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Critical congenital heart disease beyond HLHS and TGA: neonatal brain injury and early neurodevelopment

Pediatric Research volume 94, pages 691–698 (2023)Cite this article

Abstract

Background

Characterization of brain injury and neurodevelopmental (ND) outcomes in critical congenital heart disease (cCHD) has primarily focused on hypoplastic left heart syndrome (HLHS) and transposition of the great arteries (TGA). This study reports brain injury and ND outcomes among patients with heterogeneous cCHD diagnoses beyond HLHS and TGA.

Methods

This prospective cohort study included infants with HLHS, TGA, or heterogenous “Other cCHD” including left- or right-sided obstructive lesions, anomalous pulmonary venous return, and truncus arteriosus. Brain injury on perioperative brain MRI and ND outcomes on the Bayley-II at 30 months were compared.

Results

A total of 218 participants were included (HLHS = 60; TGA = 118; “Other cCHD” = 40, including 8 with genetic syndromes). Pre-operative (n = 209) and post-operative (n = 189) MRI showed similarly high brain injury rates across groups, regardless of cardiopulmonary bypass exposure. At 30 months, participants with “Other cCHD” had lower cognitive scores (p = 0.035) compared to those with HLHS and TGA, though worse ND outcome in this group was driven by those with genetic disorders.

Conclusions

Frequency of brain injury and neurodevelopmental delay among patients with “Other cCHD” is similar to those with HLHS or TGA. Patients with all cCHD lesions are at risk for impaired outcomes; developmental and genetic screening is indicated.

Impact

  • This study adds to literature on risk of brain injury in patients with critical congenital heart disease (cCHD) diagnoses other than hypoplastic left heart syndrome (HLHS) and transposition of the great arteries (TGA), a heterogenous cohort of patients that has often been excluded from imaging studies.

  • Children with cCHD beyond HLHS and TGA have similarly high rates of acquired brain injury.

  • The high rate of neurodevelopmental impairment in this heterogenous group of cCHD diagnoses beyond HLHS and TGA is primarily driven by patients with comorbid genetic syndromes such as 22q11.2 deletion syndrome.

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Fig. 1: Consort diagram.

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Data availability

The datasets generated and analyzed during the current study are not publicly available due to protected health information that, if shared, would compromise the privacy of the individuals. Data are available from the corresponding author on reasonable request.

References

  1. Spillmann, R. et al. Congenital heart disease in school-aged children: cognition, education, and participation in leisure activities. Pediatr. Res. https://doi.org/10.1038/s41390-021-01853-4 (2021).

  2. Miller, S. P. et al. Abnormal brain development in newborns with congenital heart disease. N. Engl. J. Med. 357, 1928–1938 (2007).

    CAS  PubMed  Google Scholar 

  3. Limperopoulos, C. et al. Brain volume and metabolism in fetuses with congenital heart disease: evaluation with quantitative magnetic resonance imaging and spectroscopy. Circulation 121, 26–33 (2010).

    CAS  PubMed  Google Scholar 

  4. Rollins, C. K. et al. Regional brain growth trajectories in fetuses with congenital heart disease. Ann. Neurol. 89, 143–157 (2021).

    PubMed  Google Scholar 

  5. Khalil, A. et al. Brain abnormalities and neurodevelopmental delay in congenital heart disease: systematic review and meta-analysis: brain abnormalities and neurodevelopmental delay in CHD. Ultrasound Obstet. Gynecol. 43, 14–24 (2014).

    CAS  PubMed  Google Scholar 

  6. Dimitropoulos, A. et al. Brain injury and development in newborns with critical congenital heart disease. Neurology 81, 241–248 (2013).

    PubMed  PubMed Central  Google Scholar 

  7. Peyvandi, S. et al. Association of prenatal diagnosis of critical congenital heart disease with postnatal brain development and the risk of brain injury. JAMA Pediatr. 170, e154450 (2016).

    PubMed  PubMed Central  Google Scholar 

  8. Miller, S. P. et al. Preoperative brain injury in newborns with transposition of the great arteries. Ann. Thorac. Surg. 77, 1698–1706 (2004).

    PubMed  Google Scholar 

  9. Peyvandi, S. et al. Neonatal brain injury and timing of neurodevelopmental assessment in patients with congenital heart disease. J. Am. Coll. Cardiol. 71, 1986–1996 (2018).

    PubMed  PubMed Central  Google Scholar 

  10. Lim, J. M. et al. Associations between age at arterial switch operation, brain growth, and development in infants with transposition of the great arteries. Circulation 139, 2728–2738 (2019).

    PubMed  Google Scholar 

  11. Andropoulos, D. B. et al. Brain immaturity is associated with brain injury before and after neonatal cardiac surgery with high-flow bypass and cerebral oxygenation monitoring. J. Thorac. Cardiovasc. Surg. 139, 543–556 (2010).

    PubMed  Google Scholar 

  12. Bonthrone, A. F. et al. Individualized brain development and cognitive outcome in infants with congenital heart disease. Brain Commun. 3, fcab046 (2021).

