Placental Insufficiency and Neonatal Vulnerability: Organ-Specific Mechanisms Shaping Early-Life Health

Placental insufficiency is a central pathological condition underlying fetal growth restriction and is strongly associated with adverse outcomes during the neonatal period. Although epidemiological and clinical studies have consistently linked compromised placental function to neonatal respiratory, neurological, gastrointestinal, and infectious morbidity, the mechanisms through which placental insufficiency translates into organ-specific neonatal vulnerability remain unclear. Increasing evidence from human observations and experimental animal models indicates that placental insufficiency disrupts coordinated fetal development through alterations in perfusion, vascular patterning, cellular differentiation, barrier maturation, and immune responsiveness, rather than through uniform growth failure. This review summarizes current progress in the understanding of organ-specific mechanisms by which placental insufficiency shapes neonatal vulnerability, with a focus on the lung, brain, intestine, and immune system. We further discuss how these developmental perturbations interact with postnatal environmental exposures and highlight future perspectives for identifying at-risk infants and developing targeted strategies to mitigate adverse neonatal outcomes.