The Effect of Neurodevelopmental Disorders on the Prognosis of Children Undergoing Heart Transplantation: A Retrospective Analysis of the National Inpatient Sample 2011–2019
DOI:
https://doi.org/10.59958/hsf.7289Keywords:
neurodevelopmental disorder, heart failure, heart transplant, transplant rejectionAbstract
Background: Many international governing bodies recommend against heart transplantation in patients with severe cognitive-behavioral disabilities, however no clear criteria are offered to define severity. Patients with neurodevelopmental disorders may face systematic discrimination when being evaluated for transplant. We set out to investigate whether children with neurodevelopmental disorders that undergo heart transplantation have poorer in-hospital outcomes compared to neurotypical children. Methods: A retrospective analysis of the National Inpatient Sample database was conducted to identify pediatric patients with neurodevelopmental disorders who underwent heart transplantation from 2011–2019. Baseline characteristics and in-hospital outcomes between patients were compared. Binary logistic regression was used to investigate the association between the documented presence of a neurodevelopmental disorder and in-hospital outcomes in children undergoing heart transplantation. Results: We identified a weighted sample of 3770 pediatric cardiac transplant patients, of whom 245 (6.5%) had a documented diagnosis of neurodevelopmental disorder. There was no significant difference in the odds of major adverse cardiovascular events (all-cause mortality, stroke complications or myocardial infarction), surgical complications, infection, venous thromboembolic events, delirium/restraint use, or cardiac dysrhythmia. Patients with neurodevelopmental disorders had lower overall length of stay (44.0 days interquartile range (IQR): 16.0–90.0 vs. 57.08 days IQR: 22.0–112.0, p < 0.050), and cost of stay ($956,031 IQR: 548,559.0–1,801,412.0 vs. $1,074,793 IQR: 599,089.8–2,129,086.0, p < 0.050). Patients with neurodevelopmental disorders had significantly lower odds of acute transplant complications (adjusted odds ratio (aOR): 0.39, 95% confidence interval (CI): 0.21–0.74, p < 0.050) vascular complications (aOR: 0.36, 95% CI: 0.19–0.66, p < 0.050) and acute kidney injury (AKI) (aOR: 0.52, 95% CI: 0.33–0.83, p < 0.050). Conclusions: These data suggest that patients with neurodevelopmental disorders have overall similar if not potentially improved post-transplant outcomes in the acute setting compared to neurotypical patients, possibly secondary to selection bias in the patient selection process.
References
Dipchand AI. Current state of pediatric cardiac transplantation. Annals of Cardiothoracic Surgery. 2018; 7: 31–55.
Dipchand AI, Webber SA. Pediatric heart transplantation: Looking forward after five decades of learning. Pediatric Transplantation. 2024; 28: e14675.
Williams RJ, Lu M, Sleeper LA, Blume ED, Esteso P, Fynn-Thompson F, et al. Pediatric heart transplant waiting times in the United States since the 2016 allocation policy change. American Journal of Transplantation: Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2022; 22: 833–842.
Colvin MM, Smith JM, Ahn YS, Messick E, Lindblad K, Israni AK, et al. OPTN/SRTR 2021 Annual Data Report: Heart. American Journal of Transplantation: Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2023; 23: S300–S378.
Amdani S, Bhimani SA, Boyle G, Liu W, Worley S, Saarel E, et al. Racial and Ethnic Disparities Persist in the Current Era of Pediatric Heart Transplantation. Journal of Cardiac Failure. 2021; 27: 957–964.
Zubair MM, Chen Q, Rowe G, Gill G, Thomas J, Timbalia SA, et al. Evolving Trends and Widening Racial Disparities in Children Listed for Heart Transplantation in the United States. Circulation. 2022; 146: 262–264.
Adebiyi E, Jennifer Christine MP. Temporal trends and regional variation of heart transplantation in children with intellectual and developmental disabilities. Pediatric Transplantation. 2023; 27: e14620.
Association AP. Diagnostic and Statistical Manual of Mental Disorders. American Psychiatric Association: San Francisco, CA. 2013.
Francés L, Quintero J, Fernández A, Ruiz A, Caules J, Fillon G, et al. Current state of knowledge on the prevalence of neurodevelopmental disorders in childhood according to the DSM-5: a systematic review in accordance with the PRISMA criteria. Child and Adolescent Psychiatry and Mental Health. 2022; 16: 27.