    PubMed  PubMed Central  Google Scholar 

  13. Claessens, N. H. P. et al. Brain injury in infants with critical congenital heart disease: insights from two clinical cohorts with different practice approaches. J. Pediatr. 215, 75.e2–82.e2 (2019).

    Google Scholar 

  14. Feldmann, M. et al. Delayed maturation of the structural brain connectome in neonates with congenital heart disease. Brain Commun. 2, fcaa209 (2020).

    PubMed  PubMed Central  Google Scholar 

  15. Ortinau, C. et al. Congenital heart disease affects cerebral size but not brain growth. Pediatr. Cardiol. 33, 1138–1146 (2012).

    PubMed  PubMed Central  Google Scholar 

  16. Lynch, J. M. et al. Preoperative cerebral hemodynamics from birth to surgery in neonates with critical congenital heart disease. J. Thorac. Cardiovasc. Surg. 156, 1657–1664 (2018).

    PubMed  PubMed Central  Google Scholar 

  17. Ceschin, R., Zahner, A., Reynolds, W., Beluk, N. & Panigrahy, A. Reduced cerebellar volume in term infants with complex congenital heart disease: correlation with postnatal growth measurements. Diagnostics 12, 1644 (2022).

    PubMed  PubMed Central  Google Scholar 

  18. Williams, W. G. et al. Outcomes of 829 neonates with complete transposition of the great arteries 12-17 years after repair. Eur. J. Cardio-Thorac. Surg. 24, 1–9 (2003). discussion 9-10.

    CAS  Google Scholar 

  19. Sananes, R. et al. Six-year neurodevelopmental outcomes for children with single-ventricle physiology. Pediatrics 147, e2020014589 (2021).

    PubMed  Google Scholar 

  20. Holland, J. E. et al. Psychiatric disorders and function in adolescents with tetralogy of Fallot. J. Pediatr. 187, 165–173 (2017).

    PubMed  Google Scholar 

  21. Favilla, E. et al. Early evaluation and the effect of socioeconomic factors on neurodevelopment in infants with tetralogy of Fallot. Pediatr. Cardiol. 42, 643–653 (2021).

    PubMed  PubMed Central  Google Scholar 

  22. Peyvandi, S. et al. The association between cardiac physiology, acquired brain injury, and postnatal brain growth in critical congenital heart disease. J. Thorac. Cardiovasc. Surg. 155, 291–300.e3 (2018).

    PubMed  Google Scholar 

  23. Moore, T., Johnson, S., Haider, S., Hennessy, E. & Marlow, N. Relationship between Test Scores Using the Second and Third Editions of the Bayley Scales in Extremely Preterm Children. J. Pediatr. 160, 553–558 (2012).

    PubMed  Google Scholar 

  24. Johnson, S., Moore, T. & Marlow, N. Using the Bayley-III to assess neurodevelopmental delay: which cut-off should be used? Pediatr. Res. 75, 670–674 (2014).

    PubMed  Google Scholar 

  25. IBM SPSS Statistics for Windows (IBM Corp., 2020).

  26. Miller-Hance, W. C. & Tacy, T. A. Gender differences in pediatric cardiac surgery: the cardiologist’s perspective. J. Thorac. Cardiovasc. Surg. 128, 7–10 (2004).

    PubMed  Google Scholar 

  27. Algra, S. O. et al. Minimizing the risk of preoperative brain injury in neonates with aortic arch obstruction. J. Pediatr. 165, 1116.e3–1122.e3 (2014).

    Google Scholar 

  28. Marino, B. S. et al. Neurodevelopmental outcomes in children with congenital heart disease: evaluation and management: a scientific statement from the American Heart Association. Circulation 126, 1143–1172 (2012).

    PubMed  Google Scholar 

  29. Simon, B. V. et al. Neurodevelopmental delay after the neonatal repair of coarctation and arch obstruction. Ann. Thorac. Surg. 108, 1416–1422 (2019).

    PubMed  Google Scholar 

  30. Long, S. H., Galea, M. P., Eldridge, B. J. & Harris, S. R. Performance of 2-year-old children after early surgery for congenital heart disease on the Bayley Scales of Infant and Toddler Development, Third Edition. Early Hum. Dev. 88, 603–607 (2012).

    PubMed  Google Scholar 

  31. Goldstone, A. B. et al. The Bayley-III scale may underestimate neurodevelopmental disability after cardiac surgery in infants. Eur. J. Cardiothorac. Surg. 57, 63–71 (2020).

    PubMed  Google Scholar 

  32. Claessens, N. H. P. et al. Perioperative neonatal brain injury is associated with worse school-age neurodevelopment in children with critical congenital heart disease. Dev. Med. Child Neurol. 60, 1052–1058 (2018).

    PubMed  Google Scholar 

  33. Gaynor, J. W. et al. Patient characteristics are important determinants of neurodevelopmental outcome at one year of age after neonatal and infant cardiac surgery. J. Thorac. Cardiovasc. Surg. 133, 1344–1353 (2007).

