Genetics of Recurrent Miscarriage and Pregnancy Loss in Women’s Reproductive Health

Adverse pregnancy outcomes, such as sporadic and recurrent miscarriages and stillbirths, are significant medical concerns, impacting up to 15% of clinically recognised pregnancies. These outcomes are highly complex and multifactorial, with up to 50% of cases classified as idiopathic, highlighting a substantial gap in our understanding of their biological basis. Along with external risk factors, polygenic variability contributes to idiopathic pregnancy loss, suggesting that large-scale genetic studies could offer insights into its mechanisms, reveal novel drug targets, and lead to new treatments. This study assesses current knowledge from genome-wide association studies (GWAS) using genotyping arrays, whole-genome imputation, and sequencing for variant discovery, emphasising genetic predisposition to adverse pregnancy outcomes. We summarise existing efforts identifying 30 genetic loci associated with pregnancy loss and related endophenotypes, integrating them into a polygenic score (PGS) and conducting a phenome-wide PGS association analysis of 280 ICD-10 outcomes in nearly 500,000 UK Biobank participants. We report associations between pregnancy loss PGS and an increased risk for diaphragmatic hernia (OR[95%CI]=1.02[1.01–1.03], P=9.15×10⁻⁷), eosinophilic esophagitis (OR[95%CI]=1.05[1.03–1.06], P=1.44×10⁻⁶), and asthma with exacerbation (OR[95%CI]=1.02[1.01–1.03], P=1.71×10⁻⁵), significant after correction for multiple testing and suggesting new mechanistic pathophysiology in pregnancy loss susceptibility. Additionally, Mendelian Randomisation (MR) studies identified higher BMI and smoking as risk factors for pregnancy loss, while the roles of caffeine and alcohol intake, maternal age, and family history of miscarriage warrant further investigation through adequately powered MR analyses. Well-designed and comprehensive GWAS studies, particularly across diverse ancestry groups, are urgently needed for idiopathic recurrent pregnancy loss. Such studies should overcome issues with identification of women suffering for this condition and related pregnancy losses to support better care and timely interventions, aiming for healthy live birth outcomes.