The fetal exposome: cellular and epigenetic programming of neonatal immune function

Fetal life represents a critical period in the development of the neonatal immune system. During this period of high epigenomic plasticity, environmental exposures, maternal health conditions and perinatal factors can have a lifelong impact on gene expression and function, influencing neonatal immune function and contributing to the later development of immune-mediated disease. We conducted a narrative review of human and translational evidence linking antenatal exposures with cellular and epigenetic regulation of neonatal immune function. Evidence was synthesised across maternal health, environmental and perinatal exposures, including the maternal microbiota as a potential exposome-epigenome interface, with a focus on immune-cell composition, cytokine and immunoglobulin profiles, functional immune responses and epigenetic mechanisms including DNA methylation, histone modification and microRNA regulation. Across diverse exposures, including maternal smoking, obesity, air pollution and heavy metals, antenatal factors were associated with altered neonatal immune-cell composition, dysregulated cytokine production and changes in innate and adaptive immune responses. Reported epigenetic alterations involved genes and pathways related to haematopoiesis, antigen presentation, cytokine regulation, immune-cell activation, metabolic signalling and inflammatory responses. The reviewed evidence suggests that the fetal exposome may shape neonatal immune development through epigenetic programming, with recurrent patterns including type 2 polarisation, impaired regulatory function and altered innate immune signalling. These effects may be particularly relevant in socially deprived populations, where multiple adverse exposures frequently cluster. However, evidence remains heterogeneous, and longitudinal studies integrating exposure assessment, multi-omic immune profiling and clinical follow-up are needed to define functional relevance and long-term disease risk.