Early Neurodevelopmental Outcomes in Children With Congenital Heart Disease.

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Learn more: PMC Disclaimer | PMC Copyright Notice JAMA Netw Open . 2026 Jun 1;9(6):e2615885. doi: 10.1001/jamanetworkopen.2026.15885 Early Neurodevelopmental Outcomes in Children With Congenital Heart Disease Mike Seed 1, ✉ , Dawn Ilardi 2 , Valerie Rofeberg 3 , Cynthia Ortinau 4 , Caren Goldberg 5 , Garrett Reichle 5 , Lauren Bush 5 , Justin Elhoff 6 , Amy Jo Lisanti 7, 8 , Jennifer Butcher 9 , Caitlin Rollins 10 , Andrew Van Bergen 11 , Shabnam Peyvandi 12 , Emily Bucholz 13 , Stephanie Cox 14 , Lyla Hampton 15 , Jacqueline Sanz 16, 17, 18 , Sonia Monteiro 19 , Shruti Tewar 20 , Kiona Allen 21 , Caroline Lee 22 , Kristi Glotzbach 23 , Nneka Alexander 24 , Laurel Bear 25, 26 , Corinne Anton 27, 28 , Renee Sananes 29 , Linh Ly 30 , Gina Boucher 31 , Kelly Wolfe 32 , Lindsay Edwards 33 , Elizabeth Willen 34 , Alexander Tan 35 , Christina Ortega 36 , Erica Sood 37 , Anjali Sadhwani 38 , Kari Crawford Plant 39 , Lauren Quigley 40 , Jessica Pliego 41 , Elizabeth Valles 42 , Abbey Hines 43 , David Wypij 44, 45, 46 , Thomas Miller 47 Author information Article notes Copyright and License information 1 Division of Cardiology, Department of Paediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada 2 Department of Pediatrics, Children's Healthcare of Atlanta, Atlanta, Georgia 3 Department of Cardiology, Boston Children’s Hospital, Boston, Massachusetts 4 Department of Pediatrics, Washington University School of Medicine in St Louis, St Louis, Missouri 5 Department of Pediatrics, C.S. Mott Children’s Hospital, University of Michigan, Ann Arbor 6 Sunrise Children’s Hospital/Pediatrix Medical Group, Department of Pediatrics, Kirk Kerkorian School of Medicine at University of Las Vegas, Las Vegas, Nevada 7 University of Pennsylvania School of Nursing, Philadelphia 8 Children’s Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania 9 Division of Pediatric Psychology, Department of Pediatrics, C.S. Mott Children’s Hospital, University of Michigan Medical School, Ann Arbor 10 Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts 11 Division of Pediatric Cardiac Care, Advocate Children’s Hospital, Oak Lawn, Illinois 12 Benioff Children’s Hospital, University of California, San Francisco 13 Department of Pediatrics, University of Colorado Anschutz, Aurora 14 Developmental Evaluation Clinic, Rady Children’s Hospital, San Diego, California 15 Department of Child and Adolescent Psychiatry and Behavioral Sciences, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 16 Division of Pediatric Neuropsychology, Children’s National Hospital, Washington, DC 17 Department of Psychiatry and Behavioural Sciences, The George Washington University School of Medicine, Washington, DC 18 Department of Pediatrics, The George Washington University School of Medicine, Washington, DC 19 Department of Pediatrics, Baylor School of Medicine, Houston, Texas 20 Division of Developmental and Rehabilitative Medicine, Department of Pediatrics, Arkansas Children’s Hospital, Little Rock 21 Division of Cardiology, Department of Pediatrics, Ann and Robert H. Lurie Children’s Hospital of Chicago, Northwestern Feinberg School of Medicine, Chicago, Illinois 22 Department of Pediatrics, Washington University School of Medicine in St Louis, St Louis, Missouri 23 Division of Critical Care Medicine, Department of Pediatrics, University of Utah, Salt Lake City 24 Department of Neuropsychology, Children’s Healthcare of Atlanta, Atlanta, Georgia 25 Department of Pediatrics, Medical College of Wisconsin, Milwaukee 26 Children’s Wisconsin, Milwaukee 27 Children’s Medical Center, Dallas, Texas 28 UT Southwestern Medical Center, Dallas, Texas 29 Division of Cardiology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada 30 Division of Neonatology, Department of Paediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada 31 Quality Management, Center for Heart Care, Phoenix Children’s, Phoenix, Arizona 32 Department of Pediatrics, University of Colorado Anschutz, Aurora 33 Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina 34 Children’s Mercy, University of Missouri, Kansas City 35 Department of Neuropsychology, Children’s Hospital of Orange County, Orange, California 36 Department of Psychology, Joe DiMaggio Children’s Hospital, Hollywood, Florida 37 Nemours Cardiac Center, Nemours Children’s Health, Wilmington, Delaware 38 Psychiatry and Behavioral Sciences, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts 39 Atrium Health Levine Children’s Hospital, Charlotte, North Carolina 40 Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 41 Pediatric Neurosciences, Dell Children’s, The University of Texas at Austin, Austin, 42 Rady Children’s Health, San Diego, California 43 Indiana University School of Medicine, Indianapolis 44 Department of Cardiology, Boston Children’s Hospital, Boston, Massachusetts 45 Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 46 Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 47 Division of Cardiology, Maine Medical Center, Portland Accepted for Publication: March 29, 2026. Published: June 1, 2026. doi: 10.1001/jamanetworkopen.2026.15885 Correction: This article was corrected on July 9, 2026, to fix an error in the Article Information section. Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License , which does not permit alteration or commercial use, including those for text and data mining, AI training, and similar technologies. © 2026 Seed M et al. JAMA Network Open . ✉ Corresponding Author: Mike Seed, MBBS, Division of Cardiology, Department of Paediatrics, Hospital for Sick Children, University of Toronto, 555 University Ave, Toronto, Ontario, M5G 1X8, Canada ( mike.seed@sickkids.ca ). Author Contributions: Drs Seed and Ilardi had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Seed, Ilardi, Wypij, and Miller contributed equally to this work. Concept and design: Seed, Ilardi, Rofeberg, Ortinau, Goldberg, Elhoff, Butcher, Rollins, Peyvandi, Bucholz, Sanz, Allen, Glotzbach, Alexander, Bear, Willen, Crawford Plant, Wypij, Miller. Acquisition, analysis, or interpretation of data: Seed, Ilardi, Rofeberg, Ortinau, Goldberg, Reichle, Bush, Lisanti, Butcher, Rollins, Van Bergen, Peyvandi, Cox, Hampton, Monteiro, Bucholz, Sanz, Tewar, Allen, Lee, Glotzbach, Anton, Sananes, Ly, Boucher, Wolfe, Edwards, Tan, Ortega, Sood, Sadhwani, Lorenzi-Quigley, Pliego, Valles, Hines, Wypij, Miller. Drafting of the manuscript: Seed, Ilardi, Rofeberg, Ortinau, Hampton, Allen, Wypij, Miller. Critical review of the manuscript for important intellectual content: Seed, Ilardi, Rofeberg, Ortinau, Goldberg, Reichle, Bush, Elhoff, Lisanti, Butcher, Rollins, Van Bergen, Peyvandi, Cox, Monteiro, Bucholz, Sanz, Tewar, Allen, Lee, Glotzbach, Alexander, Bear, Anton, Sananes, Ly, Boucher, Wolfe, Edwards, Willen, Tan, Ortega, Sood, Sadhwani, Crawford Plant, Lorenzi-Quigley, Pliego, Valles, Hines, Wypij, Miller. Statistical analysis: Seed, Rofeberg, Rollins, Wypij. Obtained funding: Van Bergen. Administrative, technical, or material support: Seed, Ilardi, Goldberg, Bush, Butcher, Van Bergen, Peyvandi, Monteiro, Sanz, Allen, Anton, Sananes, Ortega, Sood, Pliego, Valles, Miller. Supervision: Seed, Bush, Wypij, Miller. Conflict of Interest Disclosures: Dr Ortinau reported receiving grants from Additional Ventures outside the submitted work. Dr Goldberg reported serving as the director of the CNOC data coordinating center (no compensation). Dr Rollins reported receiving grants from the National Institute of Neurological Disorders and Stroke, Additional Ventures, Children’s Heart Foundation, US Centers for Disease Control and Prevention, and Feihe Pediatric Brain Development Research Initiative and honoraria and travel support from the Newborn Brain Society outside the submitted work. Dr Wypij reported receiving Cardiac Neurodevelopmental Outcome Collaborative Funding for statistical support during the conduct of the study. No other disclosures were reported. Funding/Support: This project was supported by the Cardiac Neurodevelopmental Outcome Collaborative (CNOC), the Pediatric Cardiac Critical Care Consortium (PC 4 ), and the Children’s Heart Foundation through their support for integrated registry initiatives as a part of Cardiac Networks United. Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Data Sharing Statement: See Supplement 2 . ✉ Corresponding author. Received 2025 Dec 13; Accepted 2026 Mar 29; Collection date 2026 Jun. Copyright 2026 Seed M et al. JAMA Network Open . This is an open access article distributed under the terms of the CC-BY-NC-ND License, which does not permit alteration or commercial use, including those for text and data mining, AI training, and similar technologies. PMC Copyright notice PMCID: PMC13227305  PMID: 42223939 This article has been corrected. See JAMA Netw Open. 2026 Jul 9;9(7):e2627139 . Key Points Question Which clinical variables are associated with early neurodevelopmental outcomes in pediatric patients with congenital heart disease? Findings This cross-sectional study of 868 children found clinical variables associated with neurodevelopmental outcomes included the presence of a genetic diagnosis, cardiac diagnosis, birth weight, sex, age at repair, length of stay, number of catheterizations, primary caregiver education, and Child Opportunity Index. Meaning This study’s results suggest that while the presence of a genetic diagnosis is associated with outcomes, early repair may be a variable of interest for future studies investigating neuroprotective strategies in congenital heart disease. This cross-sectional study assesses neurodevelopmental outcomes among infants and toddlers with congenital heart disease. Abstract Importance Neurodevelopmental impairments are common in children with congenital heart disease. Objectives To compare neurodevelopmental outcomes by cardiac diagnosis and identify associations between medical and social factors and early neurodevelopmental outcomes among children with congenital heart disease. Design, Setting, and Participants This cross-sectional analysis used neurodevelopmental follow-up data obtained between May 1, 2019, and June 30, 2022, and entered into the Cardiac Neurodevelopmental Outcome Collaborative (CNOC) registry, with linkage to the Pediatric Cardiac Critical Care Consortium registry. Children younger than 30 months from 25 CNOC sites were studied. Data analysis was performed between January 2023 and December 2024. Exposures Patients undergoing cardiac surgical repair or palliation requiring cardiopulmonary bypass at younger than 12 months who completed a neurodevelopmental assessment before 30 months of age. Main Outcomes and Measures Outcomes are the cognitive, language, and motor indexes on the Bayley Scales of Infant and Toddler Development-III/4. Factors analyzed by multivariable regression modeling include cardiac diagnosis and other previously identified medical risk factors and social drivers of adverse neurodevelopmental outcomes in patients with congenital heart disease. Results The study included 942 assessments from 868 children (median [IQR] age at index operation, 20 [6-127] days; 481 [56.1%] male, 102 [11.8%] with a genetic diagnosis). Across cardiac diagnostic groups, those with genetic diagnoses (n = 116 assessments) scored more than 1 SD lower on all Bayley indexes than those without (cognitive: 18.8; 95% CI, 15.3-22.4; language: 16.1; 95% CI, 12.2-20.0; motor: 20.9; 95% CI, 18.3-23.5; P < .001 for each). After adjustment for other characteristics, cardiac diagnosis was significantly associated with the cognitive and motor indexes, with patients with dextro-transposition of the great arteries (reference group) exhibiting the highest scores, whereas the mean scores for all