Neurodevelopmental delays constitute the most common morbidity for school-aged children with complex CHD who required cardiac surgery as neonates or young infants,1,16
because approximately half require remedial academic services.17,18
Studies from multiple centers of children with various types of CHD show a surprisingly similar pattern, including relatively preserved intelligence but a higher than expected frequency of deficits in attention, executive function, language, fine and gross motor coordination, and visual-motor integration. Their neurodevelopmental profile is qualitatively similar to that of premature infants. Both groups share a common neuropathology, PVL, which is an injury to the white matter located in a vascular watershed zone adjacent to the lateral ventricles. Hypoxia-ischemia is a common cause of PVL, and the vulnerability of the white matter to hypoxia-ischemia is heavily dependent on brain maturity and the concentration of vulnerable cell populations, known as late oligodendrocyte progenitors.10
The density of these delicate premyelinating oligodendrocyte progenitor cells peaks at a GA of 23 to 32 weeks but may persist until 35 to 36 weeks. This corresponds to a period of peak PVL prevalence in preterm infants. The high prevalence of PVL among term infants with CHD in the preoperative, intraoperative, and postoperative periods suggests that they also demonstrate an enhanced susceptibility to white matter injury from brain immaturity, possibly related to the CHD.
Well-designed investigations of neurodevelopmental outcomes of infant heart surgery have focused on intraoperative variables such as bypass strategies, hematocrit, and pH management but have failed to show clear and consistent long-term benefit.1,2,19-21
Indeed, the Bayley scales of infant development in infants after TGA repair have not changed substantially over the past 2 decades, despite many modifications in intraoperative strategy.1,19,21,22
Although intraoperative techniques are undoubtedly important, the lack of significant improvement in developmental scores in TGA suggests that it is the underlying brain substrate
in CHD in general, and TGA in particular, that contributes more significantly to longer-term outcomes than changes in intraoperative support techniques. There is a growing recognition of the stronger contribution of patient factors, such as cardiac diagnosis, genetic diagnoses, and APOE
genotype, as important determinants of neurodevelopmental outcomes.4,5
Furthermore, there is greater appreciation that in CHD, the brain is smaller than expected and commonly shows white matter injury, both before and after surgery, suggesting immaturity.6-8,11
This study tests the hypothesis that brain development is structurally delayed in infants with complex CHD. Brain development involves a rapid and predictable sequence of structural alterations of cortical and subcortical structures. In very early fetal life, the cortex begins as a smooth structure, followed by the onset of sulcation at 20 weeks EGA with the gradual appearance of deep primary and more superficial secondary cortical infoldings. The germinal matrices, sites of origin, and migration of cortical neurons and glial cells appear robust between 10 and 28 weeks EGA. The blood supply to the germinal matrix then gradually involutes as neuronal proliferation halts and glial multiplication (forming migrating bands of glial cells) begins, starting at 20 weeks EGA. Glial cell migration then continues postnatally.23
The myelination of the cerebral hemispheres is largely postnatal but can be detected in the optic radiations and posterior limbs of the internal capsule beginning at approximately 35 weeks of gestation and progresses steadily thereafter through age 2 years.23
These predictable anatomic maturational sequences can be measured by the TMS, a semiquantitative scoring system developed and validated in healthy preterm infants.13
TMS scores in our cohort were significantly lower than those of normal controls of similar GA (>36 weeks GA). The average TMS score for the study group with TGA and HLHS was at the 50th percentile for 35 weeks gestation, 4 weeks below their actual mean GA. These observations of anatomic immaturity complement a recent study of biochemical “immaturity” measured by magnetic resonance spectroscopy and diffusion tensor imaging.12
Consistent with the TMS scores, their mean head circumference was smaller than expected for their gestation age: a full standard deviation below normal. This agrees with a previous study from our group using novel semiautomated MRI techniques that demonstrated reduced brain volumes for age.24
Further, immature brain development was also seen in the incomplete closure of the cerebral operculae in approximately 90% of the infants studied. The operculum comprises an area of brain that includes the sensory motor cortical representation of buccal, glottic, and esophageal structures, as well as receptive and expressive language. Bilateral abnormalities in the cerebral operculum have been linked to feeding and language delays.15
Our cohort of preoperative infants with CHD was specifically selected to exclude patients with intrauterine growth retardation, as well as those at increased risk for brain injury from perinatal distress. Despite this selection of “lower-risk” infants, PVL was identified in more than 20% of neonates before surgery, similar to that seen in previous studies.6-9
Consistent with the hypothesis that the central nervous system in these infants is immature and thus “vulnerable” to hypoxia and ischemia, the incidence of PVL increases to at least 50% after surgery.9,25
Factors related to the increase or severity of PVL have included adverse postoperative hemodynamics, including hypoxemia, hypotension,25
and low systemic oxygen saturation as measured by near infrared spectroscopy,9
rather than factors related to intraoperative management strategies.
Low TMS scores, small head circumferences, a high prevalence of open operculae, and an increased and ongoing risk for PVL collectively suggest that in utero brain development is impaired in this population. In the fetus without CHD, the normal fetal circulation results in preferential streaming of blood with higher oxygen content from the placenta to the left atrium and ventricle, and then to the brain. This pattern is not present in TGA, where the aorta is aligned with the right ventricle, or in HLHS, where the left ventricle and aorta are hypoplastic or virtually absent. These altered fetal blood flow patterns are associated with measurable changes in fetal cerebral vascular resistance,26,27
as well as the potential for reduced oxygen delivery, which likely lead to abnormalities of brain development. Consistent with this hypothesis, we have previously noted that reduced head circumference in infants with HLHS was significantly associated with smaller diameters of the ascending aorta28
and microcephaly, as previously noted in many studies of CHD.4,5,8
In vivo experiments have demonstrated that oligodendrocyte maturation can be delayed in rat pups raised in a hypoxic environment and predisposes the brain to PVL at an age that it would not be otherwise expected.29
Similar mechanisms may be at play with severe forms of CHD.
The current study is limited by its relatively modest size. Nonetheless, the frequency of microcephaly, PVL, and open opercula is consistent with previous reports and our larger cumulative experience with preoperative brain MRI in 102 infants with complex CHD. It also must be emphasized that this study was limited to neonates with 2 cardiac diagnoses—HLHS and TGA—and the incidence of congenital brain abnormalities may be different in other populations with CHD.