Cardiac Neurodevelopment: What do single-ventricle patients look like as adolescents?

The Fontan procedure has dramatically improved the survival of children with single-ventricle heart disease. With a burgeonoing Fontan population, however, important neurodevelopmental problems are now evident in some survivors.

“Single-ventricle physiology creates cerebrovascular hemodynamics that can reduce oxygen delivery to the brain,” says Jane Newburger, MD, MPH, director of the Heart Center’s Cardiac Neurodevelopmental Program. “At birth, these children spend a longer time with cyanosis. Compared to children with other forms of congenital heart disease, they tend to have more operations and catheterizations and to have a rockier course after surgery. They are also more prone to challenges with adequate nutrition and growth.”

How does this play out in adolescence? Three recent studies provide the longest neurodevelopmental follow-up after Fontan operations tracking neurologic, cognitive, behavioral and brain structural outcomes in patients as old as 19 years. The research was a collaboration between investigators in the Departments of Cardiology, Neurology and Psychiatry.

The bottom line findings:

  • Cognitive and neurologic outcomes

A study led by Newburger and David Bellinger, PhD, of the Department of Neurology, evaluated 156 adolescents with single-ventricle disease, most who had their Fontan procedure at Boston Children’s. The single-ventricle group scored significantly lower for overall IQ, reading ability and mathematics ability (mean values in the low 90s, vs. the population norm of 100). IQ scores were also lower than those of 111 healthy control adolescents from the Boston area (see figure below). Testing showed relatively good verbal ability but poor visuospatial skills (e.g., visual memory, sense of direction), worse executive function as rated by parents and teachers, slower mental processing and lower social cognition (e.g., less able to correctly interpret facial expressions).

The Fontan group also showed more autism-like behaviors. Twenty-two percent had been diagnosed with ADHD and 37% with a learning disability.

At the individual level, scores ranged widely. Adolescents with cognitive deficits were more likely to have a definite genetic abnormality (identified in 10%) and a history of seizures (15%).

Brain MRI studies showed striking differences; abnormalities were found in 66% of the Fontan group versus 6% of controls. Nineteen Fontan patients (13%) had evidence of a prior stroke, seven of whom had not previously had a diagnosis.

Reference: Bellinger DC; et al. J Am Heart Assoc 2015 Dec 14; doi: 10.1161/JAHA.115.002302.

  • Mental health outcomes

Mental health outcomes have been under-investigated in children with CHD. A study led by Newburger and David DeMaso, MD, psychiatrist-in-chief at Boston Children’s, conducted extensive psychiatric evaluations of the same group of 156 adolescents, coupling them with parent- and self-ratings.

Overall, teens with single ventricle were much more likely to have received a psychiatric diagnosis than the controls (65% vs. 22%), especially anxiety (35% vs. 7%) and ADHD (34% vs. 6%). The single-ventricle group also scored, on average, about 20% lower on measures of psychosocial functioning. Scores indicated significantly more anxiety, disruptive behavior and depressive symptoms.

Reference: DeMaso DR; et al.. Pediatrics 2017 Mar; 139(3). doi: 10.1542/peds.2016-2241.

  • Structural brain changes

Differences in brain structure of CHD patients have been documented in utero. What changes persist into adolescence? A study led by Michael Rivkin, MD, of the Department of Neurology, built on earlier structural MRI findings to look at specific, quantitative structural differences. Rivkin and colleagues obtained volumetric brain MRI data from 128 post-Fontan pre-teens and adolescents seen at the Heart Center. They documented widespread, significant reductions in cortical and subcortical grey matter volumes (the colored portions in A and B below) and reduced cortical thicknesses (C and D) as compared to 48 healthy control subjects:

The lower volumes and thicknesses spanned the frontal, temporal, parietal and occipital lobes and were seen throughout the subcortical gray matter.

Reference: Watson CG; et al. Pediatr Res 2017 May 3; doi: 10.1038/pr.2017.30.

Takeaways for clinicians

Newburger urges early neurodevelopmental and behavioral screenings for children with single ventricle physiology, because early interventions can help them overcome some deficits. She also stresses that there is great variability in outcomes.

“We see some brilliant individuals who have undergone the Fontan procedure, and others with profound neurocognitive and psychosocial challenges,” she says.

The Cardiac Neurodevelopmental Program can help evaluate children and adolescents with single ventricle, provide guidance regarding developmental and education interventions, and contribute to the development of Individualized Education Programs (IEPs) that meet their needs. Members of the program are also conducting two clinical trials of CogMed, a game-based working memory and attention training program, in children ages 7 to 12 (NCT03023644) and adolescents ages 13 to 16 (NCT02759263). CogMed is available for Apple and Android devices. For enrollment information, contact

Research Highlights

A sample of recently published research by Heart Center faculty. 

Allan CK, Tannous P, DeWitt E, Farias M, Mansfield L, Ronai, C, Schidlow, D, Sanders SP, Lock JE, Newburger JW, Brown DW.  A Pediatric Cardiology Fellowship Boot Camp improves trainee confidence. Cardiology in the young. Dec 2016;26(8):1514-1521.

Baird CW, Zurakowski D, Bueno ABorisuk MJ, Raju V, Mokashi SA, Emani S, Marx GR, & Del Nido, PJ. 2016. Outcomes and Short-Term Follow-Up in Complex Ross Operations in Pediatric Patients Undergoing Damus-Kaye-Stansel Takedown. Semin Thorac Cardiovasc Surg, 28(1): 81-89.