other diagnoses were within the normal range (β coefficients [95% CIs] of –4.5 [–7.8 to –1.2] for coarctation, –3.8 [–10.8 to 3.1] for ventricular septal defect, –2.4 [–6.7 to 1.8] for tetralogy of Fallot, –4.0 [–6.4 to –1.7] for single-ventricle physiology, –2.4 [–9.7 to 5.0] for atrioventricular septal defect, and –3.4 [–6.1 to–0.6] for other cardiac diagnoses). Lower birth weight, male sex, older age at initial surgery, longer hospital length of stay, more cardiac catheterizations, and lower primary caregiver educational level were independently associated with worse performance on all indexes. Conclusions and Relevance In this cross-sectional study of early neurodevelopmental outcomes in children with congenital heart disease, there was significant variation in neurodevelopmental outcomes according to cardiac diagnosis; regardless of cardiac diagnosis, the presence of a genetic diagnosis was associated with lower neurodevelopmental scores. The heterogeneous outcomes found in this study reinforce the importance of surveillance for all infants undergoing heart surgery in the first year of life. Introduction Neurodevelopmental delays and disorders affect up to half of children requiring surgical intervention for congenital heart disease (CHD) during infancy. 1 Early motor and language delays may progress to cognitive, academic, social-emotional, and executive functioning concerns at school age. 2 Adults with CHD exhibit lower educational attainment, more unemployment, a higher incidence of mental health issues, and reduced quality of life. 3 , 4 The cause of neurodevelopmental differences in CHD is not fully understood and is multifactorial. Innate and prenatal factors, such as genetic variation, maternal health, and fetal cardiovascular physiology, combine with postnatal medical, surgical, and environmental risks to affect brain health and associated neurodevelopment. 5 , 6 , 7 Observational studies 2 , 8 , 9 have identified clinical risk factors predisposing individuals to neurodevelopmental delay in CHD, including genetic diagnoses, prolonged hospitalization, and preterm birth. The severity of neurodevelopmental impairments has been reported to be associated with the complexity of the heart disease. 10 , 11 Social drivers of health, including parental educational level and socioeconomic status, are also associated with neurodevelopmental outcomes in children with CHD. 12 , 13 Prior studies 14 , 15 , 16 , 17 , 18 , 19 examining associations between risk factors and neurodevelopmental outcomes have typically grouped participants with a variety of cardiac diagnoses together or focused exclusively on a specific cardiac diagnosis. However, more recent work suggests that associations between cardiac diagnosis and neurodevelopmental outcomes may be evolving as perioperative management changes, with patients with dextro-transposition of the great arteries (d-TGA) now exhibiting improved outcomes compared with earlier findings. 20 The Cardiac Neurodevelopmental Outcome Collaborative (CNOC) collects neurodevelopmental outcome data in patients with CHD through a multinational, multicenter clinical data registry. 21 Partnership with the Pediatric Cardiac Critical Care Consortium (PC 4 ), which maintains a registry of detailed perioperative clinical information, has facilitated the integration of neurodevelopmental and perioperative data. 22 CNOC site members participating in the registry use standardized neurodevelopmental measures. In tandem with the creation of the CNOC registry, a research committee prioritized 2 initial study aims. Findings from the first aim, to identify factors associated with attendance for cardiac neurodevelopmental assessment, were previously published. 22 In the current study, we aimed to describe neurodevelopmental outcomes for a comprehensive sample of infants and toddlers undergoing repair during infancy to understand the medical risk factors and social drivers associated with neurodevelopmental scores. We hypothesized that neurodevelopmental outcomes would differ by cardiac diagnosis and that clinical risk factors and social drivers of health would be associated with infant and toddler neurodevelopmental outcomes. Methods Study Design and Participants This cross-sectional study was approved by the University of Michigan institutional review board with appropriate data-sharing agreements with each of the 27 CNOC sites that contributed data. A waiver of consent was granted by the institutional review board because the research posed minimal risk, would have been impracticable to conduct without the waiver, and did not adversely affect the rights and welfare of the participants. The inclusion criteria required children to have undergone neurodevelopmental assessment using the Bayley Scales of Infant and Toddler Development-III/4 between 11 and 30 months of age from May 1, 2019, to June 30, 2022, after cardiopulmonary bypass surgery during the first year of life, the details of which needed to have been recorded in the PC 4 registry. The study followed the Strengthening the Reporting of Observational Studies in Epidemiology ( STROBE ) reporting guideline for cross-sectional studies. Sociodemographic and Medical Data The CNOC and PC 4 clinical data registries were used to collect sociodemographic and medical data. Birth characteristics included antenatal diagnosis, gestational age, preterm birth defined as less than 37 weeks’ gestation, birth weight, head circumference, and sex. Sociodemographic characteristics included race and ethnicity, primary caregiver educational level, and the Child Opportunity Index (COI), a metric of neighborhood resources and conditions based on the child’s zip code. 23 Race and ethnicity were classified according to the PC 4 protocol and collected to evaluate for associations with other sociodemographic variables and outcomes. Medical characteristics identified as pertinent by the cardiac