Prenatal Diagnosis

Rates of prenatal detection of major CHD vary considerably across centers. The best quoted European rate is 47%. However, better training in fetal echocardiography may help improve clinicians’ diagnostic skills. Prenatal diagnosis of TGA and HLHS is associated with decreased perioperative morbidity and mortality. This positive impact on the development of the brain likely is a result of earlier prostaglandin treatment and earlier monitoring of the hemodynamic state of newborns with CHD. Prenatally diagnosed infants are more likely to be transported while receiving prostaglandin E ₁ , will have a more physiologic pH on admission to a tertiary care center, and have a lower early mortality. Prenatal diagnosis also results in less WMI and/or stroke and allows for better white and grey matter maturation as evidenced by advanced MRI techniques. There is also a reduced likelihood of seizures following prenatal diagnosis. These observations support the importance of prenatal CHD screening and early prostaglandin treatment in the care of the newborn with CHD.

Postnatal Diagnosis

Delayed or missed diagnosis of critical CHD accounts for 0.4 to 2.0 deaths per 10,000 live births in a U.K. series. These infants typically present with serious and life-threatening symptoms, such as cyanosis, tachycardia, pulmonary edema, and cardiogenic shock. The timing of presentation depends on the type of cardiac malformation and its dependence on a patent ductus arteriosus to maintain oxygenated circulation to the brain and other major organs. Before pulse oximetry screening was standard practice in neonatology, 30% of infants with CHD were undiagnosed at the time of discharge from the nursery, especially if they appeared normal physically during their first few days of life. In these undiagnosed newborns, the risk of mortality reaches 30%.

Hypoplastic Left Heart Syndrome

HLHS (see Fig. 15.1 ) accounts for 2% to 3% of all CHD and is characterized by an underdevelopment of the left heart with normally connected great vessels, leaving the sole right ventricle to perfuse both the pulmonary and systemic circulations. In this syndrome, the left ventricle is significantly hypoplastic and can be associated either with atresia, stenosis, and hypoplasia of the aortic or mitral valves; with hypoplasia of the ascending aorta and arch; or both. Survival is dependent on ductus arteriosus patency to ensure adequate mixing of oxygenated and deoxygenated blood. Affected infants are relatively asymptomatic initially; however, when the ductus arteriosus closes and the pulmonary vascular resistances decrease, as expected shortly after birth, these infants rapidly go into cardiogenic shock and respiratory insufficiency. Infants with a restrictive or absent atrium septal defect at birth do not benefit from this “honeymoon period” and present with severe cyanosis and respiratory distress at birth because of inadequate interatrial blood mixing. Fortunately, prenatal diagnosis with routine obstetrical ultrasound is often possible, usually between 18 and 24 weeks’ gestation.

As with TGA, the initial management of infants with HLHS is focused on providing sufficient mixing of oxygenated and deoxygenated blood with the use of continuous intravenous prostaglandin E ₁ , which maintains the ductus arteriosus patent and allows vital flow from the right ventricle to the systemic circulation, as well as BAS. The surgical palliative repair typically consists of a three-staged approach, with initial surgery performed in the neonatal period (Norwood procedure), then at 3 to 6 months of age (bidirectional Glenn procedure), and at 18 to 30 months of age (Fontan procedure). In the Norwood procedure, a neoaorta is created by using the proximal pulmonary artery and homograft material, then connected to the native ascending aorta. A source of pulmonary blood flow is established by connecting the innominate artery with the proximal right pulmonary artery via a Gore-Tex shunt L-TGA is best described as congenitally corrected transposition of great arteries (CCTGA) in which there are discordant atrioventricular and ventriculo-arterial connections, in a procedure known as a modified Blalock-Taussig shunt. An alternative to BT shunt is the use of a right ventricle to pulmonary artery shunt. When the child reaches 3 to 6 months of age, pulmonary vascular resistance has dropped sufficiently to allow substitution of the arterial shunt to the pulmonary circulation with a venous shunt, thus unloading the ventricle. During the bidirectional Glenn procedure (or cavopulmonary shunt), the original shunt is removed and the superior vena cava is anastomosed end-to-side to the right pulmonary artery. As the child grows further, the Fontan procedure is performed, usually between 2 and 3 years of life. In this third stage, the inferior vena cava is connected to the pulmonary arteries, allowing the entire systemic venous return to flow passively to the lungs.

