Fetal Brain Development in Congenital Heart Disease

Abstract

Neurodevelopmental impairments are the most common extracardiac morbidities among patients with complex congenital heart disease (CHD) across the lifespan. Robust clinical research in this area has revealed several cardiac, medical, and social factors that can contribute to neurodevelopmental outcome in the context of CHD. Studies using brain magnetic resonance imaging (MRI) have been instrumental in identifying quantitative and qualitative difference in brain structure and maturation in this patient population. Full-term newborns with complex CHD are known to have abnormal microstructural and metabolic brain development with patterns similar to those seen in premature infants at approximately 34 to 36 weeks' gestation. With the advent of fetal brain MRI, these brain abnormalities are now documented as they begin in utero, as early as the third trimester. Importantly, disturbed brain development in utero is now known to be independently associated with neurodevelopmental outcome in early childhood, making the prenatal period an important timeframe for potential interventions. Advances in fetal brain MRI provide a robust imaging tool to use in future neuroprotective clinical trials. The causes of abnormal fetal brain development are multifactorial and include cardiovascular physiology, genetic abnormalities, placental impairment, and other environmental and social factors. This review provides an overview of current knowledge of brain development in the context of CHD, common prenatal imaging tools to evaluate the developing fetal brain in CHD, and known risk factors contributing to brain immaturity.

Figure 1.

Brain volume differences in fetuses with congenital heart disease compared with healthy fetuses (“optimal”) and CHD-related control fetuses (eg, healthy siblings of patients with known CHD). Estimated group differences in regional brain volumes for fetuses with HLHS or TGA compared with each control group are depicted in (left) axial, (middle) coronal, and (right) sagittal planes in a 32-week gestational age fetal brain. Blue indicates a relative reduction in brain volume of the structure compared with the reference group; red indicates a relative increase. Intensity reflects the magnitude of the estimated group difference in regional brain volume relative to the reference group for a 32-week gestational age male, according to the scale provided. Asterisks denote significance according to false discovery rate—adjusted P values comparing group-difference β-estimates (Table 3): *P < 0.05; **P < 0.01; ***P < 0.001. CHD, congenital heart disease; HLHS, hypoplastic left heart syndrome; TGA, dextro-transposition of the great arteries. Modified from Rollins et al. with permission from John Wiley and Sons.

Figure 2.

T2* values at baseline for control, LSOL, and TGA groups with mean and 95% confidence intervals (CIs; error bars). At baseline, cerebral tissue oxygenation (T2*) is significantly lower in the LSOL (**coeff: −15.4, 95% CI −25.3 to −5.5; P = 0.003) and TGA (*coeff: −12.0, 95% CI −24.4 to 0.4; P = 0.05) groups compared with the control group after adjusting for gestational age at MRI. LSOL, left-side obstructive lesion; MRI, magnetic resonance imaging; TGA, dextro-transposition of the great arteries. Modified from Peyvandi et al. with permission of John Wiley and Sons.

Figure 3.

Contributors to delayed brain development in utero. The etiology of prenatal delayed brain development in congenital heart disease is thought to be multifactorial with contributions from cardiovascular physiology, genetic differences, and an adverse maternal-fetal environment. d-TGA, dextro-transposition of the great arteries; HLHS, hypoplastic left heart syndrome.