neurodevelopmental literature included the presence of a genetic diagnosis, cardiac diagnosis, age at first cardiopulmonary bypass surgery (index operation), type of surgical procedure(s), history of cardiac arrest, history of stroke or clinical or electrographic seizure, extracorporeal membrane oxygenation (ECMO) during the index operation, postoperative length of stay after the index operation, and number of cardiac operations and interventional cardiac catheterizations in the first year of life. Genetic diagnoses were typically identified based on clinical suspicion and confirmed with genetic testing, although not all patients underwent genetic testing. Cardiac diagnoses were divided into 7 groups: d-TGA, coarctation of the aorta (CoA), ventricular septal defect (VSD), tetralogy of Fallot (TOF), single-ventricle physiology (SVP), atrioventricular septal defect (AVSD), and other. Cardiac surgical procedures were classified according to the Society of Thoracic Surgeons–European Association for Cardio-Thoracic Surgery (STAT) system, with higher scores reflecting operations with higher risk of mortality. 24 Neurodevelopmental Data One component of the neurodevelopmental assessment included the Bayley Scales of Infant and Toddler Development-III/4, which provide scores based on population-normed data. 25 Neurodevelopmental outcome variables included the cognitive, motor, and language standard scores (population mean [SD], 100 [15]). During the study, we identified that score conversions from raw to scaled and standard scores would need to be corrected for version 4 of the Bayley Scales. As the raw scores were required for conversion, we opted to exclude patients for whom Bayley Scales of Infant and Toddler Development-4 raw scores were not available and those for whom there were scoring errors in our primary analyses. Patients missing raw scores or with inconsistencies between raw and standard scores were only considered in a separate sensitivity analysis. Statistical Analysis Because of the known association of genetic disorders with adverse neurodevelopmental outcomes independent of CHD, patients were divided into those with vs without a known genetic diagnosis. Graphical and regression methods were used to assess associations and the impact of genetic diagnosis on neurodevelopmental outcomes. For patients without a genetic diagnosis, backward stepwise multivariable regression requiring significant improvement in the Schwarz-type penalized gaussian pseudo-likelihood criterion while maintaining P < .20 was used to identify independent variables associated with each neurodevelopmental outcome index. 26 After controlling for cardiac diagnosis and Bayley Scales version (III vs 4), candidate variables for the primary analysis consisted of antenatal diagnosis, birth weight, sex, age at surgery, cardiac arrest, stroke or seizure, ECMO, length of stay, and number of operations and catheterizations. Primary caregiver educational level and COI were excluded from the primary analysis because of higher rates of missing data but were added back for secondary analyses using smaller sample sizes. Due to strong collinearity between gestational age and birth weight as well as STAT category and cardiac diagnosis category, we opted to exclude gestational age and STAT category as candidate variables. Throughout the study, robust variances from generalized estimating equation models with independent working correlations were used to control for center-to-center variability and repeat assessments from some patients. A 2-sided P < .05 was considered statistically significant. R, version 4.3.0 (R Foundation for Statistical Computing), including the glmtoolbox package, was used for all analyses. Data analysis was performed between January 2023 and December 2024. Results Study Population and Characteristics After data validation ( Figure 1 ), our primary analysis dataset was based on 942 assessments representing 868 unique patients (median [IQR] age at index operation, 20 [6-127] days; 481 [56.1%] male and [43.9%] female) from 25 sites ( Table 1 ). Of the 695 patients who identified their race, 85 (12.2%) were Black, 142 (20.4%) were Hispanic, 386 (55.5%) were White, and 82 (11.8%) were of other races, including multiracial (n = 34), Asian (n = 23), and other (n = 25). A total of 102 patients (11.8%) had a genetic diagnosis and 766 (88.2%) did not. The most common diagnoses were SVP (223 [25.7%]) and d-TGA (152 [17.5%]). The median (range) number of cardiac operations was 1 (1-5); the median (range) number of cardiac catheterizations was 0 (0-9). A history of cardiac arrest, stroke or seizures, and ECMO were all relatively uncommon (3.8%-4.7%). Figure 1. Flow Diagram of Patients From the Cardiac Neurodevelopmental Outcome Collaborative Registry Included in Primary and Sensitivity Analyses. Open in a new tab Bayley-4 indicates Bayley Scales of Infant and Toddler Development-4. Table 1. Birth, Sociodemographic, Medical, and Neurodevelopmental Characteristics of the Study Patients . Characteristic Total (N = 868) No genetic diagnosis (n = 766) Genetic diagnosis (n = 102) No. of patients with data Summary statistics a No. of patients with data Summary statistics a No. of patients with data Summary statistics a Birth characteristics Antenatal diagnosis 787 496 (63.0) 698 434 (62.2) 89 62 (69.7) Gestational age, wk 836 37.9 (2.0) 735 38.0 (1.9) 101 37.2 (2.3) Preterm birth (<37 weeks’ gestation) 854 126 (14.8) 752 99 (13.2) 102 27 (26.5) Birth weight, kg 753 3.1 (0.6) 673 3.1 (0.6) 80 2.8 (0.7) Head circumference, cm 412 33.2 (2.1) 368 33.3 (2.1) 44 32.2 (2.1) Sex Female 857 376 (43.9) 757 330 (43.6) 100 54 (54.0) Male 481 (56.1) 427 (56.4) 46 (46.0) Sociodemographic characteristics Race and ethnicity Black, non-Hispanic 695 85 (12.2) 603 75 (12.4) 92 10 (10.9) Hispanic, any race 142 (20.4) 115 (19.1) 27 (29.3) White, non-Hispanic 386 (55.5) 337 (55.9) 49 (53.3) Other b 