Fetal Brain Volume Predicts Neurodevelopment in Congenital Heart Disease

Abstract

Background: Neurodevelopmental impairment is common in children with congenital heart disease (CHD), but postnatal variables explain only 30% of the variance in outcomes. To explore whether the antecedents for neurodevelopmental disabilities might begin in utero, we analyzed whether fetal brain volume predicted subsequent neurodevelopmental outcome in children with CHD.

Methods: Fetuses with isolated CHD and sociodemographically comparable healthy control fetuses underwent fetal brain magnetic resonance imaging and 2-year neurodevelopmental evaluation with the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) and the Adaptive Behavior Assessment System, Third Edition (ABAS-3). Hierarchical regression evaluated potential predictors of Bayley-III and ABAS-3 outcomes in the CHD group, including fetal total brain volume adjusted for gestational age and sex, sociodemographic characteristics, birth measures, and medical history.

Results: The CHD group (n=52) had lower Bayley-III cognitive, language, and motor scores than the control group (n=26), but fetal brain volumes were similar. Within the CHD group, larger fetal total brain volume correlated with higher Bayley-III cognitive, language, and motor scores and ABAS-3 adaptive functioning scores (r=0.32-0.47; all P<0.05), but this was not noted in the control group. Fetal brain volume predicted 10% to 21% of the variance in neurodevelopmental outcome measures in univariate analyses. Multivariable models that also included social class and postnatal factors explained 18% to 45% of the variance in outcome, depending on developmental domain. Moreover, in final multivariable models, fetal brain volume was the most consistent predictor of neurodevelopmental outcome across domains.

Conclusions: Small fetal brain volume is a strong independent predictor of 2-year neurodevelopmental outcomes and may be an important imaging biomarker of future neurodevelopmental risk in CHD. Future studies are needed to support this hypothesis. Our findings support inclusion of fetal brain volume in risk stratification models and as a possible outcome in fetal neuroprotective intervention studies.

Keywords: brain; heart defects, congenital; magnetic resonance imaging.

Figure 1.

Reconstructed fetal brain MRI at 28 weeks in axial (left), coronal (middle), and sagittal (right) planes with brain structures segmented in bottom row. Red = Fetal cortex; Indigo = White matter; Yellow = Subcortical gray matter; Green = Diencephalon; Purple = Brainstem; Turqoise = Cerebellum.

Figure 2.. Recruitment and retention by group

The diagram depicts subject recruitment, exclusions, and neurodevelopmental assessment by group.

Figure 3.. Associations between fetal total brain volume residuals and neurodevelopmental outcomes.

Congenital heart disease (CHD) group is shown in red, control group in blue. Total brain volume refers to residual after adjustment of fetal total brain volume for sex and gestational age (linear and quadratic terms). Within-group correlations are shown. Interaction term significance shown in bottom right corner of each pane. *P < 0.05; **P < 0.01; ***P < 0.001.

Figure 4.. Bar plots depicting the contribution to the variance explained by each set of predictors in hierarchical regression models for each developmental domain.

Stage 1 included fetal total brain volume residual, Stage 2 could add demographic information (primary caregiver education, race, or fetal sex), Stage 3 could add cardiac class, Stage 4 could add birth weight, and Stage 5 could add postnatal medical variables (total support time, stroke or seizure, ECMO, or length of stay). ECMO = Extracorporeal membrane oxygenation