The implementation of EMI-Heart, a family-tailored early motor intervention in infants with complex congenital heart disease, in practice: a feasibility RCT.

BACKGROUND: Children with congenital heart disease (CHD) who undergo open-heart surgery are at risk of developmental impairment, including motor delay, which contributes to parental concerns. Additionally, parents experience prolonged stress associated with their child's disease. There is a lack of early motor interventions in infants with CHD accounting for parental burdens. We developed a family-tailored early motor intervention (EMI-Heart), aiming to promote motor development in infants with CHD and family well-being. The primary aim was to evaluate the feasibility of the study design and the intervention. The secondary aim was to evaluate differences between the intervention and the control group in motor outcomes and family well-being at baseline (3-5 months), post-treatment (6-8 months), and at follow-up (12 months). METHOD: In this single-centre feasibility randomized control trial (RCT), infants with CHD after open-heart surgery without genetic or major neurological comorbidities were randomly allocated to EMI-Heart or the control group (standard of care). EMI-Heart's key elements promote postural functional activities and encourage parental sensitivity to infants' motor and behaviour cues. Infants assigned to EMI-Heart received nine sessions of early motor intervention at home, in the hospital, and online for a duration of 3 months by a paediatric physiotherapist. We performed descriptive statistics for feasibility and secondary outcomes. RESULTS: The recruitment rate was 59% (10/17), all participating families completed the study (10/10), and the intervention duration was 3.9 months (± 0.54), including nine intervention sessions per family. Median acceptability to parents was 3.9 (1 = not agree-4 = totally agree, Likert scale). The paediatric physiotherapist considered the intervention as feasible. The comparison of motor outcomes did not show differences between groups. However, we detected improved reliable change scores in family well-being outcomes for families of the intervention group compared to the controls. CONCLUSIONS: Our research indicates that EMI-Heart is a feasible intervention for infants with CHD after open-heart surgery. The intervention was highly acceptable both to parents and to the paediatric physiotherapist. Online treatment sessions offer a valuable alternative to home and hospital visits. This feasibility RCT provides a foundation for a future full trial. TRIAL REGISTRATION: ClinicalTrials.gov, NCTT04666857. Registered 23.11.2020.

Impact of postoperative necrotizing enterocolitis after neonatal cardiac surgery on neurodevelopmental outcome at 1 year of age.

Objectives: We analyzed the impact of postoperative necrotizing enterocolitis (NEC) after cardiac surgery in neonatal age on neurodevelopmental (ND) outcome at 1 year of age. Methods: Using data from the Swiss Neurodevelopmental Outcome Registry for Children with Congenital Heart Disease (ORCHID), we analyzed perioperative variables including postoperative NEC (Bell's stage ≥2) and 1-year ND outcome (Bayley III). Results: The included patients (n = 101) had congenital heart disease (CHD), categorized as follows: 77 underwent biventricular repair for CHD with two functional chambers, 22 underwent staged palliation until the Fontan procedure for CHD with single ventricle physiology (n = 22), or 4 underwent single ventricle palliation or biventricular repair for borderline CHD (n = 4). Neonatal cardiopulmonary bypass (CBP) surgery was performed at a median age (IQR) of 8 (6) days. NEC occurred in 16 patients. Intensive care unit (ICU) length of stay (LOS) and the total duration of the hospitalization were longer in children with NEC than those in others (14 with vs. 8 days without NEC, p < 0.05; 49 with vs. 32 days without NEC, p < 0.05). The Bayley III scores of the analyzed patients determined at an age of 11.5 ± 1.5 months showed cognitive (CCS) (102.2 ± 15.0) and language scores (LCS) (93.8 ± 13.1) in the normal range and motor composite scores (MCS) (88.7 ± 15.9) in the low-normal range. After adjusting for socioeconomic status and CHD type, patients with NEC had lower CCS scores [ß = -11.2 (SE 5.6), p = 0.049]. Using a cumulative risk score including NEC, we found a higher risk score to be associated with both lower CCS [ß = -2.8 (SE 1.3), p = 0.030] and lower MCS [ß = -3.20 (SE 1.3), p = 0.016]. Conclusions: Postoperative NEC is associated with longer ICU and hospital LOS and contributes together with other complications to impaired ND outcome at 1 year of age. In the future, national and international patient registries may provide the opportunity to analyze large cohorts and better identify the impact of modifiable perioperative risk factors on ND outcome. Clinical Trial Registration: ClinicalTrials.gov identifier: NCT05996211.

