Congenital defects are the greatest contributor to infant mortality in the U.S., but the causes for the majority of these defects are either unknown or poorly understood. Amine- and amide-containing (nitrosatable) drugs and other compounds react with nitrite in the stomach to form N-nitroso compounds, which have been found to induce a variety of congenital malformations in animal studies. Previous epidemiologic studies have focused on the separate effects of nitrates, nitrites, and nitrosatable drugs on risk of congenital malformations without consideration of their interaction in the formation of N-nitroso compounds. This study is examining the separate and joint effects of prenatal exposures to nitrates, nitrites, and nitrosatable drugs on the risk for neural tube defects, limb malformations, oral clefts, and heart defects. Cases and controls were obtained from the National Birth Defects Prevention Study (NBDPS), a CDC-funded study that covers populations in 10 different states. Subjects' usual intake of dietary nitrates, nitrites, and nitrosamines was calculated from a food frequency survey. The subject survey will also have information on medications taken one month pre-conception and during the first trimester; these will be classified as to their likelihood of nitrosatability based on the literature and chemical structure. Addresses of Iowa and Texas participants are being linked to community water systems and water nitrate sampling results. The separate and joint effects of nitrosatable precursors on risk of selected malformations will be analyzed. The effects of vitamins C and E (inhibitors of nitrosation) on the relations between nitrate/nitrite intake and nitrosatable drugs and risk of congenital malformations will also be examined. Use of over-the-counter medications is fairly common during pregnancy; several over-the-counter preparations contain nitrosatable compounds as active ingredients. This study will help us understand whether pregnant women who take nitrosatable drugs and also consume greater amounts of nitrates and nitrites are at increased risk of having offspring with birth defects