Graves' Disease Therapy Risks to Mother and Fetus

描述(由申请人提供)：Graves病(GD)占年轻人甲亢病例的绝大多数。据估计，美国有30,000名育龄妇女患有GD，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)是妊娠期GD的推荐治疗方法。根据对妊娠期接受MMI治疗的母亲的后代的出生缺陷(皮肤发育不良和后鼻孔闭锁)的观察，以及没有与PTU使用相关的报告，PTU已被推荐为GD孕妇的首选药物。在初步研究中，在美国食品和药物管理局(FDA)的不良事件报告系统(AERS)数据中，我们在怀孕期间接受PTU治疗的妇女的后代中发现了大量重大的出生缺陷。在我们对国际出生缺陷监测和研究中心(ICBDSR)数据的分析中，我们观察了孕期使用PTU(先天性心脏病)和MMI(后鼻孔闭锁)的出生缺陷。在小鼠模型中，我们观察到胚胎发育期间PTU暴露(e7.5到10.5)与头骨和心脏缺陷有关，而我们没有观察到使用MMI或高剂量左旋甲状腺素(LT4)处理的DAME胚胎中的畸形。这些观察结果表明，目前治疗妊娠期GD合并ATDS的建议可能并不是最理想的。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有关。(2)甲亢、妊娠期PTU和MMI所致出生缺陷的性质不同，类型和发生率不同。(3)甲亢本身可能是孕期出生缺陷的原因之一。(4)孕期使用PTU对孕妇有肝损伤的风险。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(120万个妊娠)和Kaiser Permanente North California(KPNC；(30万个妊娠)。将对数据库进行分析，以评估妊娠期间GD的患病率、患有GD的孕妇使用ATD治疗的情况、与妊娠期间使用GD和ATD相关的共病(即肝病)，以及患有GD并接受ATDS治疗的母亲所生婴儿的出生缺陷和其他共病情况。具体目标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研究，以评估PTU和MMI的出生缺陷风险。我们将研究与药物剂量有关的对胎儿存活率、生长和形态的影响。我们将定义胚胎对PTU和MMI影响的脆弱时期。我们将研究甲亢状态对出生缺陷的影响。我们将使用符合FDA要求的方法和测试实验室。这些研究将与数据库审讯专家James Korelitz(Westat)博士、内分泌学和数据库分析专家Joan C.Lo(Kaiser Permanente)医学博士、致畸测试专家Alan Hoberman博士和发育生物学和甲状腺疾病专家Scott Rivkees博士合作进行。预计这些研究将为妊娠期服用ATD治疗GD的风险提供新的见解。完成后，我们预计这些研究将提供必要的流行病学和基础畸胎学数据，说明PTU、MMI和甲亢对母亲和胎儿的相对风险。

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.