    PubMed  PubMed Central  Google Scholar 

  34. Fuller, S. et al. Predictors of impaired neurodevelopmental outcomes at one year of age after infant cardiac surgery. Eur. J. Cardiothorac. Surg. 36, 40–48 (2009).

    PubMed  Google Scholar 

  35. Zaidi, S. & Brueckner, M. Genetics and genomics of congenital heart disease. Circ. Res. 120, 923–940 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Patel, A. et al. Prevalence of noncardiac and genetic abnormalities in neonates undergoing cardiac operations: analysis of The Society of Thoracic Surgeons Congenital Heart Surgery Database. Ann. Thorac. Surg. 102, 1607–1614 (2016).

    PubMed  PubMed Central  Google Scholar 

  37. Landis, B. J., Cooper, D. S. & Hinton, R. B. CHD associated with syndromic diagnoses: peri-operative risk factors and early outcomes. Cardiol. Young 26, 30–52 (2016).

    PubMed  Google Scholar 

  38. Carotti, A. et al. Cardiac defects and results of cardiac surgery in 22q11.2 deletion syndrome. Dev. Disabil. Res. Rev. 14, 35–42 (2008).

    PubMed  Google Scholar 

  39. Alsoufi, B. et al. The effect of noncardiac and genetic abnormalities on outcomes following neonatal congenital heart surgery. Semin. Thorac. Cardiovasc. Surg. 28, 105–114 (2016).

    PubMed  Google Scholar 

  40. Yi, J. J. et al. Contribution of congenital heart disease to neuropsychiatric outcome in school-age children with 22q11.2 deletion syndrome. Am. J. Med. Genet. B Neuropsychiatr. Genet. 165B, 137–147 (2014).

    PubMed  Google Scholar 

  41. Gaynor, J. W. et al. Neurodevelopmental outcomes after cardiac surgery in infancy. Pediatrics 135, 816–825 (2015).

    PubMed  PubMed Central  Google Scholar 

  42. Naef, N. et al. Neurodevelopmental profiles of children with congenital heart disease at school age. J. Pediatr. 188, 75–81 (2017).

    PubMed  Google Scholar 

  43. Homsy, J. et al. De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies. Science 350, 1262–1266 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Jin, S. C. et al. Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands. Nat. Genet. 49, 1593–1601 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Bucholz, E. M. et al. Socioeconomic status and long-term outcomes in single ventricle heart disease. Pediatrics 146, e20201240 (2020).

    PubMed  Google Scholar 

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Acknowledgements

We would like to acknowledge the neuroradiologic contributions by Dr. A. James Barkovich (A.J.B.) and Dr. Kenneth Poskitt (K.P.).

Funding

This work was supported by the NINDS grant K23 NS099422 and P01 NS082330 from the National Institutes of Health.

Author information

Authors and Affiliations

  1. Division of Pediatric Neurology, Department of Neurology, Benioff Children’s Hospital, University of California, San Francisco, CA, USA

    Rachel Vassar & Dawn Gano

  2. Division of Pediatric Cardiology, Department of Pediatrics, Benioff Children’s Hospital, University of California, San Francisco, CA, USA

    Shabnam Peyvandi, Stephany Cox & Yensy Zetino

  3. Division of Developmental Medicine, Department of Pediatrics, Benioff Children’s Hospital, University of California, San Francisco, CA, USA

    Stephany Cox

  4. Department of Neurology, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada

    Steven Miller

  5. Division of Critical Care, Department of Pediatrics, Benioff Children’s Hospital, University of California, San Francisco, CA, USA

    Patrick McQuillen

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  1. Rachel Vassar
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Contributions

R.V.: substantial contributions to analysis and interpretation of data; drafting of article, revising article critically for important intellectual content; final approval of the version to be published. S.P. and P.M.: substantial contributions to conception and design, acquisition of data, and analysis and interpretation of data; drafting/revising article critically for important intellectual content; final approval of the version to be published. D.G.: substantial contributions to conception and design, analysis and interpretation of data; revising article critically for important intellectual content; final approval of the version to be published. S.C.: substantial contributions to acquisition of data, analysis and interpretation of data; revising the article critically for important intellectual content; final approval of the version to be published. Y.Z.: substantial contributions to acquisition of data; final approval of the version to be published. S.M.: substantial contributions to conception and design, acquisition of data; final approval of the version to be published.

Corresponding author

Correspondence to Rachel Vassar.

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All subjects included in this research project consented to participation in this IRB-approved study. Specific consent for inclusion in this sub-analysis was not performed as no direct contact with participants was required.

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Vassar, R., Peyvandi, S., Gano, D. et al. Critical congenital heart disease beyond HLHS and TGA: neonatal brain injury and early neurodevelopment. Pediatr Res 94, 691–698 (2023). https://doi.org/10.1038/s41390-023-02490-9

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