Patrick Sean McQuillen

Neurodevelopmental impairments are common in congenital heart disease (CHD) and fetal brain volume is an important predictor of outcomes. Social determinants of health (SDOH) and environmental factors influence brain growth in other populations and likely play a neurodevelopmental role in CHD. This study evaluated the influence of SDOH and environmental factors on fetal and neonatal brain volume, growth, and risk of brain injury in CHD. This prospective single-center longitudinal cohort study enrolled fetuses with severe CHD to undergo third-trimester fetal and preoperative brain MRIs. Controls underwent third-trimester brain MRIs. Participants completed SDOH and environmental exposure surveys. Fetal and neonatal brain volumes, brain growth, and presence of white matter injury (WMI) were assessed. 57 CHD patients and 24 controls were enrolled, resulting in 33 fetal and 44 neonatal MRIs in the CHD group and 21 fetal control MRIs. Several SDOH and environmental factors, including maternal smoking, were associated with smaller brain volume and slower brain growth in CHD but not in controls. With CHD, repeated-measures analysis showed smaller fetal brain volume (coeff: − 13.3, 95% CI − 25.5, − 1.1, p = 0.03) and slower growth (coeff: − 2.5, 95% CI − 5.0, − 0.07, p = 0.04) with exposure to any risk factor. Patients with moderate to severe WMI had significantly lower mean COI scores compared to those with no or minimal WMI (58.28 vs. 37.28, p = 0.04), but lost significance when adjusted for GA. SDOH and environmental exposures influence fetal brain growth and preoperative brain injury risk in CHD. These results highlight additive environmental prenatal risks which may be amenable to early intervention.

Fetal cerebral oxygenation was not associated with perinatal brain maturation or early neurodevelopmental outcomes, but fetal brain volume and lesion complexity were associated with improved language and worse motor outcomes, respectively.

Background: Neurodevelopmental outcomes are impaired in significant congenital heart disease (CHD) with prenatal origins. The cerebrovascular response to maternal hyperoxia (MH) varies in fetuses with CHD, which may reflect brain health in utero. We investigated the association between lack of cerebrovascular reactivity with MH and adverse neurologic outcomes in CHD measured as brain growth and risk of postnatal white matter injury. Methods: This is a prospective cohort study of pregnant participants whose fetuses had CHD requiring a neonatal operation. We performed fetal echocardiograms with MH, fetal brain magnetic resonance imaging (MRI), and postnatal preoperative brain MRI. A ≥5% change in middle cerebral artery pulsatility index with MH defined reactivity. Total brain volume was measured on MRIs. The neonatal MRI was assessed for white matter injury. Regression analyses compared responders versus nonresponders, then stratified by hypoplastic left heart syndrome and d‐transposition of the great arteries groups. Results: Fifty‐five participants underwent fetal imaging. Forty‐nine neonates underwent brain MRI. Among subjects with hypoplastic left heart syndrome, at each gestational week, total brain volume was 17.8 mL greater in responders (95% CI, 3.3–32.3; P =0.02). This pattern was not seen in d‐transposition of the great arteries. Postnatal white matter injury was less common in responders. Conclusions: Lack of fetal cerebrovascular response to MH is associated with smaller total brain volume beginning in utero in hypoplastic left heart syndrome. Postnatal white matter injury is more common among nonresponders. MH testing can help identify individual fetuses with CHD at highest risk for adverse neurologic outcomes, particularly those with hypoplastic left heart syndrome.

