Molecular Determinants of Unexplained Stillbirth: Genetic, Immune-Mediated, and Pharmacogenomic Contributors

Intrauterine fetal death, also termed stillbirth, remains a major clinical challenge, with a substantial proportion of cases unresolved despite standard postmortem evaluation, limiting effective risk stratification and prevention. This structured narrative review synthesizes evidence from genetic, immune-mediated, and pharmacogenetic studies to summarize possible contributors to stillbirth with potential application in precision-oriented diagnostics and prevention of unexplained stillbirth. Integration of cytogenetic and sequencing approaches enhances detection of clinically relevant abnormalities in previously unexplained cases, while exome sequencing reveals additional molecular diagnoses beyond conventional chromosomal analyses. Genetic contributors include chromosomal abnormalities and a wide spectrum of heterogeneous monogenic disorders affecting cardiac electrophysiology, neuromuscular function, metabolic homeostasis, and early developmental processes. Immune-mediated placental dysfunction, particularly obstetric antiphospholipid syndrome, emerges as a clinically actionable mechanism characterized by vascular and inflammatory injury and associated angiogenic imbalance. Emerging pharmacogenetic evidence indicates that genetic variability in drug metabolism and receptor signaling may influence therapeutic response in placenta-mediated complications. Collectively, these findings support an integrated, mechanism-based framework combining genomic, immune, and pharmacogenetic data with phenotypic characterization to advance etiologic resolution, improve recurrence risk assessment, and enable precision-based diagnostic and preventive strategies in stillbirth.