Hippocampal volume and cognitive performance in children with congenital heart disease.

BACKGROUND: Congenital heart disease (CHD) is associated with an increased risk of brain abnormalities. Studies indicate a particular vulnerability of the hippocampus to hypoxia and inflammation. Yet, information regarding the hippocampus and its relation to cognitive function in school-age children with CHD remains scarce. METHODS: Children who underwent cardiopulmonary bypass surgery for CHD (N = 17) and healthy controls (N = 14) at 10 years of age underwent neurodevelopmental assessment and cerebral magnetic resonance imaging to measure IQ, working memory performance and hippocampal volume. RESULTS: IQ was significantly lower in children with CHD compared to controls (98 vs 112, P = 0.02). Children with CHD showed worse working memory performance with significantly lower scores in the letter-number sequencing test (P = 0.02). After adjusting for total brain volume, hippocampal volume was smaller in children with CHD compared to controls (P < 0.01). Smaller hippocampal volume was associated with lower IQ (P = 0.04), and digit span scaled score (P = 0.03), but not with other working memory tests (P > 0.1). CONCLUSION: This study suggests that the hippocampus may be particularly susceptible in children with CHD thereby contributing to cognitive impairments. Further research is necessary to understand the contribution of the hippocampus to cognitive impairments in children with CHD. IMPACT: IQ is significantly lower in school-age children with congenital heart disease compared to controls. Working memory performance seems to be worse in children with congenital heart disease. Smaller hippocampal volume is associated with lower IQ and seems to be associated with lower working memory performance. The study adds knowledge on the etiology of cognitive impairments in school-age children with congenital heart disease.

Placental findings are not associated with neurodevelopmental outcome in neonates with hypoxic-ischemic encephalopathy - an 11-year single-center experience.

OBJECTIVES: Although neonates with moderate to severe hypoxic ischemic encephalopathy (HIE) receive therapeutic hypothermia (TH), 40-50% die or have significant neurological disability. The aim of this study is to analyse the association of placental pathology and neurodevelopmental outcome in cooled neonates with HIE at 18-24 months of age. METHODS: Retrospective analysis of prospectively collected data on 120 neonates registered in the Swiss National Asphyxia and Cooling Register born between 2007 and 2017. This descriptive study examines the frequency and range of pathologic findings in placentas of neonates with HIE. Placenta pathology was available of 69/120 neonates, whose results are summarized as placental findings. As neonates with HIE staged Sarnat score 1 (21/69) did not routinely undergo follow-up assessments and of six neonates staged Sarnat Score 2/3 no follow-up assessments were available, 42/48 (88%) neonates remain to assess the association between placental findings and outcome. RESULTS: Of the 42/48 (88%) neonates with available follow up 29% (12/42) neonates died. Major placenta abnormalities occurred in 48% (20/42). Major placenta abnormality was neither associated with outcome at 18-24 months of age (OR 1.75 [95% CI 0.50-6.36, p=0.381]), nor with death by 2 years of age (OR 1.96 [95% CI 0.53-7.78, p=0.320]). CONCLUSIONS: In this study cohort there could not be shown an association between the placenta findings and the neurodevelopmental outcome at 18-24 months of age.

Growth and Intellectual Abilities of Six-Year-Old Children with Congenital Heart Disease.

