Molecular Biomarkers and Pathways in Recurrent Spontaneous Abortion: A Systematic Review

Recurrent spontaneous abortion (RSA), defined as the loss of two or more consecutive pregnancies, affects approximately 15-25% of couples and represents a significant clinical and emotional burden in reproductive medicine. Despite advances in maternal and fetal care, a substantial proportion of cases remain idiopathic, emphasizing the need to elucidate underlying biological mechanisms. This systematic review aimed to evaluate genetic and molecular biomarkers associated with RSA and to synthesize their role in its pathogenesis, in order to inform future diagnostic and therapeutic strategies.

This systematic review synthesizes current evidence on genetic and molecular biomarkers associated with spontaneous abortion, based on a systematic search of PubMed, Scopus, Web of Science, EMBASE, and ClinicalTrials.gov (January 2012-June 2024), focusing on findings derived from next-generation sequencing (NGS), array comparative genomic hybridization (aCGH), and bioinformatics approaches; nine eligible studies were included.

Chromosomal abnormalities, including aneuploidies and structural rearrangements, account for nearly half of all first-trimester recurrent spontaneous abortions and play a central role in embryonic viability. In addition, specific gene variants and polymorphisms, including NLRP7, KHDC3L, and VEGF [e.g., rs1570360: odds ratio (OR)=1.42, 95% confidence interval (CI): 1.10-1.84; rs3025039], are associated with increased risk of recurrent pregnancy loss through disruption of embryogenesis, immune tolerance, and placental angiogenesis.

Genetic and non-coding RNA biomarkers offer biologically plausible insights into the mechanisms of RSA, but current evidence remains preliminary and derived mainly from small, single-population studies; multi-ethnic validation and standardized protocols are needed before these markers can be translated into routine clinical practice.