82 (11.8) 76 (12.6) 6 (6.5) Primary caregiver educational level Graduate degree 471 78 (16.6) 407 70 (17.2) 64 8 (12.5) College degree 163 (34.6) 146 (35.9) 17 (26.6) Less than college degree 230 (48.8) 191 (46.9) 39 (60.9) Child Opportunity Index Very high 552 130 (23.6) 476 120 (25.2) 76 10 (13.2) High 121 (21.9) 102 (21.4) 19 (25.0) Moderate 117 (21.2) 97 (20.4) 20 (26.3) Low 97 (17.6) 84 (17.6) 13 (17.1) Very low 87 (15.8) 73 (15.3) 14 (18.4) Medical characteristics Cardiac diagnosis d-TGA 868 152 (17.5) 766 151 (19.7) 102 1 (1.0) CoA 81 (9.3) 69 (9.0) 12 (11.8) VSD 87 (10.0) 70 (9.1) 17 (16.7) TOF 139 (16.0) 118 (15.4) 21 (20.6) SVP 223 (25.7) 215 (28.1) 8 (7.8) AVSD 40 (4.6) 16 (2.1) 24 (23.5) Other 146 (16.8) 127 (16.6) 19 (18.6) Age at index operation, d 868 20 (6-127) 868 13 (6-118) 102 105 (34-151) STAT category 1 866 111 (12.8) 764 90 (11.8) 102 21 (20.6) 2 135 (15.6) 118 (15.4) 17 (16.7) 3 141 (16.3) 113 (14.8) 28 (27.5) 4 319 (36.8) 291 (38.1) 28 (27.5) 5 160 (18.5) 152 (19.9) 8 (7.8) Events during index hospitalization Cardiac arrest 794 35 (4.4) 698 31 (4.4) 96 4 (4.2) Stroke or seizure 867 41 (4.7) 765 38 (5.0) 102 3 (2.9) Extracorporeal membrane oxygenation 867 33 (3.8) 765 31 (4.1) 102 2 (2.0) Index operation hospital length of stay, d ≤15 868 337 (38.8) 766 296 (38.6) 102 41 (40.2) 16-30 220 (25.3) 202 (26.4) 18 (17.6) 31-45 112 (12.9) 99 (12.9) 13 (12.7) >45 199 (22.9) 169 (22.1) 30 (29.4) No. of infant cardiac operations 1 868 618 (71.2) 766 535 (69.8) 102 83 (81.4) 2 215 (24.8) 201 (26.2) 14 (13.7) 3 or more 35 (4.0) 30 (3.9) 5 (4.9) No. of infant catheterizations 0 867 498 (57.4) 765 425 (55.6) 102 73 (71.6) 1 246 (28.4) 227 (29.7) 19 (18.6) 2 75 (8.7) 67 (8.8) 8 (7.8) ≥3 48 (5.5) 46 (6.0) 2 (2.0) Neurodevelopmental characteristics No. of Bayley evaluations 1 868 807 (93.0) 766 717 (93.6) 102 90 (88.2) 2 50 (5.8) 40 (5.2) 10 (9.8) ≥3 11 (1.3) 9 (1.2) 2 (2.0) Bayley evaluations 942 826 116 Age at testing, mo 942 18.9 (15.3-22.9) 826 18.9 (15.4-22.8) 116 19.2 (14.9-24.6) No. of Bayley-III evaluations 409 (43.4) 363 (43.9) 46 (39.7) No. of Bayley-4 evaluations 533 (56.6) 463 (56.1) 70 (60.3) Cognitive score 929 88.8 (18.1) 817 91.1 (17.2) 115 72.3 (15.2) Language score 874 86.2 (19.1) 780 88.2 (18.7) 113 72.1 (16.1) Motor score 902 86.2 (18.2) 794 88.8 (17.0) 11 67.9 (15.3) Open in a new tab Abbreviations: AVSD, atrioventricular septal defect; Bayley, Bayley Scales of Infant and Toddler Development (III or 4); CoA, coarctation; d-TGA, dextro-transposition of the great arteries; STAT, Society of Thoracic Surgeons–European Association for Cardio-Thoracic Surgery; SVP, single-ventricle physiology; TOF, tetralogy of Fallot; VSD, ventricular septal defect. a Data are presented as mean (SD), number (percentage), or median (IQR). b Other includes multiracial (n = 34), Asian (n = 23), and other (n = 25). Of the 942 assessments, 116 (12.3%) representing 102 unique patients had a genetic diagnosis. Among these patients, 47 (46.1%) had trisomy 21, 28 (27.4%) had a 22Q11.2 deletion syndrome, and 27 (26.5%) had other genetic diagnoses. The final primary analysis dataset with the 766 patients without a genetic diagnosis included 814 assessments for the cognitive index, 764 for language, and 791 for motor. Neurodevelopmental Outcomes Among children without a genetic diagnosis, mean scores were below the normative mean (100) for all 3 Bayley indexes (mean [SD] of 91.1 [17.2] for the cognitive score, 88.2 [18.7] for the language score, and 88.8 [17.0] for the motor score; P < .001 for each) ( Table 1 ). Analyses indicated that genetic diagnoses were associated with Bayley scores. Patients with genetic diagnoses scored at least 1 SD (>15 points) lower on all Bayley indexes than those without (cognitive: 18.8; 95% CI, 15.3-22.4; language: 16.1; 95% CI, 12.2-20.0; motor: 20.9; 95% CI, 18.3-23.5; P < .001 for each) (eTable 1 in Supplement 1 ). The lowest scores were observed in patients with trisomy 21, followed by 22Q11.2 deletion syndrome and other genetic diagnoses. After adjustment for cardiac diagnosis category and Bayley Scales version, those with genetic diagnoses similarly scored approximately 1 SD (>15 points) lower on all Bayley indexes than those without (eTable 1 in Supplement 1 ). Bayley indexes varied by cardiac diagnosis and STAT category, with patients with a genetic diagnosis generally having lower scores for each category ( Figure 2 ). Patients with d-TGA without a genetic diagnosis exhibited the highest scores, with mean (SD) scores of 98.2 (12.8), 94.4 (16.3), and 96.8 (12.1) for the cognitive, language, and motor indexes, respectively. Bayley scores were lowest for STAT category 5. Among children without a genetic diagnosis, Bayley scores also varied by primary caregiver educational level, hospital length of stay, and number of catheterizations ( Figure 3 ). Figure 2. Box Plots of Cognitive, Language, and Motor Scores by Cardiac Diagnosis and Society of Thoracic Surgeons–European Association for Cardio-Thoracic Surgery (STAT) Category for Patients With and Without Any Genetic Diagnosis. Open in a new tab Lower and upper ends of the boxes represent the 25th and 75th percentiles, respectively; horizontal lines inside boxes represent the medians; whiskers extend to the 5th and 95th percentiles. AVSD indicates atrioventricular septal defect; Bayley-4, Bayley Scales of Infant and Toddler Development-4; CoA, coarctation; d-TGA, dextro-transposition of the great arteries; SVP, single-ventricle physiology; TOF, tetralogy of Fallot; VSD, ventricular septal defect. Figure 3. Box Plots of Bayley Cognitive, Language, and Motor Scores by Primary Caregiver Educational Level, Hospital Length of Stay, and Number of Catheterizations for Patients Without Any Genetic Diagnosis. Open in a new tab Lower and upper ends of the boxes represent the 25th and 75th percentiles, respectively; horizontal lines inside boxes represent the medians; whiskers