Fetal brain growth and risk of postnatal white matter injury in critical congenital heart disease

Abstract

Objective: To test the hypothesis that delayed brain development in fetuses with d-transposition of the great arteries or hypoplastic left heart syndrome heightens their postnatal susceptibility to acquired white matter injury.

Methods: This is a cohort study across 3 sites. Subjects underwent fetal (third trimester) and neonatal preoperative magnetic resonance imaging of the brain to measure total brain volume as a measure of brain maturity and the presence of acquired white matter injury after birth. White matter injury was categorized as no-mild or moderate-severe based on validated grading criteria. Comparisons were made between the injury groups.

Results: A total of 63 subjects were enrolled (d-transposition of the great arteries: 37; hypoplastic left heart syndrome: 26). White matter injury was present in 32.4% (n = 12) of d-transposition of the great arteries and 34.6% (n = 8) of those with hypoplastic left heart syndrome. Overall total brain volume (taking into account fetal and neonatal scan) was significantly lower in those with postnatal moderate-severe white matter injury compared with no-mild white matter injury after adjusting for age at scan and site in d-transposition of the great arteries (coefficient: 14.8 mL, 95% confidence interval, -28.8 to -0.73, P = .04). The rate of change in total brain volume from fetal to postnatal life did not differ by injury group. In hypoplastic left heart syndrome, no association was noted between overall total brain volume and change in total brain volume with postnatal white matter injury.

Conclusions: Lower total brain volume beginning in late gestation is associated with increased risk of postnatal moderate-severe white matter injury in d-transposition of the great arteries but not hypoplastic left heart syndrome. Rate of brain growth was not a risk factor for white matter injury. The underlying fetal and perinatal physiology has different implications for postnatal risk of white matter injury.

Keywords: brain development; brain injury; congenital heart disease; neurodevelopment.

Figure 1.

Fetal brain volumetry in a fetus with congenital heart disease with segmentation of a 3-dimensional steady-state free-precession acquisition to measure total brain volume. Three orthogonal planes are depicted with the final volumetric image of the fetal brain.

Figure 2.. Rate of change in total brain volume from fetal to postnatal life in subjects with d-transposition of the great arteries(d-TGA) (A) and hypoplastic left heart syndrome (HLHS) (B) by white matter injury (WMI) severity.

The plots include fetal and neonatal brain MRI measures with a line connecting the fetal to neonatal measurement for each subject (light orange and light red) as well as a best-fitted line. The orange and light orange lines represent those with moderate to severe WMI and the red and light red lines represent those with none or mild WMI. The x-axis represents gestational age at the time of MRI and the y-axis represents total brain volume in mL. A) Among d-TGA subjects, overall total brain volume is significantly lower among those with acquired neonatal moderate to severe WMI after adjusting for gestational age at scan and site (p= 0.04) with no difference noted in rate of growth between the two time points by injury status (p=0.27); B) Among HLHS subjects, there was no significant difference in overall total brain volume or rate of growth by injury status.

Figure 3.. Rate of change in total brain volume from fetal to postnatal life by cardiac diagnosis group, d-transposition of the great arteries (d-TGA) or hypoplastic left heart syndrome (HLHS).

The plots include fetal and neonatal brain MRI measures with a line connecting the fetal to neonatal measurement for each subject (light blue and light green) as well as a best-fitted line. The blue and light blue lines represent those with d-TGA and the green and light green lines represent those with HLHS. The x-axis represents gestational age at the time of MRI and the y-axis represents total brain volume in mL. No difference was noted in overall total brain volume or in the rate of change from fetal to neonatal life between the two cardiac groups (p= 0.16).

Figure 4:

Graphical summary of study findings. A total of 63 subjects were included of which 37 had d-transposition of the great arteries (D-TGA) and 26 had hypoplastic left heart syndrome (HLHS). Subjects underwent a fetal brain MRI in the 3^rd trimester followed by a neonatal MRI prior to their cardiac operation.

Central Picture:

Fetal brain volumetry in a fetus with congenital heart disease. Segmentation of a 3-dimensional steady-state free-precession acquisition was performed to measure total brain volume. The image depicted is the final volumetric image of the fetal brain. Central Message: Smaller total brain volume beginning in utero is associated with acquired clinically significant white matter injury after birth among those with d-transposition of the great arteries.