Graves' Disease Therapy Risks to Mother and Fetus

描述（由申请人提供）：Graves病（GD）占青壮年甲状腺功能亢进症病例的绝大多数。据估计，在美国（US）有30，000名育龄妇女患有GD，每年有4，000至8，000名妇女在妊娠期间接受GD治疗。抗甲状腺药物（ATD）治疗是妊娠期GD的推荐治疗方法。 根据妊娠期间接受MMI治疗的母亲的后代中出生缺陷（皮肤发育不全和后鼻孔闭锁）的观察结果，以及缺乏与PTU使用相关的此类报告，PTU已被推荐为GD妊娠女性的首选药物。 在初步研究中，在美国食品和药物管理局（FDA）不良事件报告系统（AERS）的数据中，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重大出生缺陷。在我们对国际出生缺陷监测和研究中心（ICBDSR）数据的分析中，我们观察到妊娠期间使用PTU（先天性心脏病）和MMI（后鼻孔闭锁，脐膨出）的出生缺陷。在小鼠模型中，我们观察到胚胎发育期间（E7.5至10.5）的PTU暴露与颅骨和心脏缺陷相关，而我们没有观察到MMI或高剂量左旋甲状腺素（LT 4）处理的母鼠胚胎畸形。这些观察结果表明，目前的建议，妊娠期GD的治疗ATD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)与甲状腺功能亢进、PTU和MMI使用相关的出生缺陷的性质在类型和发生率上有所不同。(3)甲状腺功能亢进症本身可能导致妊娠期出生缺陷。(4)有一个风险，肝损伤的孕妇在怀孕期间与PTU的使用。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北方加州（KPNC;> 30万例妊娠）。将对数据库进行分析，以评估妊娠期GD的患病率、妊娠期GD女性中ATD治疗的使用、共病状况（即，与妊娠期GD和ATD使用相关的肝脏疾病），以及GD母亲所生婴儿的出生缺陷和其他合并症，并接受ATD治疗。 具体目的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。我们将研究与药物剂量相关的对胎仔活力、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。我们将研究甲状腺功能亢进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。 这些研究将涉及与数据库查询专家James Korelitz博士（Westat）、Joan C.罗医生（Kaiser Permanente），他是内分泌学和数据库分析专家; Alan Hoberman博士（Charles River Laboratory），他是致畸性测试专家; Scott Riverman博士（耶鲁大学），他是发育生物学和甲状腺疾病专家。 预计这些研究将为妊娠期GD ATD治疗相关风险提供新的见解。完成后，我们预计这些研究将提供所需的流行病学和基本畸形学数据的相对风险PTU，MMI和甲状腺功能亢进症的母亲和胎儿。

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.