extend to the 5th and 95th percentiles. Bayley-4 indicates Bayley Scales of Infant and Toddler Development-4. Neurodevelopmental Outcomes for Patients Without a Genetic Diagnosis Due to the profound impact of genetic diagnoses on neurodevelopmental outcomes, further modeling excluded children with a genetic diagnosis. After adjustment for cardiac diagnosis category and Bayley Scales version, the results of assessing birth, sociodemographic, or medical characteristics 1 at a time in patients without a genetic diagnosis are given in eTable 2 in Supplement 1 . The results of multivariable models are given in Table 2 . After adjustment for other characteristics (model 1), cardiac diagnosis was significantly associated with the cognitive and motor indexes, with patients with d-TGA (reference group) exhibiting the highest scores, whereas the mean scores for all other diagnoses were within the normal range (β coefficients [95% CIs] of –4.5 [–7.8 to–1.2] for CoA, –3.8 [–10.8 to 3.1] for VSD, –2.4 [–6.7 to 1.8] for TOF, –4.0 [–6.4 to –1.7] for SVP, –2.4 [–9.7 to 5.0] for AVSD, and –3.4 [–6.1 to–0.6] for other cardiac diagnoses). Lower birth weight, male sex, older age at first open-heart surgery, longer hospital length of stay, and more infant catheterizations were independently associated with lower scores across all indexes ( Table 2 ). Table 2. Multivariable Associations With Neurodevelopmental Outcomes on the Bayley Scales of Infant and Toddler Development (Bayley-III or Bayley-4) a . Variable β Coefficient (95% CI) Model 1 Model 2 Model 3 Cognitive No. of evaluations 702 356 417 No. of sites 24 21 18 Cardiac diagnosis d-TGA 1.0 [Reference] 1.0 [Reference] 1.0 [Reference] CoA –4.5 (–7.8 to –1.2) –4.6 (–10.4 to 1.2) –2.4 (–6.9 to 2.2) VSD –3.8 (–10.8 to 3.1) –0.9 (–9.9 to 8.1) 0.5 (–6.3 to 7.2) TOF –2.4 (–6.7 to 1.8) –1.1 (–6.9 to 4.8) –0.3 (–5.0 to 4.4) SVP –4.0 (–6.4 to –1.7) –3.4 (–7.2 to 0.4) –3.4 (–6.1 to –0.7) AVSD –2.4 (–9.7 to 5.0) –2.6 (–11.4 to 6.3) –5.2 (–15.1 to 4.7) Other –3.4 (–6.1 to –0.6) –4.7 (–8.3 to –1.3) –3.7 (–7.8 to 0.4) Bayley-4 (vs Bayley-III) –5.6 (–9.0 to –2.3) –5.7 (–9.7 to –1.2) –5.1 (–8.2 to –2.0) Birth weight (per kg) 4.0 (1.6 to 6.3) 5.8 (3.4 to 8.2) 5.4 (3.2 to 7.6) Female sex (vs male) 3.4 (1.3 to 5.6) 4.6 (2.5 to 6.7) 4.3 (1.5 to 7.0) Age at first open surgery (per wk) –0.2 (–0.4 to –0.0) –0.3 (–0.5 to –0.1) –0.3 (–0.5 to –0.1) Hospital length of stay, d ≤15 1.0 [Reference] 1.0 [Reference] 1.0 [Reference] 16-30 –3.7 (–5.8 to –1.7) –0.8 (–4.3 to 2.8) –4.4 (–7.3 to–1.4) 31-45 –7.0 (–10.9 to –3.0) –3.9 (–9.5 to 1.7) –7.9 (–13.8 to –2.0) >45 –9.4 (–12.5 to –6.3) –8.6 (–12.2 to –5.0) –10.7 (–13.0 to –8.4) No. of infant catheterizations –2.2 (–3.8 to –0.5) –1.8 (–3.4 to –0.2) –1.7 (–3.4 to –0.1) Primary caregiver education Graduate degree NA 1.0 [Reference] NA College degree NA –7.7 (–13.9 to –1.4) NA Less than college degree NA –11.5 (–16.2 to –6.8) NA Child Opportunity Index Very high NA NA 1.0 [Reference] High NA NA 1.6 (–3.3 to 6.5) Moderate NA NA 0.8 (–3.4 to 5.1) Low NA NA –4.9 (–9.4 to–0.3) Very low NA NA –3.7 (–9.5 to 2.1) Language No. of evaluations 656 342 394 No. of sites 22 20 18 Cardiac diagnosis d-TGA 1.0 [Reference] 1.0 [Reference] 1.0 [Reference] CoA –4.7 (–6.3 to 1.4) –8.5 (–15.2 to –1.9) –6.1 (–11.4 to 0.9) VSD –4.2 (–10.2 to 0.5) –9.1 (–18.8 to 0.5) –0.2 (–7.9 to 7.5) TOF –1.5 (–13.7 to 4.9) –4.2 (–11.5 to 3.0) 0.1 (–5.2 to 5.3) SVP –2.4 (–6.2 to 2.6) –3.7 (–7.9 to 0.5) –4.8 (–9.6 to –0.1) AVSD 4.1 (–6.2 to 1.2) –1.2 (–12.1 to 9.6) 3.3 (–6.9 to 13.5) Other –2.4 (–11.8 to 12.8) –7.4 (–13.1 to –1.7) –3.9 (–9.7 to 2.0) Bayley-4 (vs Bayley-III) –1.2 (–4.5 to 2.2) –1.8 (–5.5 to 2.0) –3.9 (–7.3 to –0.6) Birth weight (per kg) 3.6 (0.5 to 5.5) 3.5 (0.6 to 6.5) 4.9 (3.0 to 6.9) Female sex (vs male) 6.2 (3.6 to 8.5) 7.2 (3.6 to 10.4) 7.8 (5.0 to 10.7) Age at first open surgery (per wk) –0.3 (–0.4 to –0.1) –0.3 (–0.5 to –0.1) –0.4 (–0.5 to –0.2) Hospital length of stay, d ≤15 1.0 [Reference] 1.0 [Reference] 1.0 [Reference] 16-30 –4.3 (–6.8 to –1.7) –2.7 (–6.1 to 0.7) –4.7 (–8.2 to –1.1) 31-45 –7.8 (–12.3 to –3.2) –4.9 (–12.2 to 2.4) –9.9 (–16.7 to –3.2) >45 –9.6 (–14.9 to –4.2) –9.7 (–13.7 to –5.7) –11.4 (–15.8 to –6.9) No. of infant catheterizations –2.1 (–3.8 to –0.3) –3.0 (–5.0 to–0.9) –1.2 (–3.2 to 0.9) Primary caregiver education Graduate degree NA 1.0 [Reference] NA College degree NA –9.8 (–16.5 to –3.0) NA Less than college degree NA –15.0 (–20.7 to –9.3) NA Child Opportunity Index Very high NA NA 1.0 [Reference] High NA NA –1.5 (–5.5 to 2.5) Moderate NA NA –1.0 (–6.2 to 4.2) Low NA NA –3.9 (–9.5 to 1.7) Very low NA NA –2.2 (–9.8 to 5.3) Motor No. of evaluations 682 353 407 No. of sites 24 21 19 Cardiac diagnosis d-TGA 1.0 [Reference] 1.0 [Reference] 1.0 [Reference] CoA –4.1 (–8.0 to –0.1) –5.4 (–10.5 to –0.3) –2.3 (–6.7 to 2.2) VSD –3.9 (–13.2 to 5.3) –3.2 (–13.4 to 7.1) 1.4 (–4.5 to 7.3) TOF –4.0 (–8.5 to 0.4) –4.8 (–10.9 to 1.4) –1.9 (–6.5 to 2.7) SVP –4.5 (–6.3 to –2.6) –4.9 (–8.1 to –1.7) –4.8 (–6.8 to –2.9) AVSD –5.5 (–14.4 to 3.3) –10.5 (–21.4 to 0.3) –10.6 (–19.2 to –2.0) Other –4.1 (–6.7 to –1.5) –8.2 (–12.5 to –4.0) –4.1 (–7.9 to –0.2) Bayley-4 (vs Bayley-III) –3.2 (–6.6 to 0.1) –4.3 (–9.6 to 0.9) –3.2 (–7.9 to 1.5) Birth weight (per kg) 4.1 (1.8 to 6.5) 4.6 (1.9 to 7.3) 4.8 (2.5 to 7.2) Female sex (vs male) 3.6 (1.8 to 5.4) 3.9 (2.2 to 5.6) 4.2 (1.8 to 6.7) Age at first open surgery (per wk) –0.2 (–0.4 to –0.1) –0.2 (–0.4 to –0.1) –0.3 (–0.4 to –0.1) Hospital length of stay, d ≤15 1.0 [Reference] 1.0 [Reference] 1.0 [Reference] 16-30 –3.8 (–5.9 to –1.8) –1.1 (–4.4 to 2.2) –4.0 (–6.3 to –1.7) 31-45 –8.2 (–11.8 to –4.7) –3.5 (–7.9 to 0.8) –7.8 (–12.2 to–3.4) >45 –11.2 (–15.4 to –7.0) –10.1 (–15.0 to –5.2) –12.9 (–16.2 to –9.7) No. of infant catheterizations –2.9 (–4.6 to –1.2) –2.7 (–4.3 to–1.2) –1.8 (–3.5 to –0.2) Primary caregiver education Graduate degree NA Reference NA College degree