OBJECTIVE: To determine growth and its relationship to IQ in children with congenital heart disease (CHD) undergoing cardiopulmonary bypass surgery within the first year of life. STUDY DESIGN: Prospective single-center cohort study on 143 children (91 males) with different types of CHD (29 univentricular). Children with recognized genetic disorders were excluded. Growth (weight, height, and head circumference [HC]) was assessed at birth, before surgery, and at 1, 4, and 6 years and compared with Swiss growth charts. IQ was assessed at 6 years using standardized tests. Univariate and multivariable linear regressions were performed to determine predictors of HC and IQ at 6 years. RESULTS: HC at birth was in the low average range (33rd percentile, P = .03), and weight (49th percentile, P = .23) and length (47th percentile, P = .06) were normal. All growth measures declined until the first surgery, with a catch-up growth until 6 years for height (44th percentile, P = .07) but not for weight (39th percentile, P = .003) or for HC (23rd percentile, P < .001). Children undergoing univentricular palliation showed poorer height growth than other types of CHD (P = .01). Median IQ at 6 years was 95 (range 50-135). Lower IQ at 6 years was independently predicted by lower HC at birth, lower socioeconomic status, older age at first bypass surgery, and longer length of intensive care unit stay. CONCLUSIONS: Smaller HC at birth and postnatal factors are predictive of impaired intellectual abilities at school age. Early identification should alert clinicians to provide early childhood interventions to optimize developmental potential.

Neurodevelopmental Profiles of Children with Congenital Heart Disease at School Age.

OBJECTIVES: To assess 6-year neurodevelopmental outcomes in a current cohort of children with congenital heart disease (CHD) who underwent cardiopulmonary bypass surgery (CPB), and to determine risk factors for adverse outcomes. STUDY DESIGN: Outcomes were examined in 233 prospectively enrolled children with CHD (including 64 with a recognized genetic disorder) who underwent CPB between 2004 and 2009. Follow-up assessment included standardized neurologic, motor, and cognitive tests. Variables were collected prospectively, and multiple regression analysis was performed to determine independent risk factors for adverse outcome. RESULTS: The mean patient age at assessment was 6.3 years (range, 5.1-6.8 years). IQ was lower in children with a genetic disorder (median, 55; range, 17-115) compared with children without a genetic disorder (median, 95; range, 47-135; P < .001). Cognitive and motor performance also were lower in children without a genetic disorder compared with the norm (P < .01 for both). The prevalence of children without a genetic disorder performing below -2 SD (IQ 70) was higher than the norm (5.3% vs 2.3%; P = .008), and the prevalence of poor motor performance (<10th percentile) ranged from 21.2% to 41.1% (P < .01 for all). Significant independent risk factors for poor neurodevelopmental outcome included a genetic disorder, longer length of intensive care stay, lower birth weight, postoperative seizures, and lower socioeconomic status. CONCLUSIONS: Current cohorts of children with CHD undergoing CPB show favorable outcomes but remain at risk for long-term neurodevelopmental impairments, particularly those with a genetic disorder and a complicated postoperative course. Close neurodevelopmental surveillance is necessary to provide early therapeutic support.

Hippocampal volume reduction is associated with intellectual functions in adolescents with congenital heart disease.

BACKGROUND: Adolescents undergoing early cardiopulmonary bypass surgery for congenital heart disease (CHD) may demonstrate a variety of neurocognitive impairments. These impairments can affect overall intellectual functions, but also specific memory deficits, language, and executive functions. As the hippocampus is a critical structure involved in these functions, we sought to determine whether hippocampal volume was reduced in adolescents with CHD and whether altered volumes were related to functional outcome. METHODS: At a mean age of 13.8 y, 48 adolescent survivors of childhood cardiopulmonary bypass surgery for CHD and 32 healthy controls underwent neurocognitive testing and cerebral magnetic resonance imaging. Images were quantitatively analyzed using an automated regional segmentation tool (FSL-FIRST). RESULTS: Adolescents with CHD had 10% lower total hippocampal volumes compared with controls. After controlling for total brain volume, total hippocampal volume correlated with total IQ, with working memory, and verbal comprehension in CHD patients, but not in controls. CONCLUSIONS: In adolescent survivors of cardiopulmonary bypass surgery for CHD, specific brain regions such as the hippocampus may show long-term persistent alteration and correlate with intellectual deficits, particularly with verbal and memory functions.