Heart rate variability and cognitive functions in adolescents with complex congenital heart disease.

BACKGROUND: Heart Rate Variability (HRV) originates from the interplay between parasympathetic/sympathetic inputs to the heart, thus serving as an indicator of Autonomic Nervous System regulation. Prior research indicates that decreased HRV, marked by reduced autonomic balance, is related to poorer cognitive performance. While the population with congenital heart disease (CHD) show changes in HRV linked with the heart defect, the association between HRV and cognitive functions in CHD remains unexplored. METHODS: 46 adolescents with CHD who went through infant open-heart surgery and 64 healthy controls (50.9% males, 12.8 ± 1.4 years) underwent neurodevelopmental testing and photoplethysmograph acquisition. Group differences and associations with cognitive functions were analysed with linear regression. P values were FDR-corrected. RESULTS: Adolescents with CHD showed lower HRV (quantified by high-frequency power) compared to controls (p < 0.001). Lower HRV was correlated with worse executive function (ß = 0.24, p = 0.044) and lower IQ (ß = 0.26, p = 0.010) in the whole sample and with lower IQ (ß = 0.35, p = 0.014) in the CHD group. These associations were robust to confounders, including age, sex, and socioeconomic status. CONCLUSION: Our findings demonstrate an association between HRV and cognitive functions in adolescents with complex CHD. Early detection of alterations in HRV/autonomic regulation may help to identify children with CHD at risk for cognitive impairments. IMPACT: Adolescents with congenital heart disease (CHD) showed lower heart rate variability (HRV), indicating an imbalanced autonomic nervous system. Lower HRV was associated with lower IQ and executive function (EF) in the whole sample. The association between HRV and IQ was significantly stronger in CHD than in healthy controls. This study provides the first evidence of a link between altered HRV and cognitive impairments in the CHD population. Neurodevelopmental impairments seen in adolescents with CHD could be linked to their altered cardiac autonomic nervous activity, marked by low HRV.

Processing Speed Partially Mediates Executive Function Impairments in Adolescents with Congenital Heart Disease: Results from a Prospective Cohort Study.

OBJECTIVE: To assess processing speed, fine motor function, attention, and executive function (EF) impairments in adolescents with complex congenital heart disease (CHD) who underwent open-heart surgery during infancy. STUDY DESIGN: We administered a comprehensive neuropsychological test battery evaluating 5 EF domains: working memory, inhibition, cognitive flexibility, fluency, and planning and primary neurodevelopmental processes (PNPs): processing speed, fine motor function, and attention. The sample included 100 adolescents with complex CHD from a previous University Children's Hospital Zurich study, with 104 healthy controls for comparison. We generated scores for each EF domain and computed an EF summary score. Group comparisons and associations were analyzed with multiple regressions accounting for parental education. Mediation analysis explored how PNPs mediate the effect between a CHD diagnosis and EF. RESULTS: In adolescents with complex CHD, all EF domains and the EF summary score were impaired (ß = 0.20 to 0.37, all P < .05). Furthermore, they exhibited slower processing speed (ß = 0.27, P < .01) than healthy controls, with no differences in attention (ß = -0.07, P = .34) and fine motor function (ß = 0.08, P = .34). Processing speed showed a strong association with the EF summary score (ß = 0.60, P < .001) and partially mediated the relationship between CHD diagnosis and the EF summary score (ß = 0.37, 95% CI [0.24, 0.50], P < .001). CONCLUSION: Adolescents with complex CHD show difficulties in EFs and processing speed. Notably, processing speed is strongly associated with EFs and partly accounts for EFs disparities between patients and healthy controls. Early detection and interventions for processing speed difficulties may improve EF outcomes in these patients.

Effects of hemodynamic alterations and oxygen saturation on cerebral perfusion in congenital heart disease.