NA –5.0 (–11.0 to 1.0) NA Less than college degree NA –6.3 (–10.7 to –1.9) NA Child Opportunity Index Very high NA NA 1.0 [Reference] High NA NA 1.3 (–2.7 to 5.2) Moderate NA NA 1.5 (–3.3 to 6.3) Low NA NA –0.2 (–3.9 to 3.6) Very low NA NA –1.4 (–7.9 to 5.2) Open in a new tab Abbreviations: AVSD, atrioventricular septal defect; CoA, coarctation; d-TGA, dextro-transposition of the great arteries; NA, not applicable; SVP, single-ventricle physiology; TOF, tetralogy of Fallot; VSD, ventricular septal defect. a After controlling for cardiac diagnosis category and Bayley version, model 1 was based on stepwise regression using sex and other medical characteristics as candidate variables. Model 2 added primary caregiver education to model 1. Model 3 added Child Opportunity Index to model 1. For the cognitive index, R 2 was 0.22 for model 1, 0.31 for model 2, and 0.30 for model 3. For the language index, R 2 was 0.16 for model 1, 0.29 for model 2, and 0.24 for model 3. For the motor index, R 2 was 0.27 for model 1, 0.28 for model 2, and 0.32 for model 3. When primary caregiver educational level was added to the model (model 2), the same medical factors remained statistically significant, whereas primary caregiver educational level was also strongly associated with outcome. The largest differences were found for the language index, for which children of primary caregivers with a graduate degree scored 15.0 points higher than those without a college degree and 9.8 points higher than those with a college degree. If COI was instead added to the model (model 3), COI was associated with the cognitive index, with the low COI group having the lowest scores. COI was not associated with the language or motor indexes. Regression analyses using the sensitivity analysis dataset of patients without a genetic diagnosis included 1223 assessments representing 1107 unique patients from 27 sites, comprising 1050 assessments for the cognitive index, 995 for language, and 986 for motor. These analyses yielded results similar to those of models 1, 2, and 3, with patients with d-TGA exhibiting significantly higher language, cognitive, and motor index scores and COI was also significantly associated with language and motor indexes. Discussion In this cross-sectional study of children with CHD, we observed an association between cardiac diagnosis and early neurodevelopment outcomes. Those with d-TGA exhibited significantly higher scores on the Bayley Scales than those with other forms of CHD, whereas those with AVSD and SVP exhibited the lowest scores among the groups. Our findings are consistent with prior work demonstrating that the presence of a genetic diagnosis is strongly associated with neurodevelopment outcomes across all cardiac diagnoses. 5 Beyond genetic diagnosis, other significant medical and social risk factors for adverse neurodevelopment outcomes in patients with CHD without a genetic diagnosis included lower birth weight, male sex, older age at initial surgery, longer hospital length of stay, more cardiac catheterizations, and lower primary caregiver educational level. Lower COI scores were also associated with lower cognitive scores. Findings from this CNOC registry cohort need to be considered in the context of prior studies, including differences in the approach to classifying cardiac diagnoses, variation in outcomes associated with Bayley edition, age at neurodevelopmental assessment, and effects of the surgical era. Broadly speaking, prior studies 11 , 27 , 28 , 29 have reported more favorable early neurodevelopmental outcomes in patients undergoing biventricular repairs than those requiring single-ventricle palliation. Reductions of half an SD or more on the Bayley Scales are consistently reported for children with SVP. Our findings in infants with d-TGA suggest that there may have been an improvement in outcomes for children with d-TGA during the past 2 decades. The Boston Circulatory Arrest Trial enrolled newborns from 1988 to 1992 and found a mean (SD) score for psychomotor development of 95.1 (15.5) at 1 year using the original Bayley Scale. This apparent improvement in motor outcomes could reflect advances in surgical techniques and perioperative management occurring during the 3 decades since this seminal study. Despite the average abilities for early cognitive development reported by the Boston Circulatory Arrest Trial, subsequent follow-up at school age and later revealed a high prevalence of neurocognitive and psychosocial concerns in this cohort, emphasizing that mean scores during infancy and toddler years should not be regarded as entirely reassuring with respect to subsequent development. 16 , 17 , 30 However, possible improvements in neurodevelopmental outcomes in patients with d-TGA should be considered in relation to our finding that older age at surgery was associated with lower scores on the Bayley Scales. One prior study 31 demonstrated that brain growth and language development were adversely impacted by delayed surgery for d-TGA, which was more common in previous eras. The adverse impact of unrepaired CHD physiology on infant growth and nutrition as a potential risk factor for impaired brain development has been emphasized by the updated American Heart Association neurodevelopmental guideline. 