Study question Is endocrine disease and pregnancy loss associated, and can the association be due to inherited genetic causes? Summary answer Endocrine disease is associated with an increasing number of pregnancy losses. Endocrine disease in parents and siblings increases a woman’s risk of pregnancy loss. What is known already One in four pregnancies results in a pregnancy loss, but only 60% hereof are due to detectable chromosome abnormalities. The remaining 40% are suspected to be caused by other factors such as maternal comorbidity. Recurrent pregnancy loss (RPL) is defined as 2 or 3 consecutive losses and affects 1-3% of couples trying to conceive. Pregnancy loss has been associated with endocrine diseases, e.g., thyroid disease, diabetes, or PCOS. Furthermore, thyroid autoimmunity has been associated with RPL. It is unknown if other endocrine diseases are associated with RPL. To date, there is no evidence for a genetic basis of the risk. Study design, size, duration Danish nationwide cohort study including data from the Danish National Health Registers on ICD-8/ICD-10 diagnosis codes, all pregnancy outcomes and redeemed medicine prescriptions. Endocrine disease was defined as any endocrine disease (e.g., diabetes, thyroid disease, PCOS etc.). The study included in total 366,548 women, including 54,394 women with endocrine disease and 312,154 without endocrine diseases. The study included data from 1973 to 2022. Linkage to parent and siblings was available through the Multi-Generation Registry Lite. Participants/materials, setting, methods The cohort consisted of women born between 1977-1993 with ≥1 pregnancy. The exposure was endocrine disease. Logistic regression models adjusted for birth year provided odds ratios (ORs) for endocrine diseases according to number of pregnancy losses. Parent-offspring and sibling regression provided estimates for familial aggregation, assessing the degree of resemblance between relatives to infer the potential influence of shared familial factors. The variance-covariance matrix was adjusted using the Huber-White method to account for familial clustering. Main results and the role of chance We found a significant association between endocrine disease and pregnancy loss increasing with the number of pregnancy losses; OR and 95%CI for one loss 1.15 (1.12-1.17), two losses 1.31 (1.24-1.38) and ≥ three losses 1.81 (1.70-1.93). Further, endocrine disease was associated with RPL (OR 1.87, (1.74-2.00)). The association was strongest with primary RPL (OR 2.13 (1.94-2.35)), compared to secondary RPL (OR 1.58 (1.42-1.76)). In cases where either of a woman’s parents was diagnosed with an endocrine disease, she also had a higher risk of pregnancy loss (OR 1.06 (1.04–1.08)) and RPL (OR 1.07 (1.01–1.14)), compared to a woman with parents without endocrine disease. If a woman’s sibling had an endocrine disease, the OR for pregnancy loss was 1.07 (1.03–1.11) and RPL 1.17 (1.03–1.33). Further stratification into individual endocrine phenotypes revealed that type 2 diabetes conferred a comparable risk: for offspring of parents with this condition, the risk of pregnancy loss increased to an OR of 1.08 (1.06–1.11), and for siblings, the OR was 1.13 (1.02–1.25). This effect persisted even when adjusting for the disease in the individual experiencing the loss. Limitations, reasons for caution Very early pregnancy losses are often not handled at the hospital and therefore not part of the Danish registers. Thus, there is a risk of underdiagnosed pregnancy losses, although this would be the case for both the exposed and control cohort. Wider implications of the findings Women with RPL should be investigated for endocrine disease, and family history of endocrine disease is an important and novel risk factor that should guide the diagnostic work-up. Identifying the shared mechanism or pleiotropic effects between pregnancy loss and endocrine disease should be a focus area. Trial registration number Research related to this project was supported by the Novo Nordisk Foundation (ID: NNF22OC0077221, NNF23OC0087269) and the William Demant Foundation (salary for Pia Egerup).