BACKGROUND: Patients with severe congenital heart disease (CHD) are at risk for neurodevelopmental impairment. An abnormal cerebral blood supply caused by the altered cardiac physiology may limit optimal brain development. The aim of this study was to evaluate the effect of a systemic-to-pulmonary shunt, aortic arch obstruction and arterial oxygen saturation on cerebral perfusion in patients with severe CHD. METHODS: Patients with severe CHD requiring cardiac surgery within the first six weeks of life, who underwent pre- and/or postoperative brain magnetic resonance imaging (MRI), and healthy controls with one postnatal scan were included. Cerebral perfusion in deep and cortical gray matter was assessed by pseudocontinuous arterial spin labeling MRI. RESULTS: We included 59 CHD and 23 healthy control scans. The presence of a systemic-to-pulmonary shunt was associated with decreased perfusion in cortical (p = 0.003), but not in deep gray matter (p = 0.031). No evidence for an effect of aortic arch obstruction and arterial oxygen saturation on cerebral perfusion was found. After adjusting for hemodynamic and oxygen saturation parameters, deep (p = 0.018) and cortical (p = 0.012) gray matter perfusion was increased in patients with CHD compared to controls. CONCLUSION: We detected regional differences in compensation to the cerebral steal effect in patients with severe CHD. IMPACT: Patients with severe congenital heart disease (CHD) have altered postnatal brain hemodynamics. A systemic-to-pulmonary shunt was associated with decreased perfusion in cortical gray matter but preserved perfusion in deep gray matter, pointing towards regional differences in compensation to the cerebral steal effect. No effects of aortic arch obstruction and arterial oxygenation on cerebral perfusion were seen. Cerebral perfusion was increased in patients with CHD compared to healthy controls after adjusting for hemodynamic alterations and oxygen saturation. To improve neuroprotection and neurodevelopmental outcomes, it is important to increase our understanding of the factors influencing cerebral perfusion in neonates with severe CHD.

Perioperative Brain Injury in Relation to Early Neurodevelopment Among Children with Severe Congenital Heart Disease: Results from a European Collaboration.

OBJECTIVE: To examine the relationship between perioperative brain injury and neurodevelopment during early childhood in patients with severe congenital heart disease (CHD). STUDY DESIGN: One hundred and seventy children with CHD and born at term who required cardiopulmonary bypass surgery in the first 6 weeks after birth were recruited from 3 European centers and underwent preoperative and postoperative brain MRIs. Uniform description of imaging findings was performed and an overall brain injury score was created, based on the sum of the worst preoperative or postoperative brain injury subscores. Motor and cognitive outcomes were assessed with the Bayley Scales of Infant and Toddler Development Third Edition at 12 to 30 months of age. The relationship between brain injury score and clinical outcome was assessed using multiple linear regression analysis, adjusting for CHD severity, length of hospital stay (LOS), socioeconomic status (SES), and age at follow-up. RESULTS: Neither the overall brain injury score nor any of the brain injury subscores correlated with motor or cognitive outcome. The number of preoperative white matter lesions was significantly associated with gross motor outcome after correction for multiple testing (P = .013, ß = -0.50). SES was independently associated with cognitive outcome (P < .001, ß = 0.26), and LOS with motor outcome (P < .001, ß = -0.35). CONCLUSION: Preoperative white matter lesions appear to be the most predictive MRI marker for adverse early childhood gross motor outcome in this large European cohort of infants with severe CHD. LOS as a marker of disease severity, and SES influence outcome and future intervention trials need to address these risk factors.

Thalamic connectivity topography in newborns with spina bifida: association with neurological functional level but not developmental outcome at 2 years.

Spina bifida affects spinal cord and cerebral development, leading to motor and cognitive delay. We investigated whether there are associations between thalamocortical connectivity topography, neurological function, and developmental outcomes in open spina bifida. Diffusion tensor MRI was used to assess thalamocortical connectivity in 44 newborns with open spina bifida who underwent prenatal surgical repair. We quantified the volume of clusters formed based on the strongest probabilistic connectivity to the frontal, parietal, and temporal cortex. Developmental outcomes were assessed using the Bayley III Scales, while the functional level of the lesion was assessed by neurological examination at 2 years of age. Higher functional level was associated with smaller thalamo-parietal, while lower functional level was associated with smaller thalamo-temporal connectivity clusters (Bonferroni-corrected P < 0.05). Lower functional levels were associated with weaker thalamic temporal connectivity, particularly in the ventrolateral and ventral anterior nuclei. No associations were found between thalamocortical connectivity and developmental outcomes. Our findings suggest that altered thalamocortical circuitry development in open spina bifida may contribute to impaired lower extremity function, impacting motor function and independent ambulation. We hypothesize that the neurologic function might not merely be caused by the spinal cord lesion, but further impacted by the disruption of cerebral neuronal circuitry.

Long-term intellectual and developmental outcomes after pediatric epilepsy surgery: A systematic review and meta-analysis.

