drugs containing secondary or tertiary amines or amides with nitrite have yielded a range of N-nitroso compounds, depending on the chemical structure of the drug. Few epidemiologic studies have been conducted on the relation between nitrosatable drugs and NTDs. Olshan and Faustman (8) noted an association between exposure to nitro-satable drugs during the first 4 months of pregnancy and spina