PROJECT SUMMARY/ABSTRACT Congenital heart disease is the most common birth defect, affecting 0.5-2% of all live births. As medical and surgical advances have dramatically increased survival, the burgeoning population of children and adults with congenital heart disease has exposed a high prevalence of neurodevelopmental disabilities in survivors. By adolescence, more than 2 out of every 3 children with critical congenital heart disease experience deficits requiring developmental/special education services. As these children reach adulthood, their disabilities may limit educational opportunities, employment, and quality of life. Abnormal fetal brain development may contribute to neurodevelopmental disability in patients with congenital heart disease. Neonates with congenital heart disease have abnormal brain structure before surgery. Neurobiological processes that lay the foundation for long-term structural brain organization begin in utero. Components of fetal brain critical for this process, in particular neural progenitor cells, premyelinating oligodendrocytes, and subplate neurons, are sensitive to hypoxia-ischemia, rendering this system vulnerable to prenatal circulatory disturbances. The impact of abnormal fetal brain development on long-term brain structure and function in congenital heart disease is unknown. To date, there are no congenital heart disease cohorts that have been studied in both the fetal period and later in childhood when these deficits are typically detected. This proposal will leverage an existing fetal MRI cohort, including children both with and without congenital heart disease, to acquire long-term neuroimaging and neurodevelopmental data at 7 years of age, thereby determining the fetal contribution to long-term outcome. Specifically, the proposed study will investigate 1) the association between fetal brain structure and school-age structural brain connectivity; 2) the relationship between fetal brain structure and school-age neurodevelopmental functioning; and 3) the potential for a clinical risk stratification tool harnessing measures available in utero to predict school-age neurodevelopmental outcome. The overarching hypothesis is that abnormal fetal brain structure is associated with long-term differences in structural brain connectivity and neurodevelopmental functioning in congenital heart disease. This project will support the development of clinical risk stratification and advance the development of interventions designed to protect the brain in children with congenital heart disease.