In addition to the primary aim of seizure freedom, a key secondary aim of pediatric epilepsy surgery is to stabilize and, potentially, optimize cognitive development. Although the efficacy of surgical treatment for seizure control has been established, the long-term intellectual and developmental trajectories are yet to be delineated. We conducted a systematic review and meta-analysis of studies reporting pre- and postsurgical intelligence or developmental quotients (IQ/DQ) of children with focal lesional epilepsy aged ≤18 years at epilepsy surgery and assessed at >2 years after surgery. We determined the IQ/DQ change and conducted a random-effects meta-analysis and meta-regression to assess its determinants. We included 15 studies reporting on 341 patients. The weighted mean age at surgery was 7.1 years (range = .3-13.8). The weighted mean postsurgical follow-up duration was 5.6 years (range = 2.7-12.8). The overall estimate of the mean presurgical IQ/DQ was 60 (95% confidence interval [CI] = 47-73), the postsurgical IQ/DQ was 61 (95% CI = 48-73), and the change was +.94 IQ/DQ (95% CI = -1.70 to 3.58, p = .486). Children with presurgical IQ/DQ ≥ 70 showed a tendency for higher gains than those with presurgical IQ/DQ < 70 (p = .059). Higher gains were determined by cessation of antiseizure medication (ASM; p = .041), not just seizure freedom. Our findings indicate, on average, stabilization of intellectual and developmental functioning at long-term follow-up after epilepsy surgery. Once seizure freedom has been achieved, ASM cessation enables the optimization of intellectual and developmental trajectories in affected children.

Motor function outcomes in children with open prenatal repair of Spina Bifida Aperta at 36-month follow-up: The Zurich cohort.

PURPOSE: This study aimed to describe outcomes of motor function with a special focus on ambulation ability at 36 months among children with open prenatal repair of spina bifida aperta (SB). METHODS: A prospective cohort study was conducted including 87 patients with open prenatal repair of SB at the investigating center born between 2010 and 2018. Anatomic lesion level and motor function level in the neonatal period, as well as motor function level, ambulation status, and use of orthotics and assistive devices at 36 months were assessed. RESULTS: At 36 months, ambulation was assessed in 86 children; of those, 86% (n = 74) were ambulating. Independent of ambulation, orthotics were worn in 81.6% (71/87) and assistive devices in 47.1% (41/87). Children with a lower lumbar or sacral motor function level were the first to reach independent ambulation and were more likely to ambulate at 36 months than children with higher motor function levels (p = < .001). The anatomic lesion level determined on the neonatal MRI correlated with ambulation status at 36 months (p = < 0.001). CONCLUSION: At 36 months, most children with open prenatal repair for SB showed favourable ambulation status. However, most still used assistive devices or orthotics. Anatomic lesion level on neonatal MRI, motor function level during the neonatal period, and motor function level at 36 months were associated with ambulation status at 36 months.

Multimodal personalised executive function intervention (E-Fit) for school-aged children with complex congenital heart disease: protocol for a randomised controlled feasibility study.

INTRODUCTION: Children with congenital heart disease (CHD) are at risk for executive functions (EF) impairments. To date, interventions have limited effects on EF in children and adolescents with complex CHD. Therefore, we developed a new multimodal and personalised EF intervention (E-Fit). This study aims to test the feasibility of this intervention called 'E-Fit' for children with complex CHD and EF impairments. METHODS AND ANALYSIS: This is a single-centre, single-blinded, randomised controlled feasibility study exploring the E-Fit intervention. We aim to enrol 40 children with CHD aged 10-12 years who underwent infant cardiopulmonary bypass surgery and show clinically relevant EF impairments (T-score ≥60 on any Behaviour Rating Inventory for Executive Function questionnaire summary scale). The multimodal intervention was developed with focus groups and the Delphi method involving children and adolescents with CHD, their parents and teachers, and health professionals. The intervention is composed of three elements: computer-based EF training using CogniFit Inc 2022, performed three times a week at home; weekly EF remote strategy coaching and analogue games. The content of the computer and strategy training is personalised to the child's EF difficulties. The control group follows their daily routines as before and completes a diary about their everyday activities four times a week. Participants will be randomised in a 1:1 ratio. Feasibility is measured by the participants' and providers' ratings of the participants' adherence and exposure to the intervention, recruitment rates and the evaluation of the intended effects of the programme. ETHICS AND DISSEMINATION: Local ethics committee approval was obtained for the study (BASEC-Nr: 2021-02413). Parents provide written informed consent. Key outputs from the trial will be disseminated through presentations at conferences, peer-reviewed publications and directly to participating families. Furthermore, these results will inform the decision whether to proceed to a randomised controlled trial to investigate effectiveness. TRIAL REGISTRATION NUMBER: NCT05198583.

