BACKGROUND: In adolescents and adults with complex congenital heart disease (CHD), abnormal cortical folding is a putative predictor of poor neurodevelopmental outcome. However, it is unknown when this relationship first emerges. We test the hypothesis that it begins in utero, when the brain starts to gyrify and folding patterns first become established.

METHODS: We carried out a prospective, longitudinal case-control study, acquiring foetal MRIs at two timepoints in utero, (Scan 1 = 20-30 Gestational Weeks (GW) and Scan 2 = 30-39 GW), then followed up participants at two years of age to assess neurodevelopmental outcomes. We used normative modelling to chart growth trajectories of surface features across 60 cortical regions in a control population (n = 157), then quantified the deviance of each foetus with CHD (n = 135) and explored the association with neurodevelopmental outcomes at two years of age.

FINDINGS: Differences in cortical development between CHD and Control foetuses only emerged after 30 GW, and lower regional cortical surface area growth was correlated with poorer neurodevelopmental outcomes at two years of age in the CHD group.

INTERPRETATION: This work highlights the third trimester specifically as a critical period in brain development for foetuses with CHD, where the reduced surface area expansion in specific cortical regions becomes consequential in later life, and predictive of neurodevelopmental outcome in toddlerhood.

FUNDING: This research was supported by the NINDS (R01NS114087, K23NS101120) and NIBIB (R01EB031170) of the NIH, PHN Scholar Award, AAN Clinical Research Training Fellowship, BBRF Young Investigator Awards, and the Farb Family Fund.