Cranial Ultrasound Versus MRI

Cranial ultrasound in the neonate is a low-cost and noninvasive bedside procedure that provides an assessment of cerebral volumes and ventricle size and can often identify large hemorrhages, infarcts, and cystic WMI. Advanced ultrasound with Doppler measurements is also informative of the flow in the largest venous sinuses. Unfortunately, the reliability of cranial ultrasound for the detection of ischemic lesions is poor, with up to one-third of infarcts being missed. MRI is increasingly recognized as an important addition to the early investigation of neonates with CHD, given the high burden of radiation associated with computed tomography (CT) and the poor reliability of cranial ultrasound. In the investigation of the infant with CHD, it is important to recognize that the majority of injuries are clinically silent and can be present in well-appearing infants. MR diffusion-weighted imaging (DWI), in combination with T1- and T2-weighted imaging, is an early and sensitive test for brain ischemia and acute injury. Owing to the postinjury pseudonormalization of the DWI signal beyond 5 to 7 days in the neonate, MR DWI is best performed within the first week of life to assess for silent infarcts. Appropriate investigation of the neonate with CHD is necessary to aid determine the medical treatments, neurodevelopmental prognosis, and subsequent follow-up procedures for those at greatest risk of developmental deficits.

Cerebral Ischemia and Stroke

Up to 40% of infants with CHD will have preoperative brain injuries, with an acute cerebral infarct or stroke the most predominant early injury types. Neonates with cyanotic CHD have been shown to have ischemic lesions in up to 60% of cases. In the preoperative period, low oxygen saturation is associated with increased risk of stroke and WMI. Several groups have speculated that BAS is a cause of acute infarcts and WMI in TGA, showing an increased incidence of embolic strokes in patients treated with BAS; however, this remains controversial. As clinically silent infarcts and WMI are common in CHD and have a low risk of progressing with surgery, in most cases medically necessary surgical procedures should not be delayed in the event of brain injury findings.

White Matter Injury

WMI, the predominant injury of the premature neonate, is a well-recognized complication of CHD in the term neonate. Infants with CHD are particularly prone to WMI as a result of fluctuations in the cerebral blood flow both preoperatively and postoperatively. Although stroke is the most common preoperative complication, WMI is the most common lesion acquired after surgery, with the greatest risk in neonates with single-ventricle physiology and aortic arch obstruction. Intraoperatively, during bidirectional Glenn and Fontan procedures it has been shown that higher levels of cerebral blood flow are associated with reduced risk of WMI, suggesting the ischemic nature of this complication. The timing of the injury appears most frequently in the neonatal period, as 1- to 3-month-old infants have a significantly reduced risk of postoperative WMI (4% compared with 54% in neonates). This may reflect the relative immaturity of the cerebral autoregulation systems in the brain of the infant with CHD, much like that of the preterm neonate. In those neonates with known preoperative WMI, worsening of white matter lesions was identified in 19%, with new lesions occurring in 48%. In neonates with follow-up beyond 3 months, MRI scans will reveal that many of the existing lesions have resolved though nearly 30% of patients show new lesions. Similar to cohorts of preterm infants, the incidence of WMI in neonates with CHD appears influenced by nosocomial infections the incidence of WMI in neonates with CHD appears influenced by nosocomial infections. In the assessment of WMI and stroke it is important to remember that their pathophysiologies and subsequent outcomes are shared, and optimizing oxygenation and hemodynamic monitoring provides the best neuroprotection.

Cerebral Sinovenous Thrombosis

Cerebral sinovenous thrombosis (CSVT), a serious hemostatic complication in the ill neonate, is a common finding in autopsies of infants with cyanotic CHD. Yet in a study of several European pediatric registries, patients with CHD represented only 4% of the cases with confirmed CSVT. In an adult study, a greater incidence of thrombosis and bleeding was found in subjects with hypoxemia compared with a nonhypoxemic group (12% vs. 2% and 14% vs. 2%, respectively). The etiology of these abnormalities in hemostasis remains incompletely understood, although chronic endothelial damage, increased blood volume and viscosity, low pulmonary artery velocity, biventricular dysfunction, and chronic right-to-left shunting all likely contribute. The investigation for suspected CSVT should include either unenhanced CT and/or MRI T1- and T2-weighted imaging, in addition to venography (CT venography or MR venography) in investigating for clots within the venous sinuses as well as parenchymal injury with infarction or hemorrhage. An experienced neuroradiologist familiar with neonatal vascular imaging should be involved because of the difficult interpretation of the imaging. In a study comparing CSVT and arterial infarct presentation, parietal involvement and lack of caudate infarction were more suggestive of CSVT.

