Neurologic impairment is a major complication of complex congenital heart disease (CHD). A growing body of evidence suggests that neurologic dysfunction may be present in a significant proportion of this high-risk population in the early newborn period prior to surgical interventions. We recently provided the first evidence that brain growth impairment in fetuses with complex CHD has its origins in utero. Here, we extend these observations by characterizing global and regional brain development in fetuses with hypoplastic left heart syndrome (HLHS), one of the most severe forms of CHD. Using advanced magnetic resonance imaging techniques, we compared in vivo brain growth in 18 fetuses with HLHS and 30 control fetuses from 25.4-37.0 weeks of gestation. Our findings demonstrate a progressive third trimester fall-off in cortical gray and white matter volumes (P < 0.001), and subcortical gray matter (P < 0.05) in fetuses with HLHS. Significant delays in cortical gyrification were also evident in HLHS fetuses (P < 0.001). In the HLHS fetus, local cortical folding delays were detected as early as 25 weeks in the frontal, parietal, calcarine, temporal, and collateral regions and appear to precede volumetric brain growth disturbances, which may be an early marker of elevated risk for third trimester brain growth failure.

Normal brain development is associated with expansion and folding of the cerebral cortex following a highly orchestrated sequence of gyral-sulcal formation. Although several studies have described the evolution of cerebral cortical development ex vivo or ex utero, to date, very few studies have characterized and quantified the gyrification process for the in vivo fetal brain. Recent advances in fetal magnetic resonance imaging and post-processing computational methods are providing new insights into fetal brain maturation in vivo. In this study, we investigate the in vivo fetal cortical folding pattern in healthy fetuses between 25 and 35 weeks gestational age using 3-D reconstructed fetal cortical surfaces. We describe the in vivo fetal gyrification process using a robust feature extraction algorithm applied directly on the cortical surface, providing an explicit delineation of the sulcal pattern during fetal brain development. We also delineate cortical surface measures, including surface area and gyrification index. Our data support an exuberant third trimester gyrification process and suggest a non-linear evolution of sulcal development. The availability of normative indices of cerebral cortical developing in the living fetus may provide critical insights on the timing and progression of impaired cerebral development in the high-risk fetus.

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