Beginning in the third trimester of fetal life, patients with CHD are known to have smaller gestational age- and weight-adjusted brain volumes with impaired neuroaxonal development and metabolism (2). These abnormalities are most pronounced with more complex types of heart defects, including hypoplastic left heart syndrome (HLHS) and transposition of the great arteries (TGA).

Structural malformations of the brain occur at a much higher rate than in the general population (3). Microcephaly, microencephaly, and other malformations, including agenesis of the corpus callosum and an immature cortical mantle, have been documented in necropsy series of patients with HLHS (4). Neonates with CHD can have altered cerebral hemodynamics, often with lower-than-normal cerebral blood flow (CBF) and/or oxygen delivery. One study of neonates with complex CHD used preoperative pulsed arterial spin-label perfusion magnetic resonance imaging (MRI) to quantitate CBF (5). More than half of the cohort had developmental or acquired lesions, and the CBF was less than half of that reported in
normal, term neonates (6). There was evidence of delayed white matter development, which may lead to an increased risk of white matter injury (WMI), typically periventricular leukomalacia (PVL), and microcephaly. The same study also examined cerebrovascular responsiveness to CO₂, and found that PVL was associated with decreased CO₂ responsiveness. Abnormal cerebrovascular reactivity to CO₂ has been associated with increased mortality and worse neurodevelopmental outcomes (7,8). WMI characterized by PVL is the most common pattern of injury (9). The mechanism of this injury is thought to be due to the effects of hypoxia and/or ischemia on vulnerable premyelinating oligodendrocyte precursors during their most vulnerable time of 24 to 34 weeks’ gestation (10). Up to 40% of neonates with CHD have PVL on preoperative MRI, and PVL has been shown to be associated with poor neurodevelopmental outcomes (5,11,12) (Fig. 30.1). The incidence of PVL is highest in neonates undergoing cardiopulmonary bypass (CPB). A study by Galli et al. (13) found a 54% incidence of PVL in neonates compared to 4% in infants. PVL is the neurologic lesion associated with cerebral palsy in infants born prematurely (14). This pattern of brain injury is seen not only in preterm newborns but also in term neonates with CHD (15). A comparison of term newborns with CHD to a control cohort without heart defects revealed that almost one-third of those with CHD had WMI, while no WMI was seen in those without heart defects (16).

Preterm birth, even in infants without CHD, is a powerful predictor of worse neurodevelopmental outcome. Along with low birth weight, prematurity has been associated with longterm behavioral and learning issues. In a study of 125 very low birth weight preterm infants who were evaluated with the Bayley Scales of Infant and Toddler Development III (BSID-III) at 24 months, later gestational age was associated with better neurodevelopmental outcome (17).

Other nonmodifiable patient factors that adversely affect neurodevelopmental outcomes are socioeconomic status and maternal education. Follow-up of the Boston Circulatory Arrest Study (BCAS) cohort at 16 years of age found that family social class and parental IQ were significant predictors of neurodevelopmental outcome (18). In a study of neurodevelopmental outcome after repair of total anomalous pulmonary venous connection, lower socioeconomic status was predictive of lower scores on the Mental Developmental Index (MDI) of the Bayley Scales of Infant Development II (BSID-II) (19). The Single Ventricle Reconstruction trial is the randomized, prospective trial comparing shunt types in the Norwood procedure (20). Evaluation of this cohort at 14 months demonstrated that lower maternal education, in addition to the presence of genetic syndromes or other anomalies and lower birth weight, was associated with lower BSID-II MDI scores (21).

There are many genetic syndromes associated with CHD, and include Down syndrome, Noonan syndrome, Williams syndrome, and DiGeorge syndrome (22q11.2 microdeletion) (22,23,24,25). These syndromes are associated with developmental delay and assigning causation of neurodevelopmental delay can be challenging. For example, those with DiGeorge syndrome have a mean IQ in the 70s, a predisposition to psychiatric disorders, and an increased incidence of white matter abnormalities (26,27,28).

There is also evidence that genetic variants which modify the brain’s response to injury and subsequent recovery may also be important determinants of neurodevelopmental outcomes. The first genetic polymorphism studied in relation to CHD and surgery was apolipoprotein E (APOE) (1). APOE regulates cholesterol metabolism and is the primary lipid transport vehicle in the central nervous system. There is evidence that APOE is important for neuronal repair. There are three APOE alleles (ε₂, ε₃, ε₄) on chromosome 19 that vary by a single amino acid. Investigators at the Children’s Hospital of Philadelphia evaluated the association of APOE genotype and postoperative neurodevelopmental outcome at age 1 year
(1). On the BSID-II, the APOE ε₂ allele was associated with a significantly lower Psychomotor Developmental Index (PDI) score after adjustment for perioperative covariates including gestational age, age at operation, sex, race, socioeconomic status, cardiac defect, and the use of circulatory arrest. Further analysis of this group revealed that patient-specific factors, namely the presence of a genetic syndrome, low birth weight, and the APOE ε₂ allele, significantly predicted neurodevelopmental outcomes at age 1 year (29). Neurobehavioral outcomes evaluated in the cohort between 4 and 5 years of age revealed that those with the APOE ε₂ allele had increased behavioral problems, restricted behavior patterns, and impaired social skills (30). The entire cohort had a significantly higher proportion of patients considered either at-risk or in the clinically significant range for neurodevelopmental problems. Further evaluation of the cohort by a genome-wide association study with adjustment for the effects of APOE identified single nucleotide polymorphisms (SNP) as being associated with neurobehavioral abnormalities (31). Ten SNPs reached a threshold for suggested significant associations with neurobehavioral phenotypes.

A study comparing the relative contribution of other patient factors (gestational age, genetic syndrome, birth weight, gender, etc.) to management factors during neonatal and infant cardiac surgery on neurodevelopmental outcomes at 1 year of age showed that patient factors explained more of the variability in the PDI (21% vs. 8%) and MDI (13% vs. 5%) scores on the BSID-II than management factors (29). Accordingly, factors such as gender, birth weight, and presence of a genetic syndrome had a more significant impact on neurodevelopmental outcomes than CPB time, circulatory arrest time, and hematocrit. Not all patients with CHD enter the operating room with the same neurodevelopmental prognosis. Interindividual variation of many nonmodifiable patient factors significantly contributes to widely disparate neurodevelopmental outcomes of different patients with the same cardiac diagnosis.