Subdural Hemorrhage

Serial MRI assessments of neurologically asymptomatic infants with CHD both preoperatively and postoperatively revealed that 43% had subdural hemorrhage (SDH) on at least a single scan, with many infants having more than one focus of hemorrhage. Infants with CHD born by vaginal delivery had a higher incidence compared with those delivered by cesarean section (50% vs. 27%, respectively). These rates are altogether higher than in infants without CHD, normally ranging from 6% to 26% and are highest with assisted vaginal delivery. In neonates with CHD, 61% of SDH were small (≤2 mm deep), and only 10% were 5 mm or more deep; the locations were supratentorial in 43% and infratentorial in 57%. There was no significant difference in the location of the hemorrhages between infants with CHD and those without CHD. In monitoring SDH lesions over time, 24% of foci resolved within the first 2 to 4 weeks and 95% resolved by 3 months of age, with persistent hemorrhages generally observed in the posterior fossa. Postoperatively 9% of infants with CHD showed new foci of hemorrhage; increased size of SDH was observed in 48% in one study. The prevalence of recent preoperative SDH in neonates with chronic hypoxia did not differ significantly from nonhypoxic neonates. Although SDH appears to occur more frequently at birth and postoperatively in infants with CHD, SDHs are generally asymptomatic and resolve over time without treatment. The impact of SDH on the neurodevelopmental outcome of the infant with CHD remains unknown.

Brain Dysmaturation

Brain development during the fetal period requires a high energy supply from the placenta. Failure to meet these demands may disrupt brain growth and maturation, especially in fetuses in whom CHD determines decreased cerebral blood flow and hypoxemia. In infants with HLHS, for example, more than half have microcephaly (<10th percentile) at birth. The head growth seems to be directly linked to the degree of ascending aortic flow. Brain maturation delay and cortical malformations are frequently seen on brain MRI and autopsy. Other prospective studies performed antenatally or postnatally in newborns with CHD demonstrate impairment of brain growth and metabolism in the third trimester, decreased pyramidal tract maturation, or widespread metabolic and microstructural brain abnormalities preoperatively, similar to preterm infants. Together, these studies support the concept that brain dysmaturation in CHD originates in utero.

Brain injury in neonates with CHD shares mechanisms common to preterm infants. WMI in neonates with CHD is linked to ischemia (e.g., hypotension) and inflammation. Based on experimental data, Buser et al. described how the primary mechanism of myelination failure in the human preterm neonate involves dysmaturation rather than cell loss, through a disrupted cellular response whereby pre-oligodendrocytes fail to differentiate into mature oligodendrocytes (i.e., oligodendrocyte progenitor maturation arrest). Similar findings were recently confirmed in a rodent model of CHD-related WMI. During the third trimester of gestation, early lineage oligodendroglia are vulnerable to insults that do not affect mature myelinating oligodendroglia. This results in a preponderance of WMI in neonates born before term, rather than the gray matter vulnerability seen in term neonates. Surprisingly, WMI is the characteristic brain injury pattern in term neonates with CHD and is indistinguishable from that seen in preterm neonates. Thus brain vulnerability in CHD appears to be a consequence of dysmaturation.

In human newborns, recent works have led to the recognition of abnormal brain maturation in utero and the importance of impaired brain maturation as a substrate for postnatal injury. In similar studies of neonates born preterm term, brain dysmaturation, rather than brain injury, is the major driver of adverse neurodevelopment. As the primary issue appears to be brain maturation arrest rather than cell loss, these data highlight the potential for brain recovery from injury.

Intraoperative Monitoring

The modern surgical approach to the most complex cardiac lesions includes cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA). Both procedures carry a risk of injury for the neonatal brain and are frequently associated with postoperative lesions. Infants 3 months of age or younger who undergo CHD surgery are at greater risk of transient cerebral ischemia from hypotension than older children, likely as a result of reduced cerebral autoregulation. As neuromonitor usage has increased in recent decades, improvements in neurodevelopmental outcomes of the infant with CHD have similarly been seen. Transcranial Doppler ultrasound is one method that has shown effectiveness in determining adequate cerebral perfusion and arterial saturation in real time during the low-flow CPB period. Similarly, somatosensory evoked potentials used intraoperatively are very specific and sensitive for neurological complications from hemodynamic disturbances. A study using multimodal intraoperative neuromonitoring combining electroencephalography (EEG), transcranial Doppler ultrasound, and near-infrared spectroscopy (NIRS) identified alterations in brain perfusion in 70% of patients, allowing corrective interventions in 74%. Such interventions were shown to improve neurologic outcomes (6% complication rate vs. 26% in the no-intervention group) and resulted in a decreased hospital length of stay. With the continued focus on improving neurodevelopmental outcomes in infants with CHD, intraoperative monitoring will continue to be an important tool in maximizing intraoperative cerebral protection.

