Neonatal Brain Injury and Timing of Neurodevelopmental Assessment in Patients With Congenital Heart Disease

Abstract

Background: Brain injury (BI) is reported in 60% of newborns with critical congenital heart disease as white matter injury (WMI) or stroke. Neurodevelopmental (ND) impairments are reported in these patients. The relationship between neonatal BI and ND outcome has not been established.

Objectives: This study sought to determine the association between peri-operative BI and ND outcomes in infants with single ventricle physiology (SVP) and d-transposition of the great arteries (d-TGA).

Methods: Term newborns with d-TGA and SVP had pre-operative and post-operative brain magnetic resonance imaging and ND outcomes assessed at 12 and 30 months with the Bayley Scales of Infant Development-II. BI was categorized by the brain injury severity score and WMI was quantified by volumetric analysis.

Results: A total of 104 infants had follow-up at 12 months and 70 had follow-up at 30 months. At 12 months, only clinical variables were associated with ND outcome. At 30 months, subjects with moderate-to-severe WMI had significantly lower Psychomotor Development Index (PDI) scores (13 points lower) as compared with those with none or minimal WMI for d-TGA and SVP (p = 0.03 and p = 0.05, respectively) after adjusting for various factors. Quantitative WMI volume was likewise associated. Stroke was not associated with outcome. The Bland-Altman limits of agreement for PDI scores at 12 and 30 months were wide (-40.3 to 31.2) across the range of mean PDI values.

Conclusions: Increasing burden of WMI is associated with worse motor outcomes at 30 months for infants with critical congenital heart disease, whereas no adverse association was seen between small strokes and outcome. These results support the utility of neonatal brain magnetic resonance imaging in this population to aid in predicting later outcomes and the importance of ND follow-up beyond 1 year of age.

Keywords: brain injury; congenital heart disease; neurodevelopmental outcomes.

Figure 1. Study subject flow chart

Subjects were consecutively invited to participate in the prospective protocol obtaining pre- and post-operative MRI’s and neurodevelopmental follow-up at 12 and 30 months of age.

Figure 2. Brain MRI examples of subjects with varying degrees of white matter injury or stroke

Panels A and A.1 are pre-operative T1-weighted images from a subject with hypoplastic left heart syndrome and moderate white matter injury (>/= 3 foci or any foci > 2mm). There are at least 3 (one seen in panel A and another in A.1, arrows) small foci of hyperintensities consistent with white matter injury. Panel B is a pre-operative T-1 weighted image from a subject with hypoplastic left heart syndrome and severe white matter injury (> 5% of white matter volume). Panel C is a T2 weighted image from a pre-operative scan on a subject with d-transposition of the great arteries. The arrows demonstrate a small stroke manifested as hyperintense cortical signal in the middle cerebral artery distribution (< 1/3 of the arterial distribution). Panel C.1 is the corresponding average diffusivity map demonstrating reduced water diffusivity (dark spot) in the same region. Panel D is a T2-weighted image from a postoperative scan on a subject with d-Transposition of the great arteries with a large subacute/chronic stroke in the middle cerebral artery distribution.

Figure 3. Bland-Altman plot of psychomotor development index (PDI) at 12 months and at 30 months by site

The limits of agreement range from −40.3 (bottom line) to 31.2 (top line) suggesting wide variability between PDI scores at the two time points (the middle line represents no difference) for the entire cohort. Similar limits of agreement were obtained for each site (UCSF & UBC). Pitman’s test of variance (p= 0.28) suggests no difference in agreement across the range of PDI values.

Central Illustration. The effect of peri-operative brain injury on motor outcome at 30 months of age

Coefficients (round dots) and corresponding 95% confidence intervals for difference in psychomotor development index (PDI) at 30 months by BIS (brain injury severity) category as compared to BIS = 0 (none to minimal white matter injury) for d-TGA (d- transposition of the great arteries) and SVP (single ventricle physiology) after adjusting for site, maternal education and balloon atrial septostomy. BIS =1 (stroke); BIS=2 (moderate to severe white matter injury).