Durkin MS. Increasing Prevalence of Developmental Disabilities Among Children in the US: A Sign of Progress? Pediatrics. 2019; 144: e20192005.
Maenner MJ, Warren Z, Williams AR, Amoakohene E, Bakian AV, Bilder DA, et al. Prevalence and Characteristics of Autism Spectrum Disorder Among Children Aged 8 Years - Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2020. Morbidity and Mortality Weekly Report. Surveillance Summaries (Washington, D.C.: 2002). 2023; 72: 1–14.
Ayano G, Demelash S, Gizachew Y, Tsegay L, Alati R. The global prevalence of attention deficit hyperactivity disorder in children and adolescents: An umbrella review of meta-analyses. Journal of Affective Disorders. 2023; 339: 860–866.
Patel DR, Cabral MD, Ho A, Merrick J. A clinical primer on intellectual disability. Translational Pediatrics. 2020; 9: S23–S35.
Moll K, Kunze S, Neuhoff N, Bruder J, Schulte-Körne G. Specific learning disorder: prevalence and gender differences. PLoS ONE. 2014; 9: e103537.
Chouksey A, Pandey S. Functional Movement Disorders in Children. Frontiers in Neurology. 2020; 11: 570151.
Ruben RJ. Redefining the survival of the fittest: communication disorders in the 21st century. The Laryngoscope. 2000; 110: 241–245.
Dhanasekara CS, Ancona D, Cortes L, Hu A, Rimu AH, Robohm-Leavitt C, et al. Association Between Autism Spectrum Disorders and Cardiometabolic Diseases: A Systematic Review and Meta-analysis. JAMA Pediatrics. 2023; 177: 248–257.
Li L, Chang Z, Sun J, Garcia-Argibay M, Du Rietz E, Dobrosavljevic M, et al. Attention-deficit/hyperactivity disorder as a risk factor for cardiovascular diseases: a nationwide population-based cohort study. World Psychiatry: Official Journal of the World Psychiatric Association (WPA). 2022; 21: 452–459.
Wang H, Lee PMY, Zhang J, Svendsen K, Li F, Li J. Association of intellectual disability with overall and type-specific cardiovascular diseases: a population-based cohort study in Denmark. BMC Medicine. 2023; 21: 41.
Zwack CC, McDonald R, Tursunalieva A, Cooray A, Lambert GW, Lambert EA. Does autonomic nervous system dysfunction influence cardiovascular disease risk in young adults with intellectual disability? American Journal of Physiology. Heart and Circulatory Physiology. 2021; 320: H891–H900.
Rossi M, Wainsztein N, Merello M. Cardiac Involvement in Movement Disorders. Movement Disorders Clinical Practice. 2021; 8: 651–668.
Erickson SR, Basu T, Dorsch MP, Kamdar N. Disparities in the Use of Guideline-Based Pharmacotherapy Exist for Atherosclerotic Cardiovascular Disease and Heart Failure Patients Who Have Intellectual/Developmental Disabilities in a Commercially Insured Database. The Annals of Pharmacotherapy. 2020; 54: 958–966.
Marino BS, Lipkin PH, Newburger JW, Peacock G, Gerdes M, Gaynor JW, et al. Neurodevelopmental outcomes in children with congenital heart disease: evaluation and management: a scientific statement from the American Heart Association. Circulation. 2012; 126: 1143–1172.
Sigmon ER, Kelleman M, Susi A, Nylund CM, Oster ME. Congenital Heart Disease and Autism: A Case-Control Study. Pediatrics. 2019; 144: e20184114.
Radoeva PD, Coman IL, Salazar CA, Gentile KL, Higgins AM, Middleton FA, et al. Association between autism spectrum disorder in individuals with velocardiofacial (22q11.2 deletion) syndrome and PRODH and COMT genotypes. Psychiatric Genetics. 2014; 24: 269–272.
Wier ML, Yoshida CK, Odouli R, Grether JK, Croen LA. Congenital anomalies associated with autism spectrum disorders. Developmental Medicine and Child Neurology. 2006; 48: 500–507.
Hultman CM, Sparén P, Cnattingius S. Perinatal risk factors for infantile autism. Epidemiology (Cambridge, Mass.). 2002; 13: 417–423.
