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 schoolage 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.11,20 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 intervention43 to reduce brain injury Miller, McQuillen, and others first demonstrated alterations in white matter structure and maturation using diffusion tensor MRI.38 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.10 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.44–46 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.47–48 Similarly, in infants with cCHD, during fetal development there is lower than normal oxygen delivery in the third trimester,16 which results in delayed brain maturation10 and abnormal integrity of the white matter at birth.38 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.20 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,29 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.49 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).50 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.51 Interestingly, some of these large-scale networks may be abnormal even before the newborn has heart surgery.52 Genetic Susceptibility to Neurologic Injury and Developmental Disability All the above risk factors do not fully explain either the high frequency or the pattern of neurodevelopmental deficits described in children with cCHD, suggesting that other patient-specific factors may be important determinants of neurologic injury Intelligence quotient and cognitive functioning (e.g., academic achievement in math and reading) are highly heritable and probably are dependent on multiple genes, environmental factors, and gene-environment interactions.53 Numerous genetic defects or syndromes that are associated with compromised intellectual capacity and developmental outcomes (e.g., trisomy 21, Williams syndrome, DiGeorge syndrome) may have cCHD as part of its phenotypic expression.54 Although the genetic basis for most cardiac defects has not been delineated, specific genetic anomalies have been implicated in the pathogenesis of some defects For example, microdeletions of chromosome 22 are associated with DiGeorge syndrome and a variety of heart defects, including TOF, truncus arteriosus, and interruption of the aortic arch.55 Developmental abnormalities are present in all children with 22q11 microdeletions, even those with no cardiac abnormalities.56 Thus, children with cardiac defects and 22q11 microdeletions may be developmentally impaired independent of the cardiac defect and morbidity-related cardiac interventions However, recent studies suggest that the effects may be additive.53,57–59 Recent work by Homsy and colleagues and the Pediatric Congenital Genomics Consortium, in a cohort of over 1200 parent-offspring trios, has shown an excess of protein-damaging de novo mutations, especially in genes highly expressed in the developing heart and brain These mutations accounted for 20% of patients with cCHD, neurodevelopmental delay and additional congenital abnormalities, compared to 2% with isolated CHD.60 Risk of disease or injury in response to an environmental stimulus is a complex interaction between genetic susceptibility and environmental exposures Interindividual variation in “disease risk” and in the response to environmental factors is significant The “risk” may be modified by age, gender, ethnicity, and the extent of exposure to environmental factors Multiple genes are involved in determining an individual's response to a specific environmental factor Interindividual variation in response to environmental exposures, such as cardiac ... However, recent studies suggest that the effects may be additive.53,57–59 Recent work by Homsy and colleagues and the Pediatric Congenital Genomics Consortium, in a cohort of over 1200 parent-offspring trios, has shown an excess of protein-damaging de