Prenatal head growth and white matter injury in hypoplastic left heart syndrome

Abstract

Children with hypoplastic left heart syndrome (HLHS) have an increased prevalence of central nervous system (CNS) abnormalities. The extent to which this problem is due to CNS maldevelopment, prenatal ischemia, postnatal chronic cyanosis and/or multiple exposures to cardiopulmonary bypass is unknown. To better understand the etiology of CNS abnormalities in HLHS, we evaluated 68 neonates with HLHS; in 28 cases, both fetal ultrasound and echocardiogram data were available to assess head size, head growth and aortic valve anatomy (atresia or stenosis). In addition, we evaluated neuropathology in 11 electively aborted HLHS fetuses. The mean head circumference percentile in HLHS neonates was significantly smaller than HLHS fetuses (22 +/- 2% versus 40 +/- 4%, p < 0.001). A significant decrease in head growth, defined as a 50% reduction in head circumference percentile, was observed in half (14/28) of HLHS fetuses and nearly a quarter (6/28) were already growth restricted (<or=10%) at the time of initial evaluation. Brains from HLHS fetuses demonstrated chronic diffuse white matter injury of varying severity. These patterns of prenatal head growth and brain histopathology identify a spectrum of abnormal CNS development and/or injury in HLHS fetuses.

Figure 1. Neonatal HLHS study population

Head circumference percentile in 68 HLHS neonates with those patients also analyzed as fetuses indicated by a “X”. The average head circumference percentile in this cohort was 22%. A significant number of neonates have microcephaly (≤3%) and head growth restriction (≤10%).

Figure 2. HLHS prenatal head growth

Head circumference percentile in 28 HLHS patients at fetal (left bar) and neonatal (right bar) time points (A). Patients are divided into three subgroups: normal head size and growth (Group 1, infants 1–8), normal head size and diminished head growth (Group 2, infants 9–22), and small head size (Group 3, infants 23–28). Black bars represent HLHS with aortic atresia; grey bars HLHS with aortic stenosis; and hatched bars AS. Head circumference percentile difference for each patient by subgroup is shown (B).

Figure 3. White matter injury in HLHS fetuses

Neuropathologic evaluation using antibodies directed against GFAP and CD68 in representative sections of the germinal plate and adjacent white matter in a 22-week HLHS fetus (A,B) and a 22-week Control fetus (C,D). In the HLHS fetus, there are extensive reactive astrocytes (A) and scattered activated microglia (B) consistent with white matter injury, while in the Control fetus, there is no reactive astrocytic hypertrophy (C) and minimal microglia (D). Scale bar = 100 µm; Images at 200X.