Neurodevelopmental and Psychosocial Outcomes in Children and Young Adults With Complex Congenital Cardiac Disease

Prenatal Mechanisms of Brain Injury

There is growing recognition that the brain is abnormal at birth in the majority of neonates with cCHD. Fetal and postnatal magnetic resonance imaging (MRI) studies have identified brain immaturity at birth and a surprisingly high incidence of white matter injury (WMI), stroke, and hemmorhage. MRI and echocardiographic studies have confirmed abnormalities of cerebral vascular resistance (CVR), fetal blood flow, and reduced substrate delivery leading to immaturity of the developing brain. In addition, there is an increased incidence of congenital structural CNS abnormalities in association with cCHD, suggestive of shared (heart, brain) genetic abnormalities. In combination, these functional and anatomic abnormalities seen in the newborn with cCHD might best be considered coexisting congenital brain disease , and appear to be present in nearly 50% of these neonates.

Fetal Cerebrovascular Physiology, Oxygen Delivery, and the Placenta

Ultrasound studies in the fetus have revealed that CVR is altered in fetuses with cCHD. Fetuses with left-sided obstructive lesions (e.g., HLHS) have been shown to have decreased CVR compared to normal fetuses. In patients with aortic atresia, the combined fetal cardiac output from the right ventricle must travel through the ductus arteriosus and deliver flow cephalad (in a retrograde fashion) to the brain, as well as caudad to the viscera and low resistance placenta. In left-sided cCHD, it is speculated that CVR must therefore be lower than normal to allow adequate fetal blood flow cephalad to the developing brain. In contrast, fetuses with right-sided obstructive lesions (e.g., tetralogy of Fallot [TOF]), where the combined fetal cardiac output leaves the left heart and passes cephalad, through the ascending aorta, to the brain prior to reaching the placenta, have been shown to have increased fetal CVR. The altered CVR, whether higher or lower than normal, most likely has an effect on the developing brain. The changes in cerebral blood low that occur immediately after birth, when pulmonary vascular resistance abruptly falls, are incompletely understood; however, studies of cerebral blood flow in the first days of life suggest that cerebral blood flow and oxygen delivery is low, and continues to fall during this critical time period.

In the normal fetus, the intracirculatory patterns created by the normal fetal connections result in preferential streaming of the most highly oxygenated fetal blood to the developing brain, and the most desaturated blood to the placenta. When significant structural disease exists within the heart, these beneficial patterns are likely to be altered. Recently confirmed by fetal MRI measurements, fetuses with d-transposition of the great arteries (d-TGA) have the blood with the lowest oxygen saturation returning to the ascending aorta and brain, while blood with the highest oxygen saturation returns to the abdominal organs and placenta. Speculation on the consequences of the transposed fetal circulation (as an explanation for the high incidence of macrosomia in these infants) dates back more than 50 years, and has been offered as an explanation for the increased incidence of relative microcephaly and long-term developmental challenges seen so often in children with d-TGA. Complete mixing with a dual-distribution circulation (see Chapter 70 ), as seen in those with functionally univentricular hearts, and limitations on compensatory lowering of CVR, produce reduced fetal cerebral oxygen delivery. The contribution of the placenta adds complexity to the issue as it has been noted that placental weights are much lower than normal, and placental vascularity is abnormal in fetuses with cCHD. Furthermore, MRI measurements of umbilical vein oxygen saturations are significantly lower than expected, suggesting placental dysfunction (see also Chapters 7 and 11 ).

It has long been recognized that the neurologic status of newborns with cCHD is frequently abnormal prior to newborn heart surgery, including abnormalities in muscle tone, weak cry, and poor coordination of suck, swallow, and breathing. Following birth, cerebral blood flow may be significantly lower than normal in some patients due to abnormal cardiac physiology and frequently a “steal” of systemic cardiac output through the patent ductus arteriosus into the pulmonary arteries. In some lesions, such as total anomalous pulmonary venous return with obstruction and d-TGA with an intact atrial and ventricular septum, profound hypoxemia and acidosis may result immediately after birth. Certain procedures, such as balloon atrial septostomy, may be associated with an increased risk of stroke, although the data are conflicting in this regard. Genetic syndromes are present in approximately 25% of neonates with cCHD. Recent studies have suggested that genetic abnormalities may play a role in the abnormalities of brain structure, developmental delay, neurodevelopmental disability, as well as contribute to the risk of developing cCHD itself (see later). Finally, all patients with right to left shunting have the potential for air or thromboembolic material reaching the brain from intravenous catheters prior to, during, or after surgery. Hypoxemia, low cardiac output, and cardiac arrest in patients with uncorrected cCHD may contribute to CNS ischemia, injury, developmental delay, and neurodevelopmental disability, adding to the abnormalities that may be present at birth.

