Oxidative Stress and Potential Fetal Programming of Neuronal Dysfunction in Newborns Following Maternal COVID-19

Maternal coronavirus disease 2019 (COVID-19) has been associated with systemic inflammation, endothelial dysfunction, placental injury, and increased production of reactive oxygen species (ROS), all of which may influence fetal development. Oxidative stress has emerged as a potential mechanistic link between maternal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and adverse maternal, placental, fetal, and neonatal outcomes. This narrative review summarizes current evidence regarding the role of oxidative stress in pregnancies complicated by COVID-19, with particular emphasis on placental dysfunction, fetal programming of neuronal injury, neonatal vulnerability, and molecular mechanisms that may contribute to long-term neurodevelopmental consequences. SARS-CoV-2 infection promotes oxidative imbalance through inflammatory activation, mitochondrial dysfunction, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase stimulation, hypoxia-related pathways, and dysregulation of the renin–angiotensin system. These processes may contribute to endothelial injury, placental vascular malperfusion, impaired maternal–fetal exchange, fetal hypoxia, and activation of pathways involved in fetal programming. Maternal immune activation and elevated proinflammatory cytokines may further influence fetal brain development through neuroinflammation, microglial activation, oxidative damage, mitochondrial dysfunction, and altered neuronal signaling. Emerging evidence also suggests that prenatal exposure to maternal SARS-CoV-2 infection may be associated with alterations in gene expression, immune signaling pathways, DNA methylation patterns, and microRNA regulation, providing biologically plausible mechanisms linking maternal infection with developmental programming. Newborns, particularly preterm infants, are highly susceptible to oxidative injury because of immature antioxidant defenses, potentially increasing vulnerability to respiratory, neurological, retinal, and gastrointestinal complications. While these findings establish biological plausibility, it is essential to distinguish between these indirect mechanistic pathways and direct clinical evidence of neurodevelopmental impairment in offspring. As current evidence remains heterogeneous and insufficient to establish definitive causal relationships, available findings support a potential role for oxidative stress in mediating the effects of maternal COVID-19 on fetal and neonatal health, necessitating further prospective, mechanistic, and longitudinal studies to clarify long-term outcomes.