Blood Lactate Levels during Therapeutic Hypothermia and Neurodevelopmental Outcome or Death at 18-24 Months of Age in Neonates with Moderate and Severe Hypoxic-Ischemic Encephalopathy.

INTRODUCTION: Blood lactate levels in neonates with hypoxic-ischemic encephalopathy (HIE) vary, and their impact on neurodevelopmental outcome is unclear. We assessed blood lactate course over time in neonates with HIE during therapeutic hypothermia (TH) and investigated if blood lactate values were associated with neurodevelopmental outcome at 2 years of age. METHODS: This is a retrospective cohort study of neonates with HIE born between 2013 and 2019, treated at the University Children's Hospital Zurich. We recorded blood lactate values over time and calculated time until lactate was ≤2 mmol/L. Neurodevelopmental outcome was assessed at 18-24 months of age using the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III), and categorized as favorable or unfavorable. We investigated associations between blood lactate values and outcome using logistic regression and adjusted for Sarnat stage. RESULTS: 33/45 neonates (69%) had a favorable and 14 (31%) an unfavorable neurodevelopmental outcome. Mean initial lactate values were lower in the favorable (13.9 mmol/L, standard deviation [SD]: 2.9) versus unfavorable group (17.1 mmol/L, SD 3.2; p = 0.002). Higher initial and maximal blood lactate levels were associated with unfavorable outcome, also when adjusted for Sarnat stage (adjusted odds ratio [aOR]: 1.37, 95% CI: 1.01-1.88, p = 0.046, and aOR: 1.35, 95% CI: 1.01-1.81, p = 0.041, respectively). CONCLUSION: In neonates with HIE receiving TH, initial and maximal blood lactate levels were associated with neurodevelopmental outcome at 18-24 months of age, also when adjusted for Sarnat stage. Further investigations to analyze blood lactate as a biomarker for prognostic value are needed.

Stress Markers, Executive Functioning, and Resilience Among Early Adolescents With Complex Congenital Heart Disease.

Importance: Infants with complex congenital heart disease (cCHD) may experience prolonged and severe stress when undergoing open heart surgery. However, little is known about long-term stress and its role in neurodevelopmental impairments in this population. Objective: To investigate potential differences between early adolescents aged 10 to 15 years with cCHD and healthy controls in physiological stress markers by hair analysis, executive function (EF) performance, and resilience. Design, Setting, and Participants: This single-center, population-based case-control study was conducted at the University Children's Hospital Zurich, Switzerland. Patients with different types of cCHD who underwent cardiopulmonary bypass surgery during the first year of life and who did not have a genetic disorder were included in a prospective cohort study between 2004 and 2012. A total of 178 patients were eligible for assessment at ages 10 to 15 years. A control group of healthy term-born individuals was cross-sectionally recruited. Data assessment was between 2019 and 2021. Statistical analysis was performed from January to April 2023. Exposure: Patients with cCHD who underwent infant open heart surgery. Main Outcomes and Measures: Physiological stress markers were quantified by summing cortisol and cortisone concentrations measured with liquid chromatography with tandem mass spectrometry in a 3-centimeter hair strand. EFs were assessed with a neuropsychological test battery to produce an age-adjusted EF summary score. Resilience was assessed with a standardized self-report questionnaire. Results: The study included 100 patients with cCHD and 104 controls between 10 and 15 years of age (mean [SD] age, 13.3 [1.3] years); 110 (53.9%) were male and 94 (46.1%) were female. When adjusting for age, sex, and parental education, patients had significantly higher sums of hair cortisol and cortisone concentrations (ß, 0.28 [95% CI, 0.12 to 0.43]; P < .001) and lower EF scores (ß, -0.36 [95% CI, -0.49 to -0.23]; P < .001) than controls. There was no group difference in self-reported resilience (ß, -0.04 [95% CI, -0.23 to 0.12]; P = .63). A significant interaction effect between stress markers and EFs was found, indicating a stronger negative association in patients than controls (ß, -0.65 [95% CI, -1.15 to -0.15]; P = .01). The contrast effects were not significant in patients (ß, -0.21 [95% CI, -0.43 to -0.00]; P = .06) and controls (ß, 0.09 [95% CI, -0.11 to 0.30]; P = .38). Conclusions and Relevance: This case-control study provides evidence for altered physiological stress levels in adolescents with cCHD and an association with poorer EF. These results suggest that future studies are needed to better understand the neurobiological mechanisms and timing of alterations in the stress system and its role in neurodevelopment.

