Brain volume and metabolism in fetuses with congenital heart disease: evaluation with quantitative magnetic resonance imaging and spectroscopy

Abstract

Background: Adverse neurodevelopmental outcome is an important source of morbidity in children with congenital heart disease (CHD). A significant proportion of newborns with complex CHD have abnormalities of brain size, structure, or function, which suggests that antenatal factors may contribute to childhood neurodevelopmental morbidity.

Methods and results: Brain volume and metabolism were compared prospectively between 55 fetuses with CHD and 50 normal fetuses with the use of 3-dimensinal volumetric magnetic resonance imaging and proton magnetic resonance spectroscopy. Fetal intracranial cavity volume, cerebrospinal fluid volume, and total brain volume were measured by manual segmentation. Proton magnetic resonance spectroscopy was used to measure the cerebral N-acetyl aspartate: choline ratio (NAA:choline) and identify cerebral lactate. Complete fetal echocardiograms were performed. Gestational age at magnetic resonance imaging ranged from 25 1/7 to 37 1/7 weeks (median, 30 weeks). During the third trimester, there were progressive and significant declines in gestational age-adjusted total brain volume and intracranial cavity volume in CHD fetuses relative to controls. NAA:choline increased progressively over the third trimester in normal fetuses, but the rate of rise was significantly slower (P<0.001) in CHD fetuses. On multivariable analysis adjusted for gestational age and weight percentile, cardiac diagnosis and percentage of combined ventricular output through the aortic valve were independently associated with total brain volume. Independent predictors of lower NAA:choline included diagnosis, absence of antegrade aortic arch flow, and evidence of cerebral lactate (P<0.001).

Conclusions: Third-trimester fetuses with some forms of CHD have smaller gestational age- and weight-adjusted total brain volumes than normal fetuses and evidence of impaired neuroaxonal development and metabolism. Hemodynamic factors may play an important role in this abnormal development.

Conflict of interest statement

Conflict of Interest Disclosures: None.

Figures

Figure 1

Fetal MR image reconstruction. Raw fetal MRI images (column A), fetal intracranial cavity extraction (column B), and fetal MRI images following intensity correction and slice alignment (column C).

Figure 2

Manual segmentation of Fetal MR coronal images. 3-D manual segmentation of intracranial cavity volume (red), total brain volume (blue) and cerebral spinal fluid (yellow) using coronal images.

Figure 3

In fetal MRS, the voxel of interest was placed in the cerebral hemisphere at the level of the centrum ovale.

Figure 4

Relationships between GA and A) ICV, B) TBV, C) CSF, and D) CSF:ICV in fetuses with CHD (open blue circles) and normal control fetuses (solid red diamonds). Regression equations for fetuses with CHD and controls are: A) ICV CHD = (16.272 × GA) − 265.04, ICV control = (18.744 × GA) − 319.20; B) TBV CHD = (16.081 × GA) − 315.78, TBV control = (20.886 × GA) − 439.41; C) CSF CHD = (0.30052 × GA2) + (-19.936 × GA) + 374.92, CSF control = (0.23769 × GA2) + (-16.768 × GA) + 333.42; D) CSF:ICV CHD = (0.002308 × GA2) + (-0.16478 × GA) + 3.0873, CSF:ICV control = (0.002534 × GA2) + (-0.17985 × GA) + 3.2988. The depicted R2 values reflect the goodness of fit for the fitted curve for each group, and not for the adjusted linear regression model.

Figure 5

Relationship between NAA:Cho and GA according to diagnosis. Fetuses with HLHS are indicated with blue circles (those with absence of antegrade blood flow in the transverse aortic arch are solid and others are open), fetuses with TGA or pulmonary atresia are indicated by the open black diamonds, and control fetuses and fetuses with other forms of CHD are indicated by the red triangles.