Microcephaly

Head circumference at birth is a surrogate for growth of the brain in the fetus, and in neonates without cCHD, microcephaly is independently associated with later developmental delays and academic difficulties. The incidence of microcephaly at birth in neonates with cCHD is increased compared to heart-healthy neonates (approaching 25% of neonates in some reports), persists into later infancy, and is associated with later developmental abnormalities. While the causes are speculative, and most certainly multifactorial, Shillingford et al. reported on a series of children with HLHS where the median head circumference at birth was only at the 18th percentile. In this study, patients with microcephaly had a significantly smaller ascending aorta than those without microcephaly, suggesting that reduced flow to the brain from the left ventricle secondary to anatomic hypoplasia of the ascending aorta may result in diminished brain growth.

Decreased Central Nervous Maturity

Microcephaly, structural and biochemical immaturity of the white matter, and delay in cortical folding and white matter myelination have led researchers to delve into investigations of fetal brain development. Limperopoulos et al. have shown striking differences in brain growth in fetuses with and without cCHD, with brain growth diverging from normal in the fetuses with cCHD at the beginning of the third trimester of pregnancy. Fetuses with hypoplasia of the aortic arch fared the worst, with the most reduced brain growth during the final trimester of gestation. Wu et al also showed that measures of fetal cortical complexity similarly diverged from normal during the third trimester.

Periventricular Leukomalacia/White Matter Injury

WMI, in the form of periventricular leukomalacia (PVL), is a common finding in premature infants. Although WMI has been increasingly recognized in full-term neonates with cCHD, some feel strongly that the term PVL should be reserved for the premature infant. Importantly, while there may be no differences in the MRI appearance of the punctate WMI in the two populations, the WMI in the cCHD population never becomes cystic like PVL in the preterm. In premature infants, severe degrees of PVL have been associated with cerebral palsy, while mild degrees of injury have been associated with developmental delay, motor difficulties, and behavioral disorders. The developmental “phenotype” in children who were born prematurely is remarkably similar to that seen in school-age children with cCHD. Preoperative factors and patient-specific factors including the specific heart diagnosis, postnatal age at surgery, prenatal diagnosis, and genetic factors have been shown to be associated with WMI in neonates with cCHD. Ongoing research examining the relationship between cerebral vascular reactivity and autoregulation, cerebral perfusion, and the identification of sensitive and specific brain injury biomarkers may allow for real-time intraoperative and postoperative brain injury monitoring and intervention to reduce brain injury. Miller, McQuillen, and others first demonstrated alterations in white matter structure and maturation using diffusion tensor MRI. Thereafter, Licht used an MRI-based observational metric called the Total Maturation Scale, that demonstrated brain maturation in full-term presurgical infants with cCHD was equivalent, on average, to the expected brain maturation of a 35-week premature infant. Others have since shown that the Total Maturation Scale predicted not only the risk for preoperative and postoperative WMI but also abnormalities on neurodevelopmental outcome in childhood and adolescence. In a fetal lamb model, exposure of the fetal brain to low levels of oxygen delivery in the third trimester, results in a developmental arrest in oligodendrocytes resulting in populations of vulnerable premyelinating oligodendrocytes. Similarly, in infants with cCHD, during fetal development there is lower than normal oxygen delivery in the third trimester, which results in delayed brain maturation and abnormal integrity of the white matter at birth. In infants with cCHD, these changes result in their developmental vulnerability to WMI. Heart defect type, surgical strategy, and other exposures result in the injury. Lynch et al, using advanced optical techniques to quantify cerebral blood flow and oxygen saturations, showed that daily falls in cerebral oxygen saturations between birth and surgery increased the risk for postoperative WMI in babies with HLHS. In Lynch's study, rising cerebral oxygen extraction was not compensated with increasing cerebral blood flow. It is theorized that WMI results from a combination of cellular vulnerability and limitations in cerebral oxygen delivery. Similarly, Petit et al found an increased risk for WMI in neonates with d-TGA, as the duration between birth and surgery increases. These studies, and others, have challenged the paradigm of the timing of neonatal surgery. At the current time, there are competing risks of waiting longer for surgery (from a brain perspective) compared to proceeding early with surgery (from a renal, pulmonary, and cardiac perspective). See Chapter 15 for a similar discussion in the premature infant with cCHD.

While there are no prospective longitudinal studies to directly link the WMI seen in the newborn after heart surgery, with long-term (10-year outcomes or longer) neurodevelopmental outcomes or specific functional deficits, there is growing evidence that suggests that abnormal white matter is in fact at the core of these deficits. Brain MRIs obtained as part of the 16-year follow-up of the Boston Circulatory Arrest Study demonstrated that the white matter in the CHD subjects showed regions of decreased fractional anisotropy (a marker of WMI) compared to age-matched controls. Further investigations revealed that some of these areas of reduced fractional anisotropy were correlated with worse performance on the Conners 3 attention deficit–hyperactivity ADHD index, the Wechsler Individual Achievement Test mathematics composite, and visual spatial testing (visual closure). In this same cohort of adolescents with d-TGA, Panigrahy and colleagues used MRI analysis techniques, which allow testing the intactness of networks of white matter (whole-brain functional connectivity of resting state networks). The work demonstrated that worse neurocognitive function was mediated by global differences in white matter network topology, suggesting that disruptions of large-scale networks drive neurocognitive dysfunction. Interestingly, some of these large-scale networks may be abnormal even before the newborn has heart surgery.