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 Ϯ 2% versus 40 Ϯ 4%, p Ͻ 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 (Յ10%) 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. remains a significant cause of infant mortality and long-term morbidity despite significant advances in diagnosis and treatment (1-4). HLHS patients have an increased prevalence of central nervous system (CNS) abnormalities, which have been attributed to chronic cyanosis and multiple exposures to cardiopulmonary bypass (5,6). However, results from several studies indicate that in approximately one half of cases, CNS abnormalities are present at birth (4,7-10) and may manifest as reduced head circumference or microcephaly in the neonate (10 -12). It is unknown at what stage of development these CNS abnormalities occur and whether this represents a primary CNS developmental abnormality or a secondary insult resulting from alterations in cerebral blood flow due to HLHS.Little is known of the etiology of HLHS. Evidence supporting both genetic (13-15) and epigenetic (16 -18) factors has been reported. A widely accepted hypothesis is that HLHS develops as a result of alterations in embryonic intracardiac blood flow, such as narrowing of the foramen ovale and aortic stenosis (AS) (16 -18). Longitudinal studies of the fetus have shown that AS is part of the in utero natural history of HLHS (19,20); for this reason, there has been considerable interest in developing indications for fetal intervention for AS (21,22). By adversely affecting antegrade aortic blood flow, early progression of aortic valve obstruction may reduce cerebral blood flow, thereby adversely impacting CNS development and subsequent head growth. This possibility is supported by identification of white matter injury, reminiscent of periventricular leukomalacia, in term neonates with HLHS before surgical intervention (23)(24)(25). Neuropathologic findings have also identified white matter injury in postoperativ...

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