Reliable prognostic biomarkers are needed to support the early diagnosis of brain injury in extremely preterm infants, and to develop effective neuroprotective protocols that are tailored to the progressing phases of injury. Experimental and clinical research shows that severity of neuronal damage is correlated with changes in the electroencephalogram (EEG) after hypoxic-ischemia (HI). We have previously reported that micro-scale sharp-wave EEG waveforms have prognostic utility within the early hours of post-HI recordings in preterm fetal sheep, before injury develops. This article aims to investigate whether these subtle EEG patterns are translational in the early hours of life in clinical recordings from extremely preterm newborns. This work evaluates the existence and morphological similarity of the sharp-waves automatically identified throughout the entire duration of EEG data from a cohort of fetal sheep 6 h after HI (n = 7, at 103 ± 1 day gestation) and in recordings commencing before 6 h of life in extremely preterm neonates (n = 7, 27 ± 2.0 weeks gestation). We report that micro-scale EEG waveforms with similar morphology and characteristics (r = 0.94) to those seen in fetal sheep after HI are also present after birth in recordings started before 6 h of life in extremely preterm neonates. This work further indicates that the post-HI sharp-waves show rapid morphological evolution, influenced by age and/or severity of neuronal loss, and thus that automated algorithms should be validated against such signal variations. Finally, this article discusses the need for more focused research on the early assessment of EEG changes in preterm infants to help determine the timing of brain injury to identify biomarkers that could assist in targeting novel therapies for particular phases of injury.

Hypoxic–ischaemic encephalopathy (HIE) is a major cause of neonatal brain injury and is associated with a high rate of death and lifelong disability. Its pathogenesis is still poorly understood, and there is no proven treatment for preterm infants. Therapeutic hypothermia for term and near-term infants partially improves outcomes, highlighting the need to target additional mechanisms. This review evaluates evidence that necrosis and necroptosis contribute materially to evolving brain injury in both term and preterm brains. Serial imaging studies suggest that lesions typically develop over many days after birth for term infants and over many weeks after birth for preterm infants. Growing evidence from animal studies shows that severe white matter injury can be mediated by programmed necroptosis. In particular, lesions that evolve late after acute HI are characterised by necrosis in association with agglomerations of microglia, with little apoptotic cell death. Critically, preclinical studies in large and small animals show that outcomes can be dramatically improved by very delayed intervention after HI including with cell therapy, anti-inflammatory agents, and endogenous neurotrophins. These findings strongly support the hypothesis that there may be a window of therapeutic opportunity for days or even weeks after birth to prevent delayed necrotic lesions.