Sex effects on cortical alterations in infants with complex congenital heart disease

Congenital heart disease is linked to substantial variability in neurodevelopmental outcomes, with sex being a key contributing factor. Compared with females, male congenital heart disease infants often show greater impairments in motor, cognitive, and language development. However, studies on sex differences in early brain development among congenital heart disease patients remain limited. To fill these gaps, this study included 79 infants with complex congenital heart disease (42 males, 37 females) and 87 healthy controls (47 males, 40 females), collecting magnetic resonance imaging data, clinical information, and neurodevelopmental assessments. We examined sex-specific effects on global and regional brain development in congenital heart disease infants aged 1 to 2 yr using imaging and statistical analysis. Male congenital heart disease infants showed global brain volume reduction and regional cortical delays, including increased cortical thickness and gray matter volume. In contrast, female congenital heart disease infants had no significant global volume change but exhibited localized structural abnormalities, such as reduced surface area and increased cortical thickness. Notably, reduced global brain volume in congenital heart disease males was associated with poorer gross motor skills. Distinct sex differences in brain development exist among congenital heart disease infants during early life. Recognizing these differences is critical for developing sex-specific treatment and neuroprotective strategies.