A systematic review of early motor interventions for infants with congenital heart disease and open-heart surgery.

BACKGROUND: Motor development delay is the first neurodevelopmental impairment that becomes apparent in infants with congenital heart disease (CHD). Early interventions have addressed high-risk groups like infants born preterm, but little is known about interventions to improve motor outcome in CHD infants at risk of motor delay. The purpose of this review was to systematically review the literature on type and effect of motor intervention applied during the first year of life in infants with CHD following open-heart surgery. METHODS: Scoping searches were performed in May 2020 and April 2023 via MEDLINE, Embase, CINAHL, Cochrane, PsycINFO, PEDro, and Scopus. The review included studies published in English from 2015 to 2022. Primary outcome was infants' motor development measured by standardized and non-standardized motor assessments, and if available, infants' language and cognitive development, and any parental quality-of-life assessments as secondary outcomes. The studies' quality was evaluated with a modified Newcastle-Ottawa scale. RESULTS: Four papers with low to high methodological quality met inclusion criteria. All studies investigated the influence of early physiotherapy. Four studies involved parents, and three studies used standardized tools to assess motor outcomes. No conclusion can be drawn about any positive effect of early motor interventions. CONCLUSIONS: Early motor intervention in CHD infants may improve motor development; however, the few existing studies do not provide clear evidence. Thus, more prospective early intervention studies are needed. TRIAL REGISTRATION: PROSPERO CRD42020200981.

Long-term neurodevelopmental outcome and serial cerebral magnetic resonance imaging assessment in Fontan patients at school age.

OBJECTIVES: Children with univentricular congenital heart disease undergoing staged surgical palliation are at risk for impaired neurodevelopmental (ND) outcome. Little is known about the long-term effects on brain growth until school age. METHODS: In a prospective two-centre study, consecutive patients undergoing stage I (Hybrid or Norwood) to stage III (Fontan procedure) were evaluated by 2 serial cerebral magnetic resonance imaging examinations, somatic growth and ND testing before Fontan procedure at 2 years of age (Bayley-III) and after Fontan at 6-8 years of age (Wechsler Intelligence Scale for Children-third edition). Magnetic resonance imaging findings were compared with 8 healthy controls. Medical and sociodemographic characteristics were documented and related to cerebral and ND findings. RESULTS: We examined 33 children (16 female) at a mean age of 2.3 (0.35) and 6.8 (± 0.7) years. The mean Bayley-III cognitive scales were 99.1 (9.9), language scales 98.4 (11.9) and motor scales 98.5 (13.8) at the first examination. Follow-up at school age showed a mean total IQ of 86.7 (13.6). The rate of structural brain lesions increased from 39% at 2 years to 58% at school age. Bayley-III language scale (P = 0.021) and mean Wechsler Intelligence Scale for Children-third edition (P = 0.019) were lower in children with pathological MR findings. Total brain volume (P < 0.001), total grey matter volume (P = 0.002), deep grey matter volume (P = 0.001) and white matter volume (P < 0.001) were smaller in patients compared to age- and gender-matched healthy controls. CONCLUSIONS: Smaller brain volumes and structural brain lesions in complex congenital heart defect patients at school age are associated with impaired ND outcome. For the evaluation of predictive surgical or clinical factors, larger multicentre studies are needed.

Mental health-related quality of life in mothers of children with surgically repaired congenital heart disease: a 13-year longitudinal study.

