Abstract <p>Improvements in treatment and survival of neonates with complex congenital heart disease have led to growing recognition of the associated neurodevelopmental impairments. In this review, we explore the possible antenatal mechanisms of altered brain development in these patients with particular focus on acquired and genetic risk factors. Hypoxia, placental pathology and maternal stress are acquired factors with therapeutic potential. Among the genetic and epigenetic mechanisms, we discuss the influences of angiogenic genes, chromatin modifiers, Wnt and Notch signalling pathways, chromosomal syndromes and apolipoprotein E alleles. Understanding these antenatal risk factors will allow for further development of currently experimental fetal therapies, such as maternal hyperoxygenation.</p> Impact <p><UnorderedList Mark="Bullet"> <ItemContent> <p>Congenital heart disease has a substantial impact on neurodevelopmental outcome.</p> </ItemContent> <ItemContent> <p>This scoping review identifies and brings together overlapping genetic, environmental and hemodynamic antenatal mechanisms that impact on altered brain development.</p> </ItemContent> <ItemContent> <p>A better understanding of these mechanisms may lead to development of therapeutic potentials to improve neurodevelopment outcomes in this group.</p> </ItemContent> </UnorderedList></p>