Fourdain S, St-Denis A, Harvey J, Birca A, Carmant L, Gallagher A, et al. Language development in children with congenital heart disease aged 12-24 months. European Journal of Paediatric Neurology: EJPN: Official Journal of the European Paediatric Neurology Society. 2019; 23: 491–499.
Ji W, Ferdman D, Copel J, Scheinost D, Shabanova V, Brueckner M, et al. De novo damaging variants associated with congenital heart diseases contribute to the connectome. Scientific Reports. 2020; 10: 7046.
Assimopoulos S, Hammill C, Fernandes DJ, Spencer Noakes TL, Zhou YQ, Nutter LMJ, et al. Genetic mouse models of autism spectrum disorder present subtle heterogenous cardiac abnormalities. Autism Research: Official Journal of the International Society for Autism Research. 2022; 15: 1189–1208.
Cusmano-Ozog K, Manning MA, Hoyme HE. 22q13.3 deletion syndrome: a recognizable malformation syndrome associated with marked speech and language delay. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics. 2007; 145C: 393–398.
Ornoy A, Weinstein-Fudim L, Ergaz Z. Genetic Syndromes, Maternal Diseases and Antenatal Factors Associated with Autism Spectrum Disorders (ASD). Frontiers in Neuroscience. 2016; 10: 316.
Pierpont ME, Brueckner M, Chung WK, Garg V, Lacro RV, McGuire AL, et al. Genetic Basis for Congenital Heart Disease: Revisited: A Scientific Statement From the American Heart Association. Circulation. 2018; 138: e653–e711.
Batsukh T, Pieper L, Koszucka AM, von Velsen N, Hoyer-Fender S, Elbracht M, et al. CHD8 interacts with CHD7, a protein which is mutated in CHARGE syndrome. Human Molecular Genetics. 2010; 19: 2858–2866.
Cohen ED, Tian Y, Morrisey EE. Wnt signaling: an essential regulator of cardiovascular differentiation, morphogenesis and progenitor self-renewal. Development (Cambridge, England). 2008; 135: 789–798.
Cotney J, Muhle RA, Sanders SJ, Liu L, Willsey AJ, Niu W, et al. The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment. Nature Communications. 2015; 6: 6404.
Hubert F, Payan SM, Rochais F. FGF10 Signaling in Heart Development, Homeostasis, Disease and Repair. Frontiers in Genetics. 2018; 9: 599.
Shanks MO, Lund LM, Manni S, Russell M, Mauban JRH, Bond M. Chromodomain helicase binding protein 8 (Chd8) is a novel A-kinase anchoring protein expressed during rat cardiac development. PLoS ONE. 2012; 7: e46316.
Ko JM. Genetic Syndromes associated with Congenital Heart Disease. Korean Circulation Journal. 2015; 45: 357–361.
Lim S, Naisbitt S, Yoon J, Hwang JI, Suh PG, Sheng M, et al. Characterization of the Shank family of synaptic proteins. Multiple genes, alternative splicing, and differential expression in brain and development. The Journal of Biological Chemistry. 1999; 274: 29510–29518.
Man W, Gu J, Wang B, Zhang M, Hu J, Lin J, et al. SHANK3 Co-ordinately Regulates Autophagy and Apoptosis in Myocardial Infarction. Frontiers in Physiology. 2020; 11: 1082.
Ghebranious N, Giampietro PF, Wesbrook FP, Rezkalla SH. A novel microdeletion at 16p11.2 harbors candidate genes for aortic valve development, seizure disorder, and mild mental retardation. American Journal of Medical Genetics. Part a. 2007; 143A: 1462–1471.
Sun H, Wang Y. Branched chain amino acid metabolic reprogramming in heart failure. Biochimica et Biophysica Acta. 2016; 1862: 2270–2275.
Wang Y. Mitogen-activated protein kinases in heart development and diseases. Circulation. 2007; 116: 1413–1423.
Xie H, Hong N, Zhang E, Li F, Sun K, Yu Y. Identification of Rare Copy Number Variants Associated With Pulmonary Atresia With Ventricular Septal Defect. Frontiers in Genetics. 2019; 10: 15.
