ABSTRACT Severe forms of congenital heart disease such as transposition of the great arteries (TGA) are common birth defects. Outcomes for TGA have significantly improved with restoration of normal cardiovascular physiology after the newborn operation. Despite this, children with TGA experience significant neurodevelopmental (ND) impairments across the lifespan suggesting that prenatal and neonatal physiology may have a lasting impact on ND outcome. Newborns with TGA are known to have delayed brain development beginning in utero and are at increased risk for acquired neonatal white matter injury (WMI) with the majority observed before the neonatal operation. These observations and our preliminary data suggest that circulatory adjustments during perinatal transition from fetal to neonatal life may play a significant role in the susceptibility to WMI after birth. Perinatal transition is a key time period with potential for neuroprotective interventions such as delayed cord clamping, which has been demonstrated to provide neuroprotection to term and preterm newborns. In this proposal, we aim to fill a significant gap in our field related to how physiologic changes in cardiovascular and cerebral hemodynamics during perinatal transition affect brain health in patients with TGA. Our two centers’ experience with fetal and neonatal neuroimaging and neuromonitoring, uniquely positions us to take a longitudinal approach beginning in fetal life to first identify a prenatal biomarker of poor brain maturation and second to examine the impact of transitional physiology on acquired neonatal WMI. We will test the hypotheses that decreased cerebral tissue oxygenation in utero predisposes to brain immaturity, that the resulting immaturity increases susceptibility to acquired neonatal WMI due to perinatal circulatory features of TGA, and that this could be modified by improving perinatal cerebral oxygen delivery through delayed cord clamping. Our long term goals are to use data from this proposal to design neuroprotective trials focused on the transitional time period that have the potential to optimize ND outcomes in this patient population.