Delayed Cortical Development in Fetuses with Complex Congenital Heart Disease

Abstract

Neurologic impairment is a major complication of complex congenital heart disease (CHD). A growing body of evidence suggests that neurologic dysfunction may be present in a significant proportion of this high-risk population in the early newborn period prior to surgical interventions. We recently provided the first evidence that brain growth impairment in fetuses with complex CHD has its origins in utero. Here, we extend these observations by characterizing global and regional brain development in fetuses with hypoplastic left heart syndrome (HLHS), one of the most severe forms of CHD. Using advanced magnetic resonance imaging techniques, we compared in vivo brain growth in 18 fetuses with HLHS and 30 control fetuses from 25.4-37.0 weeks of gestation. Our findings demonstrate a progressive third trimester fall-off in cortical gray and white matter volumes (P < 0.001), and subcortical gray matter (P < 0.05) in fetuses with HLHS. Significant delays in cortical gyrification were also evident in HLHS fetuses (P < 0.001). In the HLHS fetus, local cortical folding delays were detected as early as 25 weeks in the frontal, parietal, calcarine, temporal, and collateral regions and appear to precede volumetric brain growth disturbances, which may be an early marker of elevated risk for third trimester brain growth failure.

Fetuses with Isolated Congenital Heart Defects Show Normal Cerebral and Extracerebral Fluid Volume Growth: A 3D Sonographic Study in the Second and Third Trimester

“…This finding has also been reported in an MRI study in TOF fetuses [22]. The hypothesis that the specific type of heart defect, such as HLHS and TOF, might play an important role in fetal cerebral development has been suggested in an increasing number of studies [10, 13, 26, 28, 29]. When specific types of CHD are studied in depth, it was furthermore found that neonates with minor CHD such as ventricular septal defects also demonstrate altered brain growth [30], which was the rationale for us to include minor CHD in our current study.…”

“…Previous MRI studies on brain volume or brain weight only report on third-trimester measurements, which makes comparison with our results difficult [11, 18, 19, 22-26]. Smaller brain volumes are previously demonstrated in mixed CHD types in the third trimester, but these studies comprise small cohorts and most importantly, they report on selected (severe), nonconsecutive cases, and some even included chromosomal abnormalities [18, 19].…”

Prevalence and Spectrum of In Utero Structural Brain Abnormalities in Fetuses with Complex Congenital Heart Disease

“…Together, these findings support the notion that delayed brain maturation is likely a direct consequence of the cardiac defect. In our previous studies of fetuses with CHD by using quantitative brain MR imaging techniques, we described a progressive third-trimester deceleration in cerebral growth 7 and delayed cortical maturation (in fetuses with HLHS) 8 compared with healthy fetuses. In the current study, 3 of these cases of suspected delay in brain maturation were detected by clinical MR imaging readings before the third trimester.…”

“…[3][4][5][6] More recently, our group has used quantitative MR imaging to demonstrate a progressive third-trimester deceleration in volumetric brain growth and metabolism in fetuses with CHD, 7 reduced volumes of gray (cortical and subcortical) and white matter, and significant delays in cortical gyrification and surface area in fetuses with hypoplastic left-heart syndrome (HLHS). 8 To date, there is only 1 published report of brain findings in fetuses with CHD by using conventional MR imaging. 9 This retrospective chart review of 53 cases reported a 39% incidence of brain anomalies in fetuses with CHD.…”

Severity of Fetal Brain Abnormalities in Congenital Heart Disease in Relation to the Main Expected Pattern of in utero Brain Blood Supply

“…However, recent neuroimaging [6,7], neuropathological [8] and clinical [9] studies have consistently demonstrated that fetuses and infants with CHD before postnatal surgery have evidence of abnormal neurodevelopment [10]. Moreover, we and others have shown how fetuses affected with CHD during the third trimester present brain metabolic [11,12] and structural alterations [12,13] by means of magnetic resonance imaging (MRI) and 1 H-magnetic resonance spectroscopy (MRS) studies. The identification of prenatal factors predicting neurodevelopmental impairment in CHD would facilitate future research on disease mechanisms and the introduction of early targeted interventions.…”