Nrf2 Immunohistochemical Expression in Stillbirths: A Potential Marker of Early Fetal Hypoxic Stress

Stillbirth remains a major challenge in perinatal and forensic pathology, particularly when the timing of fetal death and the mechanisms of hypoxic injury are difficult to establish using conventional morphological criteria alone. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator of cellular responses to oxidative stress and may represent an early marker of fetal cellular stress. We conducted a retrospective forensic study of stillbirth cases that underwent complete autopsy between 2017 and 2024. Clinical, pathological, and placental data were examined to estimate the timing of fetal distress and the death-delivery interval. Immunohistochemical analysis of Nrf2 expression was performed on fetal cardiac tissue sections, and cases were classified as Nrf2-positive or Nrf2-negative based on unequivocal nuclear immunoreactivity. Nrf2 nuclear expression was identified in 10/44 cases (22.7%) and was observed more frequently in cases with shorter death-delivery intervals and clinicopathological patterns compatible with acute or subacute fetal hypoxic stress, particularly placental abruption and selected acute umbilical cord-related events. These findings suggest that Nrf2 nuclear immunoreactivity may represent a potential ancillary marker of early fetal cellular stress in well-preserved stillbirth tissues. However, tissue preservation may represent an important confounding factor. Further prospective studies with controlled temporal parameters are needed to clarify its diagnostic and forensic value.