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Spontaneous preterm birth (sPTB) remains the main driver of childhood morbidity and mortality. There is a lack of predictive markers and targeted therapeutics due to an incomplete understanding of the molecular basis of this heterogenous syndrome. This study sought to determine if a cell free RNA (cfRNA) profile could reveal a molecular fingerprint in maternal blood months prior to the onset of sPTB.
Maternal samples (n=229) were obtained from a prospective cohort of individuals with a singleton pregnancy across 4 sites at 16-24 weeks. All cases (n=46 sPTB < 35 weeks) were selected from the cohort and matched with term controls (n=183). Plasma was processed via a next-generation sequencing pipeline for cfRNA. Transcripts that were differentially expressed in sPTB cases and controls were identified. Enriched pathways were identified using over-representation analysis in Gene Ontology and Reactome databases.
Demographics are in Table 1; 51 transcripts associated with an increased risk of sPTB were identified. Using 24 of these transcripts, a logistic regression model to predict sPTB was developed with an AUC=0.78. The gene discovery and model were validated through leave-one-out cross-validation (LOOCV). A unique set of 11 genes were identified from cases of early sPTB (< 25 weeks, N=14); a logistic regression classifier based on these genes yielded an of AUC=0.76 in LOOCV. Pathway analysis for transcripts associated with sPTB revealed enrichment of genes related to collagen/extracellular matrix in those who ultimately had a sPTB at < 35 weeks. Enrichment for genes in insulin-like growth factor transport and amino acid metabolism pathways were associated with sPTB at < 25 weeks.
cfRNA profiles in maternal blood in the 2nd trimester provide a non-invasive window to future risk of sPTB. The systemic finding of changes in collagen and ECM pathways may serve to identify individuals at risk for premature cervical remodeling. The use of cfRNA profiles may more accurately serve to identify those at risk for sPTB based on revealing the underlying pathophysiology.