Placental Pathology Contributes to Impaired Volumetric Brain Development in Neonates With Congenital Heart Disease

Abstract

Background: Neonates with congenital heart disease are at risk for impaired brain development in utero, predisposing children to postnatal brain injury and adverse long-term neurodevelopmental outcomes. Given the vital role of the placenta in fetal growth, we assessed the incidence of placental pathology in fetal congenital heart disease and explored its association with total and regional brain volumes, gyrification, and brain injury after birth.

Methods and results: Placentas from 96 term singleton pregnancies with severe fetal congenital heart disease were prospectively analyzed for macroscopic and microscopic pathology. We applied a placental pathology severity score to relate placental abnormalities to neurological outcome. Postnatal, presurgical magnetic resonance imaging was used to analyze brain volumes, gyrification, and brain injuries. Placental analyses revealed the following abnormalities: maternal vascular malperfusion lesions in 46%, nucleated red blood cells in 37%, chronic inflammatory lesions in 35%, delayed maturation in 30%, and placental weight below the 10th percentile in 28%. Severity of placental pathology was negatively correlated with cortical gray matter, deep gray matter, brainstem, cerebellar, and total brain volumes (r=-0.25 to -0.31, all P<0.05). When correcting for postmenstrual age at magnetic resonance imaging in linear regression, this association remained significant for cortical gray matter, cerebellar, and total brain volume (adjusted R²=0.25-0.47, all P<0.05).

Conclusions: Placental pathology occurs frequently in neonates with severe congenital heart disease and may contribute to impaired brain development, indicated by the association between placental pathology severity and reductions in postnatal cortical, cerebellar, and total brain volumes.

Keywords: brain development; congenital heart disease; fetus; magnetic resonance imaging; neonate; neuroplacentology; placenta.

Figure 1. Volumetric segmentation of brain structures.

Volumetric tissue segmentation, of the cortical gray matter, white matter, deep gray matter, brainstem, hippocampus‐amygdala, cerebellum, ventricles (not included in analysis), and extracerebral CSF (not included in analysis) on T2‐weighted magnetic resonance imaging in coronal (left), sagittal (middle), and axial (right) planes. CSF indicates cerebrospinal fluid.

Figure 2. Linear regression analyses between the placental pathology severity score and postnatal brain volumes.

Cerebral variables showing a significant correlation with the placental pathology severity score were entered as a dependent variable in linear regression models, with the placental pathology severity score as independent variable, covarying for postmenstrual age at MRI. *P<0.05. GM indicates gray matter.