AIMS: Having a child with congenital heart disease (CHD) can affect parental health-related quality of life (HR-QoL). We investigated the long-term trajectories of mental HRQoL (m-HRQoL) in mothers of children with CHD and examined risk factors for persistent low m-HRQoL. METHODS: One hundred twenty-five mothers of children with CHD completed a standardized questionnaire on m-HRQoL (mental subscale SF-12) after the children's first open-heart surgery and subsequently when the children were 1, 4, 6, 10, and 13 years old. A z-score for m-HRQoL was calculated with national norms. Latent class growth analysis (LCGA) was used to identify subgroups of mothers with regards to their m-HRQoL trajectories over time. Regression analysis investigated predictors for chronically low m-HRQoL. RESULTS: Compared to norms, mothers of children with CHD had significantly lower m-HRQoL immediately after open-heart surgery (ß = -0.30 (CI-95: -0.44, -0.15)). Subsequently, m-HRQoL increased to a normal level (m-HRQoL compared to the norm from 1 to 13 years: ß ranges between 0.05 and 0.27). LCGA revealed two distinct groups of m-HRQoL trajectories: A group with normal m-HRQoL (75% of mothers, means z-scores range between - 0.76 and 0.62) and a group with chronically low m-HRQoL (25% of mothers, mean z-scores range between -1.32 and -0.10). Chronically, low m-HRQoL was associated with poorer social support (OR = 3.39 (CI-95: 1.40, 8.49), p = 0.008) but not with parental education, migration background, number of open-heart surgeries, diagnosis of a univentricular CHD, or low IQ. CONCLUSION: A quarter of mothers of children with CHD have chronically low m-HRQoL throughout their child's development, especially those mothers with poor social support. Further studies of family-oriented approaches are needed to identify and support these mothers and reinforce parental well-being.

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.

Neurometabolic changes in neonates with congenital heart defects and their relation to neurodevelopmental outcome.

BACKGROUND: Altered neurometabolite ratios in neonates undergoing cardiac surgery for congenital heart defects (CHD) may serve as a biomarker for altered brain development and neurodevelopment (ND). METHODS: We analyzed single voxel 3T PRESS H1-MRS data, acquired unilaterally in the left basal ganglia and white matter of 88 CHD neonates before and/or after neonatal cardiac surgery and 30 healthy controls. Metabolite ratios to Creatine (Cr) included glutamate (Glu/Cr), myo-Inositol (mI/Cr), glutamate and glutamine (Glx/Cr), and lactate (Lac/Cr). In addition, the developmental marker N-acetylaspartate to choline (NAA/Cho) was evaluated. All children underwent ND outcome testing using the Bayley Scales of Infant and Toddler Development Third Edition (BSID-III) at 1 year of age. RESULTS: White matter NAA/Cho ratios were lower in CHD neonates compared to healthy controls (group beta estimate: -0.26, std. error 0.07, 95% CI: -0.40 - 0.13, p value <0.001, FDR corrected p value = 0.010). We found no correlation between pre- or postoperative white matter NAA/Cho with ND outcome while controlling for socioeconomic status and CHD diagnosis. CONCLUSION: Reduced white matter NAA/Cho in CHD neonates undergoing cardiac surgery may reflect a delay in brain maturation. Further long-term MRS studies are needed to improve our understanding of the clinical impact of altered metabolites on brain development and outcome. IMPACT: NAA/Cho was reduced in the white matter, but not the gray matter of CHD neonates compared to healthy controls. No correlation to the 1-year neurodevelopmental outcome (Bayley-III) was found. While the rapid change of NAA/Cho with age might make it a sensitive marker for a delay in brain maturation, the relationship to neurodevelopmental outcome requires further investigation.

Congenital heart disease in school-aged children: Cognition, education, and participation in leisure activities.

BACKGROUND: Children with congenital heart disease (CHD) are at risk for neurodevelopmental deficits. This study aimed to investigate the impact of cognitive deficits on educational outcome and participation in leisure activities. METHODS: A prospective cohort of 134 children with CHD who underwent cardiopulmonary bypass surgery (CPB) was examined at 10 years of age. IQ was assessed with the WISC-IV and executive functions with the BRIEF (parent- and teacher-report). Parents reported on type and level of education and educational support, and leisure activity participation. Ordinal regression analyses assessed the association between cognitive deficits and educational outcome and participation. RESULTS: Total IQ (P = 0.023), working memory (P < 0.001), processing speed (P = 0.008), and teacher-reported metacognition (P = 0.022) were lower than norms. Regular school was attended by 82.4% of children with CHD compared to 97% of the general Swiss population (P < 0.001). Seventy-five percent of children participated in leisure activities. Lower total IQ and teacher-rated global executive functions were associated with more educational support and lower IQ was associated with less participation. CONCLUSION: As school-aged children with CHD experience cognitive deficits, follow-up is required to provide optimal support with regard to educational outcome and participation in leisure activities. IMPACT: Contemporary cohorts of children with congenital heart disease undergoing cardiopulmonary bypass surgery remain at increased risk for cognitive deficits. Cognitive deficits affect educational outcome and leisure activities. These findings underline the importance of early detection of cognitive deficits and recommend support with respect to cognitive functioning.