Bezzerides VJ, Zhang D, Pu WT. Modeling Inherited Arrhythmia Disorders Using Induced Pluripotent Stem Cell-Derived Cardiomyocytes. Circulation journal : official journal of the Japanese Circulation Society 2016;81:12-21.

Callahan R, Bergersen L, Baird CW, et al. Mechanism of valve failure and efficacy of reintervention through catheterization in patients with bioprosthetic valves in the pulmonary position. Annals of pediatric cardiology 2017;10:11-7.

Cevallos PC, Armstrong AK, Glatz AC, Goldstein BH, Gudausky TM, Leahy RA, Petit CJ, Shahanavaz S, Trucco SM, Bergersen, LJ. Radiation dose benchmarks in pediatric cardiac catheterization: A prospective multi-center C3PO-QI study. Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions. Feb 15 2017.

Chowdhury D, Gurvitz M, Marelli A, Anderson J, Baker-Smith C, Diab KA, Edwards TC, Hougen T, Jedeikin R, Johnson JN, Karpawich P, Lai W, Lu JC, Mitchell S, Newburger JW, Penny DJ, Portman MA, Satou G, Teitel D, Villafane J, Williams R, Jenkins K. American College of Cardiology’s Adult, Congenital, Pediatric Cardiology Section’s Ambulatory Pediatric Cardiology Quality Metrics Working, Group. Development of Quality Metrics in Ambulatory Pediatric Cardiology. Journal of the American College of Cardiology. Feb 07 2017;69(5):541-555.

de Ferranti SD, Rodday AM, Parsons SK, Cull WL, O’Connor KG, Daniels SR, Leslie, LK. Cholesterol Screening and Treatment Practices and Preferences: A Survey of United States Pediatricians. The Journal of pediatrics. Feb 13 2017.

Freud LR, Marx GR, Marshall AC, Tworetzky W, & Emani SM. 2016. Assessment of the Melody valve in the mitral position in young children by echocardiography. J Thorac Cardiovasc Surg.

Howard TS, Kalish BT, Wigmore D, Nathan M, Kulik TJ, Kaza AK, Williams K, Thiagarajan RR. Association of Extracorporeal Membrane Oxygenation Support Adequacy and Residual Lesions With Outcomes in Neonates Supported After Cardiac Surgery. Pediatr Crit Care Med. Nov 2016;17(11):1045-1054.

Kaza AKWamala I, Friehs I, Kuebler JD, Rathod RH, Berra I, Ericsson M, Yao R, Thedsanamoorthy JK, Zurakowski D, Levitsky S, Del Nido PJ, Cowan DB, McCully JD. Myocardial rescue with autologous mitochondrial transplantation in a porcine model of ischemia/reperfusion. The Journal of thoracic and cardiovascular surgery 2017;153:934-43

Kim YY, Rathod RH, Gauvreau K, Keenan EM, Del Nido P, & Geva T. 2016. Factors associated with severe aortic dilation in patients with Fontan palliation. Heart.

Laraja K, Sadhwani A, Tworetzky W, Marshall AC, Gauvreau K, Freud LHass C, Dunbar-Masterson CWare JLafranchi T, Wilkins-Haug L, Newburger JW. Neurodevelopmental Outcome in Children after Fetal Cardiac Intervention for Aortic Stenosis with Evolving Hypoplastic Left Heart Syndrome. The Journal of pediatrics 2017;184:130-6 e4.

Mah DY, Shakti D, Gauvreau K, Colan SD, Alexander ME, Abrams DJ, Brown DW. Relation of Left Atrial Size to Atrial Fibrillation in Patients Aged </=22 Years. The American journal of cardiology 2017;119:52-6.

Mayer JE, Jr. 2016. Making progress toward a tissue engineered heart valve. J Thorac Cardiovasc Surg, 152(4): 1165-1166.

O’Connell C, Ziniel S, Hartwell L, Connor J. Management of Opioid and Sedative Weaning in Pediatric Congenital Heart Disease Patients: Assessing the State of Practice. Dimensions of critical care nursing : DCCN. Mar/Apr 2017;36(2):116-124..

Schidlow DN, Jenkins KJ, Gauvreau K, Croti, UA, Giang, DT, Konda, RK, Novick, WM, Sandoval, NF, Castaneda, A. Transposition of the Great Arteries in the Developing World: Surgery and Outcomes. Journal of the American College of Cardiology 2017;69:43-51.

Stern KW, Gauvreau K, Emani S, Geva T. Utility of a standardized postcardiopulmonary bypass epicardial echocardiography protocol for stage I Norwood palliation. Congenital heart disease. Feb 16 2017;12:350-6.

Wu FM, Kogon B, Earing MG, Aboulhosn JA, Broberg CS, John AS, Harmon A, Sainani NI, Hill AJ, Odze RD, Johncilla ME, Ukomadu C, Gauvreau K, Valente AM, Landzberg MJ, Alliance for Adult Research in Congenital Cardiology, Investigators. Liver health in adults with Fontan circulation: A multicenter cross-sectional study. The Journal of thoracic and cardiovascular surgery 2017;153:656-64.

Yuki K, Matsunami E, Tazawa K, Wang W, DiNardo JA, Koutsogiannaki S. Pediatric Perioperative Stress Responses and Anesthesia. Translational perioperative and pain medicine. 2017;2(1):1-12.