Graves' Disease Therapy Risks to Mother and Fetus

描述（由申请人提供）：格雷夫斯病（GD）占年轻人甲状腺功能亢进的绝大多数病例。据估计，在美国有30,000名患有GD的育龄妇女，每年有4,000至8,000名妇女在怀孕期间接受GD治疗。抗甲状腺药物（ATD）治疗是妊娠期GD的推荐治疗。基于对妊娠期间接受MMI治疗的母亲的后代出生缺陷（皮肤发育不全和后肛门闭锁）的观察，以及缺乏与PTU使用相关的报道，PTU被推荐为妊娠GD妇女的首选药物。在初步研究中，根据美国食品和药物管理局（FDA）不良事件报告系统（AERS）的数据，我们发现在怀孕期间接受PTU治疗的妇女的后代中有大量的主要出生缺陷。在我们对国际出生缺陷监测和研究信息中心（ICBDSR）数据的分析中，我们观察到在妊娠期间使用PTU（先天性心脏缺陷）和MMI（后肛门闭锁，脐囊）的出生缺陷。在小鼠模型中，我们观察到PTU暴露在胚胎发生期间（E7.5至10.5）与颅骨和心脏缺陷有关，而我们没有观察到MMI或高剂量左旋甲状腺素（LT4）处理的小鼠胚胎畸形。这些观察结果表明，目前对ATDs妊娠期间GD治疗的建议可能不是最佳的。考虑到上述数据，我们假设：(1)妊娠期间使用PTU与重大出生缺陷的风险相关。(2)与甲亢、妊娠期间使用PTU和MMI相关的出生缺陷的性质在类型和发生率上存在差异。(3)甲亢本身可能导致妊娠期出生缺陷。(4)妊娠期孕妇使用PTU有肝损伤的危险。为了验证这些假设，提出了两个具体目标：具体目标1：评估妊娠期间ATD治疗对母亲和胎儿的风险。队列研究将使用大型临床数据库进行，包括Marketscan（120万例妊娠）和Kaiser Permanente Northern California （KPNC， 30万例妊娠）的数据库。将对数据库进行分析，以评估妊娠期GD的患病率、妊娠期GD和ATD治疗的孕妇使用情况、妊娠期GD和ATD治疗相关的合并症（即肝脏疾病）、妊娠期GD和ATD治疗的母亲所生婴儿的出生缺陷和其他合并症。专项目的2：评估PTU和MMI的致畸潜力。为了补充人类队列研究，我们将进行基本的致畸性研究，以评估PTU和MMI的出生缺陷风险。我们将检查药物剂量对胎儿生存能力、生长和形态的影响。我们将定义胚胎易受PTU和MMI影响的时期。我们将检查甲状腺功能亢进状态对出生缺陷的贡献。我们将使用符合FDA要求的方法和测试实验室。这些研究将涉及与数据库查询专家James Korelitz博士（Westat）的合作努力；Joan C. Lo博士（Kaiser Permanente），内分泌学和数据库分析专家；艾伦·霍伯曼博士（查尔斯河实验室）是致畸测试方面的专家，斯科特·里夫基斯博士（耶鲁大学）是发育生物学和甲状腺疾病方面的专家。预计这些研究将为妊娠期妊娠期ATD治疗所涉及的风险提供新的见解。完成后，我们预计这些研究将提供PTU、MMI和甲亢对母亲和胎儿的相对风险所需的流行病学和基本畸形学数据。

DESCRIPTION (provided by applicant): Graves' disease (GD) accounts for the vast majority of cases of hyperthyroidism in young adults. It is estimated that there are 30,000 women of childbearing age with GD in the United States (US), and that 4,000 to 8,000 women are treated for GD during pregnancy annually. Antithyroid drug (ATD) therapy is the recommended treatment of GD during pregnancy. Based on observations of birth defects (aplasia cutis and choanal atresia) in offspring of mothers treated with MMI during pregnancy, and the absence of such reports related to PTU use, PTU has been recommended as the drug-of-choice for pregnant women with GD. In preliminary studies, in US Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) data, we discovered a substantial number of major birth defects in the offspring of women treated with PTU during pregnancy. In our analysis of International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR) data, we observed birth defects with PTU (congenital heart defects) and MMI (choanal atresia, omphalocelle) use during pregnancy. In murine models, we observed that PTU exposure during embryogenesis (E7.5 to 10.5) is associated with skull and cardiac defects, whereas we do not observe malformations in embryos of dams treated with MMI or high doses of levo-thyroxine (LT4). These observations suggest that current recommendations for the treatment of GD during pregnancy with ATDs may not be optimal. Considering the above data, we hypothesize that (1) PTU use during pregnancy is associated with a risk of major birth defects. (2) The nature of birth defects associated with hyperthyroidism, PTU and MMI use during pregnancy differ in type and incidence. (3) Hyperthyroidism itself may contribute to birth defects during pregnancy. (4) There is a risk of liver injury to pregnant mothers during pregnancy associated with PTU use. To test these hypotheses, two specific aims are proposed: Specific Aim 1: Assess the risks of ATD treatment during pregnancy on mother and fetus. Cohort studies will be performed using large clinical databases, including those of Marketscan (>1.2 million pregnancies) and Kaiser Permanente Northern California (KPNC; (>300,000 pregnancies). Databases will be analyzed to assess the prevalence of GD in pregnancy, ATD treatment use in pregnant women with GD, co-morbid conditions (i.e., liver disease) associated with GD and ATD use in pregnancy, and birth defects and other co-morbid conditions in infants born to mothers with GD and treated with ATDs. Specific Aim 2: Assess teratogenic potential of PTU and MMI. To complement human cohort studies, we will perform basic teratogenicity studies to assess the birth defect risks of PTU and MMI. We will examine effects on fetal viability, growth and morphology, as related to drug dose. We will define periods of vulnerability of the embryo to affects of PTU and MMI. We will examine the contribution of the hyperthyroid state to birth defects. We will use methods and a testing laboratory that satisfies requirements of the FDA. These studies will involve collaborative efforts with Dr. James Korelitz (Westat), who is an expert in database interrogation; Dr. Joan C. Lo, M.D. (Kaiser Permanente), who is an expert in endocrinology and database analysis; Dr. Alan Hoberman (Charles River Laboratory), who is an expert in teratogenicity testing and Dr. Scott Rivkees (Yale University) who is an expert in developmental biology and thyroid disorders. It is anticipated that these studies will provide new insights into the risks involved with ATD treatment of GD during pregnancy. When completed, we anticipate that these studies will provide needed epidemiology and basic-teratology data about the relative risks of PTU, MMI, and hyperthyroidism to mother and fetus. PUBLIC HEALTH RELEVANCE: The goal of these studies is to determine the risks of antithyroid drug therapy during pregnancy on mother and fetus. When completed, we anticipate that these studies will provide needed epidemiology and basic-teratology data about the relative risks of PTU, MMI, and hyperthyroidism to mother and fetus.