Molecular Mechanism and Pathways of Spontaneous Preterm Birth in Different Gestational Tissues: A Systematic Review of Transcriptome Studies.

This systematic review assessed transcriptomic evidence on the molecular mechanisms underlying spontaneous preterm birth (sPTB). Major electronic databases were searched from inception to October 2025. Eligible studies examined RNA transcriptomic profiles from maternal pregnancy-related tissues or biofluids in spontaneous preterm labor (sPTL) or preterm prelabor rupture of membranes (PPROM), while indicated or iatrogenic preterm births were excluded. Two reviewers independently screened studies, extracted differentially expressed genes (DEGs), and assessed study quality. DEGs were summarized by tissue type, and recurrent concordant genes were analyzed using Gene Ontology, Reactome, and Kyoto Encyclopedia of Genes and Genomes enrichment analyses, with false discovery rate < 0.05 considered significant. Twenty studies were included. Transcriptomic data were derived from placental villi, maternal peripheral blood, decidua, fetal membranes, myometrium, amniotic fluid, and vaginal secretions. Placental villi findings suggested proliferative-metabolic reprogramming and impaired maternal-fetal immune-structural homeostasis, whereas maternal blood profiles reflected systemic immune-inflammatory activation and dysregulated lipid-metabolic pathways. sPTL and PPROM showed potentially distinct signatures involving extracellular matrix disruption, collagen remodeling, matrix degradation, and myeloid/neutrophil-associated inflammation. Transcriptomic profiling may support non-invasive sPTB risk assessment, but standardized, phenotype-specific longitudinal studies are needed to confirm predictive value and clinical utility.