Microcephaly is associated with early adverse neurologic outcomes in hypoplastic left heart syndrome

nature publishing group Clinical Investigation Articles Microcephaly is associated with early adverse neurologic outcomes in hypoplastic left heart syndrome Patrick T. Hangge1, James F. Cnota1, Jessica G. Woo2, Andrea C. Hinton3, Allison A. Divanovic1, Peter B. Manning4, Richard F. Ittenbach2 and Robert B. Hinton1 Background: Hypoplastic left heart syndrome (HLHS) is associated with significant mortality and morbidity. Fetal head growth abnormalities have been identified in a subset of HLHS fetuses, but it is unclear whether specific patterns of maladaptive growth affect clinical outcomes. We hypothesized that poor fetal head growth is associated with an increased frequency of adverse clinical outcomes. Methods: We retrospectively examined a cohort of HLHS patients from midgestation to 1 y of age. Fetal and birth anthropometric measurements were analyzed using the Olsen standard, and clinical outcomes were obtained. Results: A total of 104 HLHS patients were identified over a 12-y period; fetal data were available in 38 cases. HLHS neonates demonstrated a high incidence of microcephaly (12%), small head size (27%), and poor head growth (32%). Allcause mortality was 31% at 30 d and 43% at 1 y. Neurologic outcomes were observed in 12% of patients and were significantly increased with microcephaly (43 vs. 4%; P = 0.02). The average length of hospital stay following stage I palliation was 33.4 ± 33 d, correcting for early death. Conclusion: In term nonsyndromic HLHS, fetal and neonatal microcephaly are associated with early adverse neurologic outcomes but not mortality. H ypoplastic left heart syndrome (HLHS) is a complex cardiovascular malformation (CVM) strictly defined as atresia or stenosis of the aortic and mitral valves and hypoplasia of the left ventricle and ascending aorta (1). HLHS is uniformly fatal without a series of palliative reconstructive surgeries in the first years of life. Despite dramatic improvements in treatment, HLHS continues to be associated with significant mortality and morbidities (2–4), including short- and long-term central nervous system (CNS) abnormalities (5–7). In addition, there is a rapidly growing population of adult survivors with chronic morbidities that are only now beginning to be understood (8). Although some surgical risk factors have been identified, such as the presence of a genetic syndrome, low birth weight (LBW, <2.5 kg), or a prohibitively small ascending aorta, our ability to predict adverse clinical outcomes remains limited (4,9,10). Understanding the noncardiac parameters of fetal HLHS may lead to the identification of new risk factors that may ultimately improve clinical management. Impaired postnatal growth is commonly associated with many types of CVM, including HLHS, and has been attributed to disruption of normal feeding behavior in the neonatal period. Postoperative failure to thrive is common, often requiring gastrostomy (G)-tube placement (11). Poor growth has been associated with genetic and environmental factors, but the prevailing view identifies a hypermetabolic state and malabsorption as common causes (11,12). However, increasing evidence shows that growth abnormalities begin before birth (11–13), suggesting the contribution of other necessary genetic and environmental factors. The majority of HLHS cases are now diagnosed in utero, contributing to increased survival, and are not typically associated with fetal demise (9,14). Given the complexity of development and growth in general, it remains unclear why some HLHS fetuses and infants have growth abnormalities and others do not. Late CNS outcomes have been observed in stage III surgical survivors at school age, including learning disabilities, attention-deficit hyperactivity disorder, fine and gross motor abnormalities, and speech and behavioral problems (2,15). The prevailing view is that chronic cyanosis and multiple cardiopulmonary bypass surgeries early in life lead to cognitive, motor, and behavioral deficits later in life (6,16). However, recent studies have implicated additional factors in the relationship between CNS abnormalities identified in neonates after birth but before surgery (17,18). Furthermore, early CNS abnormalities, including agenesis of the corpus callosum, as well as holoprosencephaly and microcephaly, have been identified in approximately one-quarter of HLHS neonates (5,15). Recently, we described poor fetal head growth and white matter injury despite normal brain weight in HLHS, identifying a spectrum of fetal CNS pathology (19). It is unknown whether these fetal head growth abnormalities are associated with adverse clinical outcomes. In this study, we examined fetal head growth and clinical outcomes in HLHS. There is an emerging interest in fetal Division of Cardiology, The Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; 2Division of Biostatistics and Epidemiology, Cincinnati Children’s ospital Medical Center, Cincinnati, Ohio; 3Division of Maternal Fetal Medicine, Good Samaritan Hospital, Cincinnati, Ohio; 4Division of Cardiothoracic Surgery, The Heart H Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio. Correspondence: Robert B. Hinton () 1 Received 28 June 2012; accepted 13 December 2012; advance online publication 15 May 2013. doi:10.1038/pr.2013.61 Volume 74 | Number 1 | July 2013      Pediatric Research  61 Articles Hangge et al. growth in the context of CVM, but its relationship to clinical course is largely unknown. We hypothesized that poor fetal head growth would be associated with an increased frequency of early adverse clinical outcomes. In term nonsyndromic HLHS, fetal and neonatal microcephaly is associated Table 1. Fetal and neonatal anthropometrics by timing of diagnosis All patients Fetal Neonatal 104 42 62 69 (66) 26 (62) 43 (69)    Aortic atresia/mitral atresia (n, %) 51 (55) 27 (64) 24 (48)    Aortic atresia/mitral stenosis (n, %) 21 (23) 5 (12) 16 (32)    Aortic stenosis/mitral stenosis (n, %) 20 (22) 10 (24) 10 (20) N General characteristics Male sex (n, %)  Newborn HLHS phenotype Fetal characteristics EGA (wk) 26.6 ± 5.0 NA Fetal weight (g) 1,211 ± 783 NA 61 ± 29 NA  SGA (weight ≤ 10th percentile) 3 (9%) NA Fetal HC (mm) 242 ± 47 NA Fetal HC percentile 46 ± 29 NA  Fetal microcephaly (HC ≤ 3rd percentile) 3 (8%) NA  Fetal small head (HC ≤ 10th percentile) 5 (13%) NA Fetal weight percentile with early adverse neurologic outcomes but not with mortality or other clinical outcomes. A better understanding of fetal growth, especially fetal head growth, may improve long-term risk stratification and counseling for late outcomes in HLHS and other CVM patients. RESULTS Study Population A total of 157 HLHS patients were identified at Cincinnati Children’s Hospital Medical Center over the 12-y period. Among the 104 patients who qualified for the study, there were 42 fetal diagnoses and anthropom (...truncated)