Immunological maladaptation preceding spontaneous preterm birth in human pregnancies

The majority of spontaneous preterm births (sPTB) occurs without identifiable clinical indications or apparent risk factors. A dysregulated maternal immune adaptation at delivery has been associated with sPTB. Yet, a precise understanding of maternal immune dynamics preceding sPTB remains lacking. Here we show, in a nested case-control study within a low-risk, population-based pregnancy cohort, that an abnormal immune adaptation in mothers' blood precedes sPTB by weeks to months and discriminates sPTB cases from term controls (AUROC: 0.7). Prominent features include enhanced immune cell responses to an adrenergic stimulus during the first and second trimesters, followed by increased production of pro-inflammatory cytokines in the third trimester in sPTB vs. term pregnancies. Transcriptome analysis of second trimester single-cell CD4⁺ T cells reveals a Th17-skewed, neuroactive-protein responsive phenotype in sPTB pregnancies. Our study provides a multi-omics resource and a conceptual framework for early identification of individuals at increased risk for sPTB with broad translational implications for advancing targeted preventive measures.