A Systematic Review of Sterile Intrauterine Inflammation, Immune-Metabolic Cues, and Epigenetic Programming: The Hidden Path to Preterm Birth

Abstract Preterm birth often emerges from inflammatory pathways that unfold in the absence of detectable infection, reflecting a multifaceted interplay between immune activation, metabolic imbalance, environmental stressors, and epigenetic regulation. To clarify how these processes converge, we conducted a systematic review aligned with PRISMA 2020, examining evidence from human observational and interventional studies, mechanistic experiments, and prior systematic reviews across major biomedical databases through March 2025. Forty-eight eligible studies were identified from an initial pool of 2,643 records. Across diverse methodologies, a coherent pattern of four mechanistic themes emerged. Alarmin- and inflammasome-driven signaling—marked by molecules such as IL-1β and S100A12—appeared central to sterile inflammatory activation. A second theme involved metabolic disturbance, particularly obesity-associated impairment in lipid-mediated resolution pathways. Environmental exposures, including fine particulate matter, PFAS, metals, and newly described microplastic contaminants, formed a third mechanistic axis through oxidative stress and epigenetic disruption. A fourth contributor involved alterations in gut or reproductive microbiota and short-chain fatty acid availability, which together influence immune priming. Across these domains, a growing set of translational biomarkers—including amniotic fluid IL-6, extracellular-vesicle microRNAs, maternal cell-free RNA, cfDNA methylation and fragmentomic patterns, and placental T2* MRI (a noninvasive imaging measure of placental oxygenation and perfusion)—show potential for early risk stratification. Interventional signals were noted for omega-3 supplementation, IL-1 pathway modulation, microbiome-targeted strategies, and exposure reduction. Collectively, current evidence supports a model in which sterile inflammation links immune triggers with metabolic, environmental, and epigenetic programming to shape susceptibility to preterm birth. This integrated perspective highlights opportunities for multi-omic screening, biomarker-guided trials, and policy actions aimed at reducing upstream inflammatory drivers.