Genetic determinants of pregnancy loss: Mechanisms, diagnostic advances, and clinical implications

Pregnancy loss affects up to 15% of clinically recognized pregnancies, posing a major clinical and emotional burden. While chromosomal abnormalities account for most early miscarriages, many previously unexplained cases involve monogenic, mitochondrial, epigenetic, immunogenetic, and paternal factors. Advances in genomic technologies have improved detection of pathogenic variants in both sporadic and recurrent pregnancy loss.

To synthesize current evidence on genetic determinants of pregnancy loss across chromosomal, monogenic, mitochondrial, epigenetic, immunologic, and thrombophilia-related pathways, and evaluate how genomic diagnostics inform management and reproductive counseling.

This narrative review integrates data from studies on chromosomal abnormalities, copy-number variants, maternal-effect genes, paternal genetic contributions, mitochondrial dysfunction, epigenetic dysregulation, immune-mediated mechanisms, and inherited thrombophilias. Evidence from next-generation sequencing, chromosomal microarray, whole-exome sequencing, and preimplantation genetic testing highlights diagnostic yield and clinical relevance.

Chromosomal abnormalities, including aneuploidy and pathogenic copy-number variants, remain the predominant cause of early pregnancy loss. Mutations in maternal-effect genes, ciliogenesis and morphogenesis defects, mitochondrial variants, imprinting disturbances, and paternal factors, such as sperm DNA fragmentation, also contribute to implantation failure, embryonic arrest, and recurrent loss. Immunogenetic and thrombophilia-associated variants affect placental development and late outcomes. Genomic platforms (CMA, WES, NGS, PGT) increase diagnostic detection and improve counseling, especially for recurrent loss.

Pregnancy loss arises from a spectrum of genetic mechanisms beyond chromosomal abnormalities. Integrating genomic, immunologic, and environmental assessment improves diagnostic precision, supports risk stratification, and informs targeted management. Modern genetic testing should be part of comprehensive evaluation for pregnancy loss.

Genetic contributors to pregnancy loss span chromosomal abnormalities, single-gene disorders, mitochondrial variants, epigenetic disturbances, immune dysregulation, and thrombophilia. Advances in genomic testing improve diagnostic precision and support individualized reproductive counseling for affected patients.