2 With respect to prenatal brain development, patients with d-TGA are spared some of the more profound fetal circulatory disturbances and impairment of fetal brain growth seen in more severe forms of CHD, such as SVP. 32 The initial findings from the CNOC registry prompt us to reconsider how to conceptualize risk specific to CHD subtype. Attention has so far focused on the severity of heart disease and complexity of the index operation. However, although patients with d-TGA are considered to be medically at higher risk than those with less profound cardiac malformations, such as CoA or VSD, neurodevelopmental outcomes for d-TGA may be better, as suggested by the findings of a recent meta-analysis of cognitive and executive function in children with CHD. 30 The current analysis of the CNOC data suggest that the use of a CHD classification system based on the presence of biventricular vs univentricular physiologic structure with or without aortic arch obstruction results in a wide variety of cardiovascular physiologic findings and timing of surgery being grouped together that may reduce the prognostication possible with more specific diagnoses. One example is the somewhat unexpected finding that among patients without a genetic diagnosis, those with AVSD exhibited lower neurodevelopmental outcomes than patients with other cardiac diagnoses, including SVP. Prolonged hospital length of stay was strongly associated with outcome in our analysis of the CNOC registry data. Longer hospitalizations have been associated with adverse neurodevelopmental outcomes in the setting of CHD in multiple studies. 7 , 33 The basis of this association is likely related to a range of factors, including innate patient factors and treatment effects, that reflect medical complexity, also indicated by the association we observed between neurodevelopmental outcomes and number of cardiac catheterizations. Similarly, patients in STAT category 5 from the CNOC registry exhibited lower neurodevelopmental scores. A complex course in the hospital may interfere with brain development through a number of mechanisms, including abnormal cerebrovascular physiology, brain injury, decreased developmental interactions due to medical fragility, and poor nutrition. Our data therefore reinforce the importance of an approach to inpatient care that promotes optimal neurodevelopment and minimizes the impact of intensive care on developmental trajectory. 34 , 35 The impact of genetic variation on brain development that has previously been identified in the setting of CHD is reinforced by the findings from the CNOC registry. Of note, in patients with CHD and a genetic diagnosis, there were fewer differences in neurodevelopmental outcomes among different cardiac diagnoses than were present in patients without a genetic diagnosis. This initial analysis of the registry also supports the findings of other studies that have identified the importance of social drivers of health on neurodevelopmental outcomes. 12 , 13 In keeping with our findings, prior studies have shown that higher parental educational level is associated with improved early developmental skills as well as fewer behavioral and emotional concerns. 11 , 18 , 36 Other studies in children with CHD have shown that higher median household income, lower percentage below poverty, and lower unemployment rate are associated with higher infant and toddler abilities. 19 , 37 Although our current findings showed only a modest association for cognitive outcomes with COI, this may be attributable to limited zip code data currently available through the CNOC registry. Limitations There are several limitations to this study. The data are contributed through the clinical CNOC registry, whereby some variables cannot be entered by some sites, including zip code. The size of our dataset was further limited by our conservative approach to excluding patients from the primary analyses for whom the Bayley raw scores were not available. In addition, clinical registry data may be subject to patient heterogeneity and practice variation by site. Selection bias is also an important limitation of this study. We previously reported that 29% of eligible patients in our cohort attended for neurodevelopmental assessment. 22 Attendance was associated with factors that may have impacted development, including hospital-initiated rather than family-initiated scheduling of follow-up, antenatal diagnosis, absence of trisomy 21, higher STAT category, longer hospitalization, private insurance, and residing a shorter distance from the hospital. Importantly, patients may have been more likely to attend for follow-up if there were concerns about their development, which may have resulted in downward skewing of the scores. Lastly, our reliance on the clinical detection of genetic diagnoses likely resulted in some patients with occult genetic diagnoses being included in the group without genetic diagnoses. Despite these potential shortcomings of registry research, our findings align with the 2024 Scientific Statement of the American Heart Association, which recommends serial developmental evaluation for all children undergoing cardiac surgery with cardiopulmonary bypass during infancy to detect neurodevelopmental issues early, thus facilitating timely intervention. 2 Conclusions In this cross-sectional study of children with CHD, we observed an association between cardiac diagnosis and early neurodevelopmental outcomes, with improved outcomes in participants with d-TGA in toddlerhood. Previously identified medical risk factors, including preterm birth, low birth weight, and prolonged hospitalization, were associated with an increased risk of adverse neurodevelopmental outcomes, whereas more cardiac catheterizations and older age at first open-heart surgery were also associated with lower scores on neurodevelopmental testing. The presence of trisomy 21 and 22Q11.2 deletion syndrome were the most important risk factors for neurodevelopmental delay, whereas previously identified social drivers of health, such as parental educational level and COI, were also significant. The finding of lower scores on neurodevelopmental testing in children with somewhat less severe forms of CHD, such as CoA, VSD, TOF, and AVSD, compared with d-TGA, emphasizes the importance of follow-up for all infants undergoing infant heart surgery. Supplement 1. eTable 1. Association of Genetic Diagnosis with Neurodevelopmental Outcomes on the Bayley Scales of Infant Development eTable 2. 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