Rett syndrome: The Natural History Study journey.

Neonatal hypoxic‐ischemic encephalopathy (HIE) results from perinatal reduction in cerebral oxygen and blood flow. Despite the use of therapeutic hypothermia, the only established treatment, HIE remains a leading cause of long‐term neurodevelopmental impairment, including cerebral palsy, epilepsy, and cognitive deficits []. Accurate prediction of neurodevelopmental outcomes is essential to stratifying for future adjunctive therapies, guiding rehabilitation, informing parental counseling, and optimizing healthcare resource allocation. Previous studies have shown that the severity and location of brain injury on magnetic resonance imaging (MRI) correlate with long‐term neurodevelopmental outcomes. Semi‐quantitative scoring systems, including those developed by the National Institute of Child Health and Human Development Neonatal Research Network (NICHD‐NRN) and others, highlight the prognostic importance of lesions in the thalamus, posterior limb of the internal capsule, and basal ganglia. Diffusion MRI (dMRI), which quantifies the microstructural integrity of white matter using metrics such as fractional anisotropy (FA) and mean diffusivity (MD) [, ], has further refined prognostic models. FA decreases in the basal ganglia and thalamus during the first week in moderate to severe HIE [, ], and diffusion metrics from these regions are predictive for adverse outcomes, with area under the curve (AUC) values exceeding 0.73 [, ]. Most studies have adopted hypothesis‐driven region‐of‐interest (ROI) approaches, overlooking the prognostic value of other anatomical regions not historically associated with HIE. Whole‐brain, data‐driven methods such as tract‐based spatial statistics address some of these issues but fail to capture smaller white matter pathways and gray matter structures, limiting their scope []. Additionally, these studies often focus exclusively on predicting severe neurodevelopmental impairment, rather than identifying infants who will go on to develop typically. The ability to predict typical neurodevelopment trajectories is equally important for reassuring families, avoiding unnecessary interventions, and ensuring appropriate follow‐up for infants at risk.