Viral lower respiratory tract infection (vLRTI) is a leading cause of hospitalization and death in children worldwide. Despite this, no studies have employed proteomics to characterize host immune responses to severe pediatric vLRTI in both the lower airway and systemic circulation. To address this gap, gain insights into vLRTI pathophysiology, and test a novel diagnostic approach, we assayed 1,305 proteins in tracheal aspirate (TA) and plasma from 62 critically ill children using SomaScan. We performed differential expression (DE) and pathway analyses comparing vLRTI (n=40) to controls with non-infectious acute respiratory failure (n=22), developed a diagnostic classifier using LASSO regression, and analyzed matched TA and plasma samples. We further investigated the impact of viral load and bacterial coinfection on the proteome. The TA signature of vLRTI was characterized by 200 DE proteins (P _adj <0.05) with upregulation of interferons and T cell responses and downregulation of inflammation-modulating proteins including FABP and MIP-5. A nine-protein TA classifier achieved an AUC of 0.96 (95% CI 0.90-1.00) for identifying vLRTI. In plasma, the host response to vLRTI was more muted with 56 DE proteins. Correlation between TA and plasma was limited, although ISG15 was elevated in both compartments. In bacterial coinfection, we observed increases in the TNF-stimulated protein TSG-6, as well as CRP, and interferon-related proteins. Viral load correlated positively with interferon signaling and negatively with neutrophil-activation pathways. Taken together, our study provides fresh insight into the lower airway and systemic proteome of severe pediatric vLRTI, and identifies novel protein biomarkers with diagnostic potential. IMPORTANCE: We describe the first proteomic profiling of the lower airway and blood in critically ill children with severe viral lower respiratory tract infection (vLRTI). From tracheal aspirate (TA), we defined a proteomic signature of vLRTI characterized by increased expression of interferon signaling proteins and decreased expression of proteins involved in immune modulation including FABP and MIP-5. Using machine learning, we developed a parsimonious diagnostic classifier that distinguished vLRTI from non-infectious respiratory failure with high accuracy. Comparative analysis of paired TA and plasma specimens demonstrated limited concordance, although the interferon-stimulated protein ISG15 was significantly upregulated with vLRTI in both compartments. We further identified TSG-6 and CRP as airway biomarkers of bacterial-viral coinfection, and viral load analyses demonstrated positive correlation with interferon-related protein expression and negative correlation with the expression of neutrophil activation proteins. Taken together, our study provides new insight into the lower airway and systemic proteome of severe pediatric vLRTI.

Neonatal brain injury may impact brain development and lead to lifelong functional impairments. Hypoxic-ischemic encephalopathy (HIE) and congenital heart disease (CHD) are two common causes of neonatal brain injury differing in timing and mechanism. Maturation of whole-brain neural networks can be quantified during development using diffusion magnetic resonance imaging (dMRI) in combination with graph theory metrics. DMRI of 35 subjects with CHD and 62 subjects with HIE were compared to understand differences in the effects of HIE and CHD on the development of network topological parameters and functional outcomes. CHD newborns had worse 12–18 month language (P<0.01) and 30 month cognitive (P<0.01), language (P = 0.05), motor outcomes (P = 0.01). Global efficiency, a metric of brain integration, was lower in CHD (P = 0.03) than in HIE, but transitivity, modularity and small-worldness were similar. After controlling for clinical factors known to affect neurodevelopmental outcomes, we observed that global efficiency was highly associated with 30 month motor outcomes (P = 0.02) in both groups. To explore neural correlates of adverse language outcomes in CHD, we used hypothesis-based and data-driven approaches to identify pathways with altered structural connectivity. We found that connectivity strength in the superior longitudinal fasciculus (SLF) tract 2 was inversely associated with expressive language. After false discovery rate correction, a whole connectome edge analysis identified 18 pathways that were hypoconnected in the CHD cohort as compared to HIE. In sum, our study shows that neonatal structural connectivity predicts early motor development after HIE or in subjects with CHD, and regional SLF connectivity is associated with language outcomes. Further research is needed to determine if and how brain networks change over time and whether those changes represent recovery or ongoing dysfunction. This knowledge will directly inform strategies to optimize neurologic functional outcomes after neonatal brain injury.

Poor and asymmetric fetal growth have been associated with neonatal brain injury (BI) and worse neurodevelopmental outcomes (NDO) in the growth-restricted population due to placental insufficiency. We tested the hypothesis that postnatal markers of fetal growth (birthweight (BW), head circumference (HC), and head to body symmetry) are associated with preoperative white matter injury (WMI) and NDO in infants with single ventricle physiology (SVP) and d-transposition of great arteries (TGA). 173 term newborns (106 TGA; 67 SVP) at two sites had pre-operative brain MRI to assess for WMI and measures of microstructural brain development. NDO was assessed at 30 months with the Bayley Scale of Infant Development-II (n = 69). We tested the association between growth parameters at birth with the primary outcome of WMI on the pre-operative brain MRI. Secondary outcomes included measures of NDO. Newborns with TGA were more likely to have growth asymmetry with smaller heads relative to weight while SVP newborns were symmetrically small. There was no association between BW, HC or asymmetry and WMI on preoperative brain MRI or with measures of microstructural brain development. Similarly, growth parameters at birth were not associated with NDO at 30 months. In a multivariable model only cardiac lesion and site were associated with NDO. Unlike other high-risk infant populations, postnatal markers of fetal growth including head to body asymmetry that is common in TGA is not associated with brain injury or NDO. Lesion type appears to play a more important role in NDO in CHD.