Perinatal brain development in congenital heart disease: Pathways to protection

This thesis shows that children with critical congenital heart disease (CCHD) have altered brain growth trajectories that begin during fetal life and continue after neonatal cardiac surgery. These changes are not limited to a single brain region, but affect multiple brain structures. The timing and pattern of altered brain growth differ between CCHD subtypes. In transposition of the great arteries, brain growth abnormalities are diffuse and already visible early in the third trimester of pregnancy. In contrast, in univentricular heart defects and aortic arch anomalies, cerebral vulnerability appears to be more region-specific and emerges later in development.

The mechanisms underlying delayed brain development are likely complex and multifactorial. Besides altered oxygen delivery and cerebral blood flow, both during fetal life and around the time of cardiac surgery, placental dysfunction, disruption of the insulin-like growth factor axis, and maternal health and stress may also contribute. Importantly, disturbances in early brain development appear to have long-term consequences, as neonatal brain volumes and brain injury are strongly associated with brain structure at school-age. At the same time, some regions, particularly the white matter, remain vulnerable beyond the neonatal period, especially in children who undergo additional cardiac interventions.

The findings of this thesis highlight the importance of the perinatal period as a window for neuroprotection. Prenatally, optimizing placental function, treating maternal conditions, and reducing maternal stress may help support fetal brain development. Postnatally, allopurinol may offer opportunities to reduce brain injury around birth and neonatal cardiac surgery. In the future, it will also be important to investigate neuroprotective strategies for cardiac interventions beyond the neonatal period.