O-315 Familial endocrine disease increases the risk of pregnancy loss and recurrent pregnancy loss– a nationwide register-based study of 366,548 Danish women
Authors: Egerup P , Bliddal S , Westergaard D , Glintborg D , Bonnema S , Feldt-Rasmussen U , Nyegaard M , Mortensen L  H , Nielsen H  S 
Published: July 2024

Abstract

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).