Nitrates, Nitrites, and Nitrosatable Drugs and Risk of Selected Birth Defects

描述(申请人提供)：先天性缺陷仍然是导致婴儿死亡的最大因素；然而，这些缺陷中的大多数原因要么未知，要么知之甚少。含有胺和酰胺的药物和其他化合物在胃中与亚硝酸盐反应生成N-亚硝基化合物。在动物模型中，已发现N-亚硝基化合物可诱发多种先天性畸形。以往的流行病学研究主要集中在硝酸盐、亚硝酸盐和亚硝酸类药物对先天畸形风险的单独影响上，而没有考虑它们在N-亚硝基化合物的内源性形成过程中的相互作用。这项病例对照研究将考察产前暴露于硝酸盐、亚硝酸盐和亚硝酸盐类药物对选定的先天性畸形(神经管缺陷、肢体畸形、口腔裂隙和心脏缺陷)风险的单独和联合影响。病例和对照将从国家出生缺陷预防研究(NBDPS)中获得，这是一项涵盖10个不同州人口的多中心研究。受试者日常饮食中硝酸盐、亚硝酸盐和亚硝胺的摄入量将从NBDPS食物频率问卷中计算出来。从NBDPS访谈中，根据文献和化学结构，将根据文献和化学结构对怀孕前一个月和怀孕前三个月报告服用的药物进行亚硝酸盐可能性分类。爱荷华州和得克萨斯州参与者的概念性地址将与社区水系统和相关的水硝酸盐采样结果联系起来。对于德克萨斯州的私人油井参与者，我们将使用多维流动和传输模型对硝酸盐水平进行建模和预测。我们将分析亚硝酸盐前体对所选畸形风险的单独和联合影响。我们还将研究维生素C和E(亚硝化抑制剂)对硝酸盐/亚硝酸盐摄入量和亚硝酸盐类药物之间的关系以及选定的先天畸形风险的影响。根据最近发表的一项研究，在怀孕期间使用非处方药是相当普遍的。一些非处方药含有亚硝酸盐化合物作为活性成分。这项拟议的研究将帮助我们了解服用这些类型药物并同时摄入更多硝酸盐和亚硝酸盐的孕妇是否会增加生育患有出生缺陷的后代的风险。这项研究还旨在检查更高的维生素C或E摄入量是否会降低这些潜在的风险。

DESCRIPTION (provided by applicant): Congenital defects remain the greatest contributor to infant mortality; yet, 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. In animal models, N-nitroso compounds have been found to induce a variety of congenital malformations. The few epidemiologic studies conducted in the past have focused on the separate effects of nitrates, nitrites, and nitrosatable drugs on risk of congenital malformations without consideration of their interaction in the endogenous formation of N- nitroso compounds. This case-control study will examine the separate and joint effects of prenatal exposures to nitrates, nitrites, and nitrosatable drugs on risk of selected congenital malformations (neural tube defects, limb malformations, oral clefts, and heart defects). Cases and controls will be obtained from the National Birth Defects Prevention Study (NBDPS), a multi-center study that covers populations in 10 different states. Subjects' usual intake of dietary nitrates, nitrites, and nitrosamines will be calculated from the NBDPS food frequency questionnaire. From the NBDPS interview, medications reported taken one month preconception and during the first trimester will be classified as to their likelihood of nitrosatability based on the literature and chemical structure. The periconceptional addresses of Iowa and Texas participants will be linked to community water systems and pertinent water nitrate sampling results. For Texas participants on private wells, we will model and predict nitrate levels with a multi-dimensional flow and transport model. We will analyze the separate and joint effects of nitrosatable precursors on risk of the selected malformations. We will also examine the effects of vitamins C and E (inhibitors of nitrosation) on the relations between nitrate/nitrite intake and nitrosatable drugs and risk of selected congenital malformations. Use of over-the- counter medications is fairly common during pregnancy according to a recently published study. Several over-the-counter preparations contain nitrosatable compounds as active ingredients. The proposed study will help us understand whether pregnant women who take these types of drugs and also consume greater amounts of nitrates and nitrites are at increased risk of having offspring with birth defects. The study is also designed to examine whether higher intakes of vitamin C or E decrease these potential risks.