Functional networks of working memory abilities in children with complex congenital heart disease: a sleep EEG study.

Working memory is frequently impaired in children with complex congenital heart disease (CHD), but little is known about the functional neuronal correlates. Sleep slow wave activity (SWA; 1-4.5 Hz EEG power) has previously been shown to reliably map neurofunctional networks of cognitive abilities in children with and without neurodevelopmental impairments. This study investigated whether functional networks of working memory abilities are altered in children with complex CHD using EEG recordings during sleep. Twenty-one children with complex CHD (aged 10.9 [SD: 0.3] years) and 17 typically-developing peers (10.5 [0.7] years) completed different working memory tasks and an overnight high-density sleep EEG recording (128 electrodes). The combined working memory score tended to be lower in children with complex CHD (CHD group: -0.44 [1.12], typically-developing group: 0.55 [1.24], d = 0.59, p = .06). The working memory score and sleep SWA of the first hour of deep sleep were correlated over similar brain regions in both groups: Strong positive associations were found over prefrontal and fronto-parietal brain regions - known to be part of the working memory network - and strong negative associations were found over central brain regions. Within these working memory networks, the associations between working memory abilities and sleep SWA (r between -.36 and .58, all p < .03) were not different between the two groups (no interactions, all p > .05). The current findings suggest that sleep SWA reliably maps working memory networks in children with complex CHD and that these functional networks are generally preserved in these patients.

White matter microstructure and executive functions in congenital heart disease from childhood to adulthood: A pooled case-control study.

Congenital heart disease (CHD) patients are at risk for alterations in the cerebral white matter microstructure (WMM) throughout development. It is unclear whether the extent of WMM alterations changes with age, especially during adolescence when the WMM undergoes rapid maturation. We investigated differences in WMM between patients with CHD and healthy controls from childhood until early adulthood in a pooled sample of children, adolescents, and young adults. The association between WMM and EF was assessed. Patients with CHD (N=78) and controls (N=137) between 9 and 32 years of age underwent diffusion tensor imaging and an executive function test-battery. Mean fractional anisotropy (FA) was calculated for each white matter tract. Linear regression tested age and group effects (CHD vs control) and their interaction on FA. Relative Variable Importance (RI) estimated the independent contribution of tract FA, presence of CHD, CHD complexity, and parental education to the variability in EF. Mean FA was lower in patients compared to controls in almost all tracts (p between 0.057 and <0.001). WMM alterations in patients were not different depending on age (all interaction effects p>0.074). Predictors of EF were CHD group (RI=43%), parental education (RI=23%), CHD complexity (RI=10%), FA of the hippocampal cingulum (RI=6%) and FA of the corticospinal tract (RI=6%). The lack of group-FA-interactions indicates that the extent of altered FA remains similar across age. Altered FA is associated with EF impairments. CHD is a chronic disease with cerebral and neurocognitive impairments persisting into adulthood and, thus, long-term follow-up programs may improve overall outcome for this population.

Postoperative Improvement of Brain Maturation in Infants With Congenital Heart Disease.

