Blood-based predictive biomarkers for preterm birth: Redefining risk stratification in modern perinatal care

Spontaneous preterm birth (sPTB) remains a leading cause of neonatal morbidity and mortality worldwide, with current screening tools - such as cervical length measurement and fetal fibronectin - showing limited predictive value, particularly in asymptomatic women. Recent advances in molecular diagnostics have identified blood-based biomarkers that capture transcriptomic, proteomic, and metabolomic changes preceding labor. This systematic review synthesizes recent high-quality studies published between 2018 and 2025, selected through a Preferred Reporting Items for Systematic Reviews and Meta-analyses-guided search and appraised using AMSTAR-2 and the Newcastle-Ottawa Scale. Transcriptomic signatures, including cell-free RNA profiles, demonstrate area-under-the-curve (AUC) values up to 0.94 when measured in early gestation (10-20 weeks). Proteomic panels targeting inflammatory mediators and matrix-remodeling proteins achieve AUCs of 0.80-0.89, while metabolomic assays identify arginine derivatives and lipid shifts with AUCs of 0.78-0.84. Multiomic models integrating these molecular layers with machine-learning algorithms further improve prediction, reaching AUCs above 0.93 across diverse cohorts. Optimal sampling windows range from 10 to 24 weeks, with the strongest evidence for use in high-risk women or as part of universal mid-trimester screening. Emerging clinical pathways outline how these assays could integrate into prenatal care to enable timely interventions such as progesterone therapy, cervical cerclage, or intensified monitoring. Key barriers to implementation include assay standardization, cost, regulatory approval, and ethical considerations in patient counseling. Standardized protocols, multicenter validation, and equitable deployment strategies will be critical to translating these promising technologies into practice. If successfully implemented, blood-based predictive models could help shift obstetric care toward more personalized and preventive management of sPTB.