Neuromonitoring, neuroimaging, and neurodevelopmental follow-up practices in neonatal congenital heart disease: a European survey.

BACKGROUND: Brain injury and neurodevelopmental impairment remain a concern in children with complex congenital heart disease (CHD). A practice guideline on neuromonitoring, neuroimaging, and neurodevelopmental follow-up in CHD patients undergoing cardiopulmonary bypass surgery is lacking. The aim of this survey was to systematically evaluate the current practice in centers across Europe. METHODS: An online-based structured survey was sent to pediatric cardiac surgical centers across Europe between April 2019 and June 2020. Results were summarized by descriptive statistics. RESULTS: Valid responses were received by 25 European centers, of which 23 completed the questionnaire to the last page. Near-infrared spectroscopy was the most commonly used neuromonitoring modality used in 64, 80, and 72% preoperatively, intraoperatively, and postoperatively, respectively. Neuroimaging was most commonly performed by means of cranial ultrasound in 96 and 84% preoperatively and postoperatively, respectively. Magnetic resonance imaging was obtained in 72 and 44% preoperatively and postoperatively, respectively, but was predominantly reserved for clinically symptomatic patients (preoperatively 67%, postoperatively 64%). Neurodevelopmental follow-up was implemented in 40% of centers and planned in 24%. CONCLUSIONS: Heterogeneity in perioperative neuromonitoring and neuroimaging practice in CHD in centers across Europe is large. The need for neurodevelopmental follow-up has been recognized. A clear practice guideline is urgently needed. IMPACT: There is large heterogeneity in neuromonitoring, neuroimaging, and neurodevelopmental follow-up practices among European centers caring for neonates with complex congenital heart disease. This study provides a systematic evaluation of the current neuromonitoring, neuroimaging, and neurodevelopmental follow-up practice in Europe. The results of this survey may serve as the basis for developing a clear practice guideline that could help to early detect and prevent neurological and neurodevelopmental sequelae in neonates with complex congenital heart disease.

A family-tailored early motor intervention (EMI-Heart) for infants with complex congenital heart disease: study protocol for a feasibility RCT.

BACKGROUND: Children with congenital heart disease (CHD) undergoing open-heart surgery are at risk for developmental impairments with motor delay manifesting first and contributing to parental concerns. Only a few interventional studies aim to improve neuromotor development in infants with CHD with inconclusive results. We thus developed a family-tailored early motor intervention (EMI-Heart), which aims to promote motor development and family well-being in the first year of life after open-heart surgery. The primary aim described in this protocol is to evaluate feasibility of EMI-Heart. The secondary aim is to describe the difference between the intervention and control group in motor outcomes and family well-being at baseline, post-treatment, and follow-up. METHODS: This prospective, parallel single-center feasibility randomized controlled trial (RCT) will compare EMI-Heart with standard of care in infants with complex CHD. Sixteen infants and their families, randomly allocated to EMI-Heart or the control group, will participate within the first 5 months of life. Infants assigned to EMI-Heart will receive early motor intervention for 3 months. The intervention's key is to promote infants' postural control to enhance motor development and partnering with parents to encourage family well-being. Feasibility outcomes will be (a) clinical recruitment rate and percentage of families completing EMI-Heart, (b) average duration and number of sessions, and (c) acceptability of EMI-Heart using a parental questionnaire post-treatment, and descriptive acceptability of EMI-Heart to the pediatric physiotherapist. Secondary outcomes of the intervention and control group will be infants' motor outcomes and questionnaires assessing family well-being at 3-5 months (baseline), at 6-8 months (post-treatment), and at 12 months of age (follow-up). We will evaluate feasibility using descriptive statistics. Non-parametric statistical analysis of secondary outcomes will assess differences between the groups at baseline, post-treatment, and follow-up. DISCUSSION: This feasibility RCT will provide information about a newly developed family-tailored early motor intervention in infants with complex CHD. The RCT design will provide a foundation for a future large-scale interventional trial for infants with CHD after open-heart surgery. TRIAL REGISTRATION: This study protocol (version 1.3, 01.02.2022) was approved by the Cantonal Ethics Commission Zurich (BASEC-Nr. 2019-01,787) and is registered by Clinicaltrials.gov (NCTT04666857).

Risk Factors for Perioperative Brain Lesions in Infants With Congenital Heart Disease: A European Collaboration.