Children with severe congenital heart disease are at risk for neurodevelopmental impairments. We examined brain maturation in infants undergoing neonatal cardiopulmonary bypass surgery or hybrid procedure for hypoplastic left heart syndrome compared to controls. This is a prospective cohort study on term-born infants with congenital heart disease with cerebral MRI pre- and postoperatively. Healthy infants served as controls. Brain maturation was measured using a semiquantitative scoring system. The progress of brain maturation from the preoperative to postoperative MRI within patients was compared. Neurodevelopment was assessed at 1 year with the Bayley Scales of Infant and Toddler Development III. A total of 92 patients with congenital heart disease and 46 controls were studied. Median total maturation score in patients was 12 (interquartile range 10.6-13.0) preoperatively and 14 (12.0-15.0) postoperatively, in controls it was 14 (13.0-15.0). Median time interval between scans was 19 days (interquartile range 14-26). After correction for postmenstrual age at MRI, the pre- and postoperative maturation score was lower in patients compared to controls (preoperative P = 0.01, postoperative P = 0.03) and increased between pre- and postoperative assessment (P ≤ 0.001). Brain maturation scores did not correlate with neurodevelopmental outcome at 1 year, when corrected for socioeconomic status and postmenstrual age at MRI. This study confirms delayed brain maturation in children with congenital heart disease, and despite neonatal cardiac bypass surgery followed by postoperative intensive care medicine brain maturation is ongoing. We encourage further investigation in outcome prediction in this population, potentially by combining more advanced MRI measures with clinical methods.

Neurodevelopmental outcome of children with congenital heart disease.

Congenital heart disease (CHD) constitutes the most common congenital malformation, with moderate or severe CHD occurring in around 6 in 1000 live births. Due to advances in medical care, survival rates have increased significantly. Thus, the majority of children with CHD survive until adolescence and adulthood. Children with CHD requiring cardiopulmonary bypass surgery are at risk for neurodevelopmental impairments in various domains, including mild impairments in cognitive and neuromotor functions, difficulties with social interaction, inattention, emotional symptoms, and impaired executive function. The prevalence for these impairments ranges from 20% to 60% depending on age and domain ("high prevalence-low severity"). Domains are often affected simultaneously, leading to school problems with the need for learning support and special interventions. The etiology of neurodevelopmental impairments is complex, consisting of a combination of delayed intrauterine brain development and newly occurring perioperative brain injuries. Mechanisms include altered intrauterine hemodynamic flow as well as neonatal hypoxia and reduced cerebral blood flow. The surgical procedure and postoperative phase add to this cascade of factors interfering with normal brain development. Early identification of children at high risk through structured follow-up programs is mandated to provide individually tailored early interventions and counseling to improve developmental health.

Persistence of visuo-constructional and executive deficits in adolescents after open-heart surgery.

AIM: This study assesses whether previously reported performance deficiencies in visuo-constructional and executive functions, using the Rey-Osterrieth Complex Figure Test (ROCFT) in pediatric patients with congenital heart disease (CHD), persist into adolescence. METHODS: 53 adolescent CHD patients (mean age 13.7) and 39 healthy controls (mean age 14.1) participated. ROCFT performance was measured by three different scoring methods, focusing either on quantitative (Meyers & Meyers, 1995), qualitative (Wallon & Mesmin, 2009), or both performance aspects (Bernstein & Waber, 1996). Potential confounders (i.e., intelligence and visuomotor integration) and surgery-related risk factors were included in the data analysis. RESULTS: Adolescents with CHD demonstrated immature copy and recall approaches on the ROCFT using the qualitative system by Wallon and Mesmin (p<.001). Memory performance was also predicted by Bernstein and Waber scores (p<.03), whereas group differences were not significant according to the other scoring methods. Intelligence and visuomotor skills, but not surgery-related risk factors, were positively correlated with ROCFT performance (each p<.02). Interpretation: Visuoconstructional and executive deficiencies could be found in adolescent patients with CHD. However, not all ROCFT scoring methods were equally apt to detect group differences: especially the qualitative scoring method developed by Wallon and Mesmin seems sufficiently sensitive to detect long-lasting visuo-constructional and executive deficiencies in CHD patients.

