The fetal exposome and Preterm Birth: a systematic synthesis of environmental exposures and multi-omics evidence

Objectives Preterm birth (PTB), defined as delivery before 37 weeks of gestation, is a leading cause of neonatal mortality and long-term developmental impairment. Its complex etiology, spanning environmental, genetic, psychosocial, and socio-economic domains, limits effective prediction and prevention. We systematically synthesized evidence on how environmental exposures influence PTB risk through multi-omic disruptions within a fetal exposome framework. Methods A comprehensive literature search was conducted in major biomedical databases, following PRISMA guidelines. Ninety-five human studies published through May 2025 were included, encompassing exposures such as ambient air pollution, endocrine-disrupting chemicals, maternal stress, nutrition, occupational hazards, climate variability, and microbiome alterations. Two reviewers independently extracted data (exposure type, omics platform, biospecimen, PTB subtype) with inter-rater reliability assessment, and study quality was evaluated using the Newcastle–Ottawa Scale. Findings were narratively stratified by exposure category, study design, and spontaneous vs. indicated PTB. Results Environmental exposures were consistently associated with disruptions in oxidative stress, inflammation, immune regulation, hormonal signaling, placental aging, and microbial ecology, mediated by multi-omic signatures in maternal, placental, and fetal tissues. Candidate biomarkers show promise for early risk stratification but lack validation and population-level predictive performance due to heterogeneous exposure assessment and study design. Conclusions Integrating fetal exposome concepts with multi-omics enhances mechanistic insight into PTB risk and may support biomarker discovery and precision-guided prenatal interventions. Clinical translation requires standardized exposure measurement, biomarker validation, and equity-focused implementation.