In the present study, we found that impaired metrics of microstructural and metabolic brain development are associated with increasing BIS, especially preoperatively in term newborns with CHD. Additionally, preoperative brain injuries are associated with further abnormal brain microstructure and metabolism postoperatively, attesting to the longer-term impact of these injuries. Both preoperative and postoperative brain injuries are related to potentially modifiable clinical risk factors.
The predominance of WMI in this cohort of term newborns with CHD, a pattern of brain injury expected in the premature newborn, is consistent with previous findings.11,13–17,35,36
While WMI is identified in 23%–40% of preoperative scans,10,25
it has not yet been reported on fetal imaging.20,37
Within the preoperative cross-sectional analyses, lower FA and NAA/choline, consistent with delayed brain development, were associated with an increasing severity of brain injury. One explanation for this finding, as documented previously in this population and in the preterm neonate, is that focal brain injuries on MRI are associated with more widespread brain abnormalities detected with DTI and MRSI (see reference 21
for review). Yet abnormalities in brain development (decreased total brain volume and NAA) have been recently documented during the third trimester of gestation in the fetus with CHD without focal brain injury.20
Considering this delayed fetal brain development and the very short postnatal time period, it seems very likely that abnormal brain development measured after birth precedes the acquisition of preoperative brain injury. In contrast, abnormalities in preoperative brain development did not predict new postoperative injuries.
Longitudinal studies in the developing fetus and preterm newborn have described distinct patterns of change over time in quantitative MRI parameters. Theoretical understanding of the physical (i.e., water diffusion) and chemical (i.e., metabolite concentrations) processes influencing these parameters combined with experimental knowledge of certain brain cellular and molecular developmental events offer a simplistic paradigm for assessing brain development with diffusion and spectroscopic MRI. For certain neurodevelopmental processes (e.g., myelination), this concept is both logical and supported by animal studies combining imaging and brain histology. Acquired brain injuries may differentially influence quantitative MRI measurements based on severity (i.e., chronic mild vs acute severe), timing, and mechanism. While many neurodevelopmental processes are not measured by diffusion and spectroscopic imaging (e.g., specific axonal targeting, synapse formation, or maturation of glial/neuronal signaling pathways), this simple paradigm presents an opportunity to discern the complex relationships between brain development and acquired brain injury in a longitudinal study of newborns with CHD.
The relationship between brain immaturity and brain injury has been controversial in the literature and may relate to the different metrics of brain development applied in each study.14,25
Brain immaturity, as reflected in the Total Maturation Index, was previously associated with the risk of preoperative and postoperative brain injury. In our current study, we observed a relationship between preoperative brain immaturity and preoperative brain injury but not postoperative brain injury. These differences may be related to the method for measuring brain development. MRSI and DTI provide dynamic metrics of brain development that exhibit changes with acquired injury and with development in the timescale from the preoperative to postoperative periods.19,38
In contrast, the Total Maturation Index is a qualitative scoring system based on gross morphologic brain features (e.g., presence of fetal structures, gyral development, and myelination) that may not evolve as rapidly. Thus it is possible that the reported association of the Total Maturation Index with postoperative injuries may reflect the observed relationship with preoperative brain immaturity. While these brain metrics may also reflect different aspects of brain development, these modalities each suggest an approximate 4-week lag in brain development measured preoperatively.
The severity of preoperative brain injury was associated with higher postoperative Dav
and lactate/choline. This is consistent with our earlier finding of abnormal corticospinal tract maturation from the preoperative to postoperative scans in newborns with CHD and preoperative brain injury,24
as well as with observations in the premature newborn with WMI.21
WMI and preoperative delayed brain maturity were not related in a previous study using diffusion imaging and simplified brain metrics.25
However, diffusion imaging in this study was limited to a subset of that cohort (n = 19), and simplified brain metrics may not be especially sensitive to the mild degree of WMI observed. Taken together, the accumulated data suggest that focal lesions (i.e., stroke and WMI) in the rapidly developing newborn brain have longer-term impacts not limited to the immediate vicinity of the original lesion evident on MRI.
Consistent with previous observations, preoperative and postoperative brain injuries are related to potentially modifiable clinical risk factors. In keeping with some previous studies,12,17,36
preoperative BIS was predicted by SNAP-PE, lower preoperative oxygen saturation, hypotension, and balloon atrial septostomy. These associations were significant for the entire cohort, even though some risk factors, such as balloon atrial septostomy, were specific to the subset of newborns with TGA. Postoperative lowest mean and systolic blood pressure were associated with the severity of brain injuries after bypass surgery.26
Similarly, a strong relationship between postoperative WMI and lowest diastolic blood pressure has been previously reported.16
A recent study performed on adolescents with corrected CHD in the neonatal period demonstrated that white matter abnormalities and volume loss were present on MRI scan at age 14 years.39
These long-term brain abnormalities were also associated with neurodevelopmental deficits at this age.39
Despite improvements in perioperative care, rates of long-term neurodevelopmental deficits in children with CHD have remained stable.2,5
Our findings point to complex relationships between perioperative clinical factors, abnormal brain development, and acquired brain injuries.
While a strength of this study is the dual-center design, providing more practice variability than a single-center cohort, the limited sample size among subgroups of CHD diagnoses prohibited our ability to contrast risk factors between these groups. Region of interest–based analysis of DTI and MRSI can be limited by reliable sampling of voxels between scans and risk of partial averaging. Future advances in MRI acquisition and analysis that allow for automatic segmentation and quantification of DTI and MRSI parameters from the preoperative to postoperative periods may also refine our ability to detect differences related to CHD subgroups and critical illness. Studies addressing the in utero interplay of brain development, brain injury, and clinical factors are under way so that novel brain protection strategies can be considered before birth.
Our findings suggest that in term newborns with CHD, delayed brain maturation is the substrate on which preoperative brain injuries, notably WMI, occur. In contrast, newly acquired postoperative brain injuries may be more strongly influenced by perioperative factors. Our findings point to the need for in utero strategies to promote optimal brain development, as well as the potential for clinical interventions targeting hemodycnamic stability and optimal oxygenation to reduce the burden of preoperative and postoperative brain injuries. The association of delayed brain maturation with the impaired long-term neurodevelopmental outcome in children with CHD undergoing heart surgery remains unclear and is the focus of ongoing studies as these newborns are followed through childhood.