Cerebral lesions on magnetic resonance imaging correlate with preoperative neurological status in neonates undergoing cardiopulmonary bypass surgery.

OBJECTIVES: To determine the prevalence, spectrum and course of cerebral lesions in neonates with congenital heart disease (CHD) undergoing full flow cardiopulmonary bypass (CPB) surgery using magnetic resonance imaging (MRI) and to examine the correlation between cerebral lesions and clinical neurological abnormalities. METHODS: Prospective cohort study of neonates with d-transposition of the great arteries (n = 22), univentricular heart malformation with hypoplastic aortic arch (n = 6) and aortic arch obstructions (n = 2) undergoing CPB. Neonates underwent cerebral MRI and blinded standardized neurological examination before (median day 6) and after surgery (day 13). The MRI findings were compared with those of 20 healthy controls. RESULTS: Preoperative cerebral lesions were present in 7 of 30 patients (23%) with isolated mild or moderate white matter injury (WMI) (n = 4), isolated small cerebral stroke (n = 1) and combined WMI and stroke (n = 2). None of the healthy controls had cerebral lesions on MRI. CHD neonates with preoperative cerebral lesions had more neurological abnormalities (P = 0.01) than neonates without cerebral lesions. Low arterial oxygen saturation (P = 0.03) was a risk factor for preoperative cerebral lesions, while balloon atrioseptostomy (P = 0.19) was not. After surgery, preoperative cerebral lesions persisted in 5 of 7 neonates, and 2 neonates (7%) showed signs of additional WMI in their postoperative MRI. CONCLUSIONS: In neonates with severe CHD, WMI was the predominant preoperative finding, while cerebral strokes were less frequent. New postoperative lesions were rare. Preoperative neurological abnormalities correlated with the presence of cerebral lesions on MRI.

Mortality and neurodevelopmental outcome at 1 year of age comparing hybrid and Norwood procedures.

OBJECTIVES: Neonates with hypoplastic left heart syndrome (HLHS) are at risk of high mortality and neurodevelopmental morbidity. As an alternative to Norwood-type stage I palliation, the hybrid procedure has been developed. It consists of bilateral pulmonary artery banding, catheter-based stenting of the arterial duct and balloon atrioseptostomy and delays open-heart surgery. Thus, it may be associated with a better outcome. The aim of this study was to determine the mortality and neurodevelopmental outcome in patients with HLHS and other univentricular heart (UVH) defects treated with hybrid or Norwood procedures. METHODS: Thirty-one children (18 males) with HLHS and other UVH defects undergoing Norwood or hybrid procedure between 2004 and 2008 were consecutively enrolled. Mortality and neurodevelopmental outcome at 1 year of age were determined. RESULTS: One-year mortality was 36% (31% in the hybrid vs. 39% in the Norwood group, P=0.71). Predictors of mortality were lower birth weight (P=0.02), older age at first procedure (P=0.02) and smaller size of ascending aorta (P=0.05). Overall, median psychomotor development index (PDI) and mental development index (MDI) of the Bayley Scales of Infant Development II were lower than the norm of 100 [PDI 57 (49-99), P<0.001; MDI 91 (65-109), P=0.002]. No effect of surgical treatment on neurodevelopmental outcome was found. Predictors of impaired motor outcome were length of hospital stay (LOHS) (P=0.01), lower body weight at second procedure (P=0.004) and female sex (P=0.01). Predictors of impaired cognitive outcome were longer mechanical ventilation time (P=0.03), intensive care unit stay (P=0.04) and LOHS (P<0.001), respectively. CONCLUSIONS: Mortality at 1 year of age is comparable between patients undergoing hybrid and Norwood procedures. Early neurodevelopmental outcome is significantly impaired in patients with both HLHS and other UVH defects. Multicentre randomized studies are needed to determine the long-term neurodevelopmental outcome of children treated with the hybrid procedure.