BACKGROUND: Infants with congenital heart disease are at risk of brain injury and impaired neurodevelopment. The aim was to investigate risk factors for perioperative brain lesions in infants with congenital heart disease. METHODS: Infants with transposition of the great arteries, single ventricle physiology, and left ventricular outflow tract and/or aortic arch obstruction undergoing cardiac surgery <6 weeks after birth from 3 European cohorts (Utrecht, Zurich, and London) were combined. Brain lesions were scored on preoperative (transposition of the great arteries N=104; single ventricle physiology N=35; and left ventricular outflow tract and/or aortic arch obstruction N=41) and postoperative (transposition of the great arteries N=88; single ventricle physiology N=28; and left ventricular outflow tract and/or aortic arch obstruction N=30) magnetic resonance imaging for risk factor analysis of arterial ischemic stroke, cerebral sinus venous thrombosis, and white matter injury. RESULTS: Preoperatively, induced vaginal delivery (odds ratio [OR], 2.23 [95% CI, 1.06-4.70]) was associated with white matter injury and balloon atrial septostomy increased the risk of white matter injury (OR, 2.51 [95% CI, 1.23-5.20]) and arterial ischemic stroke (OR, 4.49 [95% CI, 1.20-21.49]). Postoperatively, younger postnatal age at surgery (OR, 1.18 [95% CI, 1.05-1.33]) and selective cerebral perfusion, particularly at ≤20 °C (OR, 13.46 [95% CI, 3.58-67.10]), were associated with new arterial ischemic stroke. Single ventricle physiology was associated with new white matter injury (OR, 2.88 [95% CI, 1.20-6.95]) and transposition of the great arteries with new cerebral sinus venous thrombosis (OR, 13.47 [95% CI, 2.28-95.66]). Delayed sternal closure (OR, 3.47 [95% CI, 1.08-13.06]) and lower intraoperative temperatures (OR, 1.22 [95% CI, 1.07-1.36]) also increased the risk of new cerebral sinus venous thrombosis. CONCLUSIONS: Delivery planning and surgery timing may be modifiable risk factors that allow personalized treatment to minimize the risk of perioperative brain injury in severe congenital heart disease. Further research is needed to optimize cerebral perfusion techniques for neonatal surgery and to confirm the relationship between cerebral sinus venous thrombosis and perioperative risk factors.

ORCHID (Outcome Registry for CHIldren with severe congenital heart Disease) a Swiss, nationwide, prospective, population-based, neurodevelopmental paediatric patient registry: framework, regulations and implementation.

INTRODUCTION: Congenital heart disease (CHD) is the most frequent birth defect. As survival has significantly improved, attention has turned to neurodevelopmental outcomes of children undergoing heart surgery in early infancy. Since multiple risk factors contribute to neurodevelopmental alterations, a nationwide registry collecting data on medical characteristics, interventions, clinical course and neurodevelopment until school-age is needed to improve the quality of management, identify risk- and protective factors affecting neurodevelopment, and facilitate multicentre trials. METHODS AND ANALYSIS: The Swiss Outcome Registry for CHIldren with severe congenital heart Disease (ORCHID) is a nationwide, prospective, population-based patient registry developed (1) to collect baseline characteristics and clinical data of CHD patients operated with bypass-surgery or hybrid procedures in the first 6 weeks of life in Switzerland, (2) to monitor long-term neurodevelopment, and (3) to relate clinical characteristics and neurodevelopment to identify risk and protective factors in these children. This registry started data collection relating to pregnancy, birth, preoperative course, catheter-based and surgical treatment, postoperative course and reinterventions in 2019. The primary outcome includes standardised neurodevelopmental assessments at 9 to 12 months, 18 to 24 months and 5.5 to 6 years. We expect to include 80 to 100 children per year. Correlation and regression analyses will be used to investigate risk- and protective factors influencing neurodevelopment. ETHICS AND DISSEMINATION OF RESULTS: Swiss ORCHID received support by the Accentus Charitable Foundation, the Anna Mueller Grocholoski Stiftung, the Swiss Society of Paediatric Cardiology, the Verein Kinderherzforschung, and the Corelina - Stiftung für das Kinderherz, and was approved by the cantonal ethics committees. Findings will be presented at national and international scientific meetings, and published in peer-reviewed journals. Results will also be shared with patient organizations, primary health care providers, and public health stakeholders to ensure a widespread dissemination of the results.