Oxidative Stress in Neonatal Disease: Established Organ Injury and Emerging Evidence for Skeletal Involvement.

Abstract

Reactive oxygen and nitrogen species participate in physiological signaling and adaptation during fetal and neonatal development, whereas excessive, prolonged, or spatially dysregulated production may contribute to oxidative and nitrosative tissue injury. Redox dysregulation has been extensively investigated in neonatal conditions, including bronchopulmonary dysplasia (BPD), hypoxic-ischemic encephalopathy, retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC), congenital heart disease (CHD), and hyperbilirubinemia. Its relationship with bone metabolism is well established in adult and pediatric disorders, including osteoporosis, inflammatory bone loss, and iron-overload-related bone disease. However, the potential contribution of perinatal redox imbalance to early skeletal development remains comparatively underexplored. This narrative review critically examines the biochemical mechanisms of reactive species generation, their interaction with inflammatory pathways, and the experimental and clinical evidence linking redox dysregulation to neonatal organ injury. Particular attention is given to the developing skeleton as a potentially underrecognized target. Experimental studies indicate that excessive reactive species can impair chondrogenesis, alter osteoblast and osteoclast activity, disrupt collagen and osteogenic signaling, and interfere with skeletal growth. Human evidence is predominantly observational. Preliminary longitudinal data show inverse associations between cord-blood markers of oxidative DNA and protein modification and REMS-derived skeletal Z-scores during the first year of life. These findings suggest that early redox imbalance may impair bone quality and growth trajectories in newborns. Prospective studies integrating standardized redox biomarkers, bone-metabolism indices, imaging, nutrition, medication exposure, growth, and fracture outcomes are needed to determine whether redox dysregulation independently contributes to impaired skeletal development.