Total and Regional Brain Volumes in Fetuses With Congenital Heart Disease

Abstract

Background: Congenital heart disease (CHD) is common and is associated with impaired early brain development and neurodevelopmental outcomes, yet the exact mechanisms underlying these associations are unclear.

Purpose: To utilize MRI data from a cohort of fetuses with CHD as well as typically developing fetuses to test the hypothesis that expected cerebral substrate delivery is associated with total and regional fetal brain volumes.

Study type: Retrospective case-control study.

Population: Three hundred eighty fetuses (188 male), comprising 45 healthy controls and 335 with isolated CHD, scanned between 29 and 37 weeks gestation. Fetuses with CHD were assigned into one of four groups based on expected cerebral substrate delivery.

Field strength/sequence: T2-weighted single-shot fast-spin-echo sequences and a balanced steady-state free precession gradient echo sequence were obtained on a 1.5 T scanner.

Assessment: Images were motion-corrected and reconstructed using an automated slice-to-volume registration reconstruction technique, before undergoing segmentation using an automated pipeline and convolutional neural network that had undergone semi-supervised training. Differences in total, regional brain (cortical gray matter, white matter, deep gray matter, cerebellum, and brainstem) and brain:body volumes were compared between groups.

Statistical tests: ANOVA was used to test for differences in brain volumes between groups, after accounting for sex and gestational age at scan. P_FDR-values <0.05 were considered statistically significant.

Results: Total and regional brain volumes were smaller in fetuses where cerebral substrate delivery is reduced. No significant differences were observed in total or regional brain volumes between control fetuses and fetuses with CHD but normal cerebral substrate delivery (all P_FDR > 0.12). Severely reduced cerebral substrate delivery is associated with lower brain:body volume ratios.

Data conclusion: Total and regional brain volumes are smaller in fetuses with CHD where there is a reduction in cerebral substrate delivery, but not in those where cerebral substrate delivery is expected to be normal.

Evidence level: 3 TECHNICAL EFFICACY: Stage 3.

Keywords: MRI; congenital heart disease; fetal brain development.

Figure 1. Example 3D slice-to-volume reconstructions of T2-weighted fetal brain MR images in coronal (first row), axial (second row), and sagittal (third row) views.

These images were acquired at a gestational age of 34⁺⁰ weeks. Regional segmentations, based on the developing Human Connectome Project atlas segmentation protocol with 19 label regions of interest, generated by BOUNTI automated fetal brain MRI segmentation tool are shown in axial (bottom left) and coronal (bottom right) slices.

Figure 2. 3D representations of fetal brain MRI segmentations, for a fetus imaged at 34⁺⁰ weeks, from which total and regional volumes were generated.

Figure 3. Automatically generated whole-fetus segmentations, allowing estimation of total fetal body volumes, from T2-weighted balanced steady-state free precession (bSSFP) sequences.

Coronal bSSFP + segmentation (left), 3D fetal body rendering (middle), Sagittal bSSFP + segmentation (right).

Figure 4. Histograms showing counts for gestational age at the time of MRI scan for all 380 fetuses (192 female, 188 male) included in this study, classified according to their expected cerebral substrate delivery.

Figure 5. Scatter plots showing total brain tissue (top panel) and regional brain volumes across gestational age for 45 typically developing fetuses and 210 fetuses with CHD where cerebral substrate delivery is expected to be normal.

After accounting for sex and gestational age at scan, no significant group difference was seen in any brain tissue regions or CSF volumes (All P_FDR > 0.12) between these two groups.

Figure 6. Scatter plots showing total brain tissue (top panel) and regional brain volumes across gestational age for fetuses grouped according to expected cerebral substrate delivery for 380 fetuses.

There is a significant difference in total brain tissue (P_FDR = 4.8 × 10⁻⁸), cortical gray matter (top left; P_FDR = 8.3 × 10⁻⁶), white matter (top right; P_FDR = 1.19 × 10⁻⁸), deep gray matter (middle left; P_FDR = 3.7 × 10⁻⁵), cerebellum (middle right; P_FDR = 3.44 × 10⁻²), and brainstem (bottom left; P_FDR = 4.0 × 10⁻³) volumes between groups after accounting for sex and gestational age at scan, but not cerebrospinal fluid volumes (bottom right; P_FDR = 0.13).

Figure 7. Violin plots comparing brain:body volume ratios for 256 fetuses, grouped according to expected cerebral substrate delivery.

Fetuses with severely reduced cerebral substrate delivery have significantly lower brain:body ratios than those with normal cerebral substrate delivery (P_FDR = 0.004).