Near-Infrared Spectroscopy

NIRS is a noninvasive bedside monitor that uses nonpulsatile oximetry to monitor hemoglobin oxygen saturation in a localized tissue bed. When used on the head, NIRS provides real-time information on the cerebral cortex oxygenation. NIRS has been shown to correlate well with superior vena cava oxygen saturation, highlighting its utility as a cerebral monitor. NIRS appears useful in both cyanotic and acyanotic heart disease, with optimal correlation at superior vena cava oxygenation concentrations of 40% to 60%, a point at which it is critical to intervene and improve oxygenation to protect brain function and homeostasis. As an intraoperative neuromonitoring system, NIRS has been shown to be a valuable tool in the assessment of hypocarbia and hypoxia and can alarm the surgical team to low cerebral perfusion. Whether or not intraoperative NIRS results in measurable improvements in neurodevelopmental outcomes remains uncertain; one study suggested that the only measurable negative outcome correlated with the NIRS intraoperative nadir was receptive language delay. Another report showed that neonates with values 20% to 40% below baseline during CHD surgery had increased neurologic dysfunction 12 months after surgery. NIRS as a marker of cerebral functioning is well supported by the literature, with its use in multimodal neuromonitoring providing significant benefit to both the infant with CHD as well as the surgical and clinical care teams.

Amplitude-Integrated Electroencephalography

As a marker of cerebral activity, amplitude-integrated EEG (aEEG) provides clinicians with valuable bedside information about the background electrical activity and can identify abnormal activity consistent with seizures. In a study of neonates with cyanotic and acyanotic CHD, aEEG patterns before and after the initiation of prostaglandin treatment showed abnormal voltage patterns in 60% of neonates at some point in the first 72 hours versus only 13% that continued to be abnormal at 72 hours after administration of prostaglandin. Severely abnormal patterns of burst suppression, continuous low voltage, or flat tracings were identified in 15% of neonates with no difference between the acyanotic and cyanotic groups. Abnormal aEEG patterns directly correlated with preoperative brain MRI injury scores; infants with severely abnormal aEEGs had the highest MRI injury scores. Severely abnormal aEEG background activity was associated with brain atrophy in 80% of cases with fewer numbers of focal infarcts and/or WMI. Sleep-wake cycling was present in up to 60% of neonates in the first 72 hours and was not associated with brain injury, although those with brain atrophy were less likely to have sleep-wake cycling present. Electrical seizures were identified in 19% of neonates; 11 of 12 were characterized as having acyanotic CHD. Clinical seizures strongly correlated with aEEG, with subclinical seizures identified in 2 of 12 neonates with seizures. Three neonates with suspected clinical seizures and aEEG patterns not consistent with a seizure were identified on conventional EEG to have focal electrographic seizure activity. This reflects a difficulty of aEEG as it has poor sensitivity for focal seizures not localized near the electrodes and showcases the importance of conventional EEG for further characterization of suspected seizures.

Continuous Electroencephalography

Neonates with CHD are at risk of seizures in both the preoperative and postoperative periods. The American Clinical Neurophysiology Society guideline on neonatal EEG monitoring in infants with CHD recommends consideration for continuous EEG (cEEG) monitoring during the postoperative period where seizure rates are 5% to 20%. HLHS has been shown to carry a greater risk of seizures in the postoperative period with 18% having seizures, compared with 4% in tetralogy of Fallot (TOF), 8% in TGA, and 12% with other biventricular defects. In a study of cEEG in the postoperative period at a single center, 8% of all infants with CHD had electrographic seizures with a median onset time at 20 hours (interquartile range 15–34 hours) after return to the cardiac intensive care unit. Clinical seizures with an electrographic correlate occurred in 15% of patients, with 85% of seizures occurring subclinically and identified purely on the basis of cEEG changes. Status epilepticus, classified as a single seizure lasting more than 30 minutes or recurrent seizures lasting for at least 30 minutes in a 60-minute period, occurred in 62% of those with seizures or 5% of all infants with CHD. Younger age at surgery, longer CPB and DHCA times, single-ventricle physiology and arch obstruction, delayed sternal closure, postoperative cardiac arrest, and extracorporeal membrane oxygenation were all factors that increased the likelihood of seizures. For every 10-minute increase in DHCA time, the odds ratio of developing seizures was 1.47, indicating an association with increased surgical time and subsequent brain dysfunction and injury. All infants with seizures were identified on neuroimaging as having either diffuse or multifocal lesions on either head ultrasound or brain MRI. Electrical seizure activity itself was associated with a 14-fold increase in the likelihood of an abnormal MRI scan. Given the strong association between seizures and CHD, cEEG should be considered in all neonates with CHD, particularly in the postoperative period, to better identify seizures, allowing for timely treatment, and assist in the identification of underlying brain injury.