中文翻译：

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O-315 家族内分泌疾病会增加流产和反复流产的风险——一项针对 366,548 名丹麦女性的全国登记研究


研究问题 内分泌疾病和流产是否相关，这种相关性是否是由于遗传原因造成的？摘要答案 内分泌疾病与流产数量的增加有关。父母和兄弟姐妹的内分泌疾病会增加女性流产的风险。已知四分之一的怀孕会导致流产，但其中只有 60% 是由于可检测到的染色体异常造成的。剩下的40%被怀疑是由母亲合并症等其他因素引起的。复发性流产 (RPL) 被定义为连续 2 或 3 次流产，影响 1-3% 的试图怀孕的夫妇。流产与内分泌疾病有关，例如甲状腺疾病、糖尿病或多囊卵巢综合症。此外，甲状腺自身免疫与 RPL 相关。目前尚不清楚其他内分泌疾病是否与 RPL 相关。迄今为止，没有证据表明该风险的遗传基础。研究设计、规模、持续时间丹麦全国队列研究，包括来自丹麦国家健康登记册的 ICD-8/ICD-10 诊断代码、所有妊娠结局和兑换药物处方的数据。内分泌疾病被定义为任何内分泌疾病（例如糖尿病、甲状腺疾病、多囊卵巢综合征等）。该研究总共纳入了 366,548 名女性，其中 54,394 名患有内分泌疾病的女性和 312,154 名未患有内分泌疾病的女性。该研究包括 1973 年至 2022 年的数据。可通过 Multi-Generation Registration Lite 与父母和兄弟姐妹建立联系。参与者/材料、环境、方法 该队列由 1977 年至 1993 年出生且妊娠次数≥1 次的女性组成。暴露的是内分泌疾病。 根据出生年份调整的逻辑回归模型根据流产次数提供了内分泌疾病的比值比 (OR)。亲子回归和兄弟姐妹回归提供了对家族聚集的估计，评估亲属之间的相似程度，以推断共同家族因素的潜在影响。使用 Huber-White 方法调整方差-协方差矩阵以考虑家族聚类。主要结果和机会的作用我们发现内分泌疾病和流产之间的显着关联随着流产次数的增加而增加；一次损失的 OR 和 95%CI 为 1.15 (1.12-1.17)，两次损失为 1.31 (1.24-1.38)，以及 ≥ 3 次损失为 1.81 (1.70-1.93)。此外，内分泌疾病与 RPL 相关（OR 1.87，（1.74-2.00））。与继发性 RPL (OR 1.58 (1.42-1.76)) 相比，原发性 RPL (OR 2.13 (1.94-2.35)) 的相关性最强。如果女性的父母之一被诊断患有内分泌疾病，则与患有内分泌疾病的女性相比，她的流产风险（OR 1.06 (1.04–1.08)）和 RPL（OR 1.07 (1.01–1.14)）也更高。父母无内分泌疾病。如果女性的兄弟姐妹患有内分泌疾病，则流产的 OR 为 1.07 (1.03–1.11)，RPL 为 1.17 (1.03–1.33)。对个体内分泌表型的进一步分层显示，2 型糖尿病具有相当的风险：对于患有这种疾病的父母的后代，流产的风险增加到 1.08 (1.06–1.11)，而对于兄弟姐妹，流产的风险为 1.13 ( 1.02–1.25）。即使在调整了经历损失的个体的疾病后，这种效应仍然持续存在。 局限性、谨慎原因 极早妊娠流产通常不在医院处理，因此不属于丹麦登记的一部分。因此，存在未确诊妊娠丢失的风险，尽管暴露组和对照组都会出现这种情况。研究结果的更广泛意义 患有 RPL 的女性应接受内分泌疾病调查，内分泌疾病家族史是一个重要且新颖的危险因素，应指导诊断检查。确定妊娠丢失和内分泌疾病之间的共同机制或多效性应该是一个重点领域。试验注册号 与该项目相关的研究得到了诺和诺德基金会（ID：NNF22OC0077221、NNF23OC0087269）和 William Demant 基金会（Pia Egerup 的工资）的支持。