Xu M, Yao J, Shi Y, Yi H, Zhao W, Lin X, et al. The SRCAP chromatin remodeling complex promotes oxidative metabolism during prenatal heart development. Development (Cambridge, England). 2021; 148: dev199026.
Hunter JE, Berry-Kravis E, Hipp H, Todd PK. FMR1 Disorders. GeneReviews® [Internet]. 2019. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1384/ (Accessed: 1 October 2023).
Mlczoch E, Brugger P, Ulm B, Novak A, Frantal S, Prayer D, et al. Structural congenital brain disease in congenital heart disease: results from a fetal MRI program. European Journal of Paediatric Neurology: EJPN: Official Journal of the European Paediatric Neurology Society. 2013; 17: 153–160.
Schellen C, Ernst S, Gruber GM, Mlczoch E, Weber M, Brugger PC, et al. Fetal MRI detects early alterations of brain development in Tetralogy of Fallot. American Journal of Obstetrics and Gynecology. 2015; 213: 392.e1–392.e7.
Mehra MR, Canter CE, Hannan MM, Semigran MJ, Uber PA, Baran DA, et al. The 2016 International Society for Heart Lung Transplantation listing criteria for heart transplantation: A 10-year update. The Journal of Heart and Lung Transplantation: the Official Publication of the International Society for Heart Transplantation. 2016; 35: 1–23.
Houchens R, Elixhauser A. Using the HCUP Nationwide Inpatient Sample to Estimate Trends. US Agency for Healthcare and Research Quality. Rockville, MD. 2005.
Hsich EM, Rogers JG, McNamara DM, Taylor DO, Starling RC, Blackstone EH, et al. Does Survival on the Heart Transplant Waiting List Depend on the Underlying Heart Disease? JACC. Heart Failure. 2016; 4: 689–697.
Breathett K, Yee E, Pool N, Hebdon M, Crist JD, Knapp S, et al. Does Race Influence Decision Making for Advanced Heart Failure Therapies? Journal of the American Heart Association. 2019; 8: e013592.
Pendo E. Equal Access to Organ Transplantation for People with Disabilities. The Hastings Center Report. 2021; 51: 4–6.
Richards CT, Crawley LM, Magnus D. Use of neurodevelopmental delay in pediatric solid organ transplant listing decisions: inconsistencies in standards across major pediatric transplant centers. Pediatric Transplantation. 2009; 13: 843–850.
Goel AN, Iyengar A, Schowengerdt K, Fiore AC, Huddleston CB. Heart transplantation in children with intellectual disability: An analysis of the UNOS database. Pediatric Transplantation. 2017; 21: e12858.
Bircan E, Politis MD, Gokun Y, Luo C, Leonard H, Bourke J, et al. Intellectual disabilities and autism among children with congenital heart defects, Western Australia, 1983-2010. BMC Pediatrics. 2023; 23: 106.
Downing KF, Oster ME, Klewer SE, Rose CE, Nembhard WN, Andrews JG, et al. Disability Among Young Adults With Congenital Heart Defects: Congenital Heart Survey to Recognize Outcomes, Needs, and Well-Being 2016-2019. Journal of the American Heart Association. 2021; 10: e022440.
Hirota T, King BH. Autism Spectrum Disorder: A Review. JAMA. 2023; 329: 157–168.
a] Bailey D, Schneider L, Maeda K, Hollander S, Shaw R, Rosenthal D. Orthotopic Heart Transplant in a Child with Nonverbal Autism. Austin Journal of Autism and Related Disabilities. 2016; 2: 1017.
Todaro JF, Fennell EB, Sears SF, Rodrigue JR, Roche AK. Review: cognitive and psychological outcomes in pediatric heart transplantation. Journal of Pediatric Psychology. 2000; 25: 567–576.
Mahoney WJ, Villacrusis M, Sompolski M, Iwanski B, Charman A, Hammond C, et al. Nursing care for pediatric patients with autism spectrum disorders: A cross-sectional survey of perceptions and strategies. Journal for Specialists in Pediatric Nursing: JSPN. 2021; 26: e12332.
Gilmore-Bykovskyi AL, Fuhr H, Jin Y, Benson C. Use of Direct In-Person Observation in the Care of Hospitalized Older Adults with Cognitive Impairment: A Systematic Review. Journal of Gerontological Nursing. 2020; 46: 23–30.
