Individualized brain development and cognitive outcome in infants with congenital heart disease

Abstract

Infants with Congenital Heart Disease are at risk of neurodevelopmental impairments, the origins of which are currently unclear. The aim of this study was to characterise the relationship between neonatal brain development, cerebral oxygen delivery and neurodevelopmental outcome in infants with Congenital Heart Disease. A cohort of infants with serious or critical Congenital Heart Disease (N = 66; N = 62 born ≥37 weeks) underwent brain MRI prior to surgery on a 3 T scanner situated on the neonatal unit. T2-weighted images were segmented into brain regions using a neonatal-specific algorithm. We generated normative curves of typical volumetric brain development using a data-driven technique applied to 219 healthy infants from the Developing Human Connectome Project (dHCP). Atypicality indices, representing the degree of positive or negative deviation of a regional volume from the normative mean for a given gestational age, sex and postnatal age, were calculated for each infant with Congenital Heart Disease. Phase contrast angiography was acquired in 53 infants with Congenital Heart Disease and cerebral oxygen delivery was calculated. Cognitive and motor abilities were assessed at 22 months (N = 46) using the Bayley scales of Infant and Toddler Development—3rd Edition. We assessed the relationship between atypicality indices, cerebral oxygen delivery and cognitive and motor outcome. In addition, we examined whether cerebral oxygen delivery was associated with neurodevelopmental outcome through the mediating effect of brain volume. Negative atypicality indices in deep grey matter were associated with both reduced neonatal cerebral oxygen delivery and poorer cognitive abilities at 22 months across the whole sample. In infants with Congenital Heart Disease born ≥37 weeks negative cortical grey matter and total tissue volume atypicality indices, in addition to deep grey matter structures, were associated with poorer cognition. There was a significant indirect relationship between cerebral oxygen delivery and cognition through the mediating effect of negative deep grey matter atypicality indices across the whole sample. In infants born ≥37 weeks, cortical grey matter and total tissue volume atypicality indices were also mediators of this relationship. In summary, lower cognitive abilities in toddlers with Congenital Heart Disease were associated with smaller grey matter volumes prior to cardiac surgery. The aetiology of poor cognition may encompass poor cerebral oxygen delivery leading to impaired grey matter growth. Interventions to improve cerebral oxygen delivery may promote early brain growth and improve cognitive outcomes in infants with Congenital Heart Disease. Bonthrone et al. assessed individualized brain growth in infants with congenital heart disease compared to a large normative sample to determine atypicality indices in the patient group. Low cerebral oxygen delivery was associated with impaired grey matter development and resulted in poor cognitive outcome in this population.

Neonatal frontal-limbic connectivity is associated with externalizing behaviours in toddlers with Congenital Heart Disease

“…Overall, each infant was categorized into two brain injury groups: normal/mild (mild: intraventricular haemorrhage, and/or cerebellar hemorrhage ≤2 mm, and/or mild WMI) and moderate/severe (moderate: cerebellar hemorrhage >2 mm and/or moderate WMI; severe: severe WMI) ( Bonthrone et al, 2021b , Kelly et al, 2019a ). Brain injury ratings are summarized in Table 2 .…”

“…At follow-up assessment parents completed the cognitively stimulating parenting scale (CSPS) ( Wolke et al, 2013 ), a 21‐item questionnaire adapted from the Home Observation for Measurement of the Environment (HOME) Inventory ( Bradley and Caldwell, 1984 ) designed to assess the level of cognitive stimulation at home (CSPS score range 0–46). Details of this questionnaire have been published previously ( Bonthrone et al, 2021b ).…”

“…Hospital records were reviewed to calculate days on the intensive care unit (ICU) post-surgery, time on bypass during surgery, and days to corrective or final palliative surgery. In children who underwent more than one surgery, days on ICU and time on bypass were summed across procedures ( Bonthrone et al, 2021b ).…”

A novel KLF13 mutation underlying congenital patent ductus arteriosus and ventricular septal defect, as well as bicuspid aortic valve

“…Based on the occurrence of cardiac lesions in certain locations, CHD is clinically classified into >20 distinct subtypes, including ventricular septal defect (VSD), patent ductus arteriosus (PDA), transposition of the great arteries (TGA), double outlet of the right ventricle (DORV), tricuspid valve atresia (TVA), atrial septal defect (ASD), endocardial cushion defect, aortic stenosis, a right aortic arch, a single ventricle, tetralogy of Fallot, hypoplastic left heart and hypoplastic right heart (3)(4)(5)(6). Irrespective of minor CHD that may resolve spontaneously (3), major CHD may contribute to diminished health-associated quality of life (7)(8)(9), decreased exercise performance (10)(11)(12)(13)(14), delayed neurodevelopment and brain injury (15)(16)(17)(18), ischemic or hemorrhagic cerebral stroke (19)(20)(21), pulmonary arterial hypertension or Eisenmenger syndrome (22)(23)(24), viral pneumonia (25)(26)(27), infective endocarditis (28)(29)(30), acute myocardial infarction (31,32), chronic congestive heart failure (33)(34)(35), ventricular or supraventricular A novel KLF13 mutation underlying congenital patent ductus arteriosus and ventricular septal defect, as well as bicuspid aortic valve arrhythmia (36)(37)(38) and death (39)…”

Can Erythropoietin Reduce Hypoxemic Neurological Damages in Neonates With Congenital Heart Defects?

“…Complex cyanotic CHD are characterized by hypoxemia due to reduced oxygen delivery to the fetus during a critical period of brain development, often resulting in a smaller head circumference at birth, reflective of brain growth in infants ( Williams et al, 2015 ; Bonthrone et al, 2021 ). The term hypoxemia refers to any situation in which oxygen is not available in sufficient amounts to maintain adequate cellular homeostasis.…”