Spontaneous preterm birth causes a major burden of childhood morbidity and mortality. The incomplete understanding of the molecular pathways that result in spontaneous preterm birth, makes accurate predictive markers and target therapeutics remain elusive.A recent study determined if a cell-free RNA profile reveals a molecular signature in maternal blood months before the onset of spontaneous preterm birth.The study utilized Maternal samples (n=242) obtained from a prospective cohort of individuals with a singleton pregnancy across 4 clinical sites at 12–24 weeks. Plasma was processed through a next-generation sequencing pipeline for cell-free RNA using the Mirvie RNA platform. Differentially expressed Transcripts in next-generation sequencing cases and controls were determined. Enriched pathways were identified in the Reactome database employing overrepresentation analysis.The study identified 25 transcripts associated with an increased risk of spontaneous preterm birth. These transcripts were used to develop a logistic regression model to predict spontaneous preterm birth with an area under the curve =0.80 (sensitivity=0.76, specificity=0.72). The gene discovery and model were validated via leave-one-out cross-validation. The study also identified a unique set of 39 genes from cases of very early spontaneous preterm birth; a logistic regression classifier based on these genes yielded an area under the curve=0.76 in leave-one-out cross-validation. Pathway analysis for the transcripts associated with spontaneous preterm birth showed enrichment of genes related to collagen or the extracellular matrix in those who ultimately had a spontaneous preterm birth at