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Preterm congenital heart disease and neurodevelopment: the importance of looking beyond the initial hospitalization

Abstract

Congenital heart disease (CHD) and prematurity are leading causes of infant mortality in the United States. Infants with CHD born prematurely are often described as facing “double jeopardy” with vulnerability from their underlying heart disease and from organ immaturity. They endure additional complications of developing in the extrauterine environment while healing from interventions for heart disease. While morbidity and mortality for neonates with CHD have declined over the past decade, preterm neonates with CHD remain at higher risk for adverse outcomes. Less is known about their neurodevelopmental and functional outcomes. In this perspective paper, we review the prevalence of preterm birth among infants with CHD, highlight the medical complexity of these infants, and emphasize the importance of exploring outcomes beyond survival. We focus on current knowledge regarding overlaps in the mechanisms of neurodevelopmental impairment associated with CHD and prematurity and discuss future directions for improving neurodevelopmental outcomes.

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Fig. 1: Major determinants of neurodevelopmental outcomes in preterm infants with congenital heart disease.

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References

  1. Hoffman JIE, Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol. 2002;39:1890–900. https://doi.org/10.1016/s0735-1097(02)01886-7.

    Article  PubMed  Google Scholar 

  2. Reller MD, Strickland MJ, Riehle-Colarusso T, Mahle WT, Correa A. Prevalence of congenital heart defects in metropolitan Atlanta, 1998-2005. J Pediatr. 2008;153:807–13. https://doi.org/10.1016/j.jpeds.2008.05.059.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Tanner K, Sabrine N, Wren C. Cardiovascular malformations among preterm infants. Pediatrics. 2005;116:e833–8. https://doi.org/10.1542/peds.2005-0397.

    Article  PubMed  Google Scholar 

  4. Natarajan G, Anne SR, Aggarwal S. Outcomes of congenital heart disease in late preterm infants: double jeopardy? Acta Paediatr. 2011;100:1104–7. https://doi.org/10.1111/j.1651-2227.2011.02245.x.

    Article  PubMed  Google Scholar 

  5. Abrishamchian R, Kanhai D, Zwets E, Nie L, Cardarelli M. Low birth weight or diagnosis, which is a higher risk?—a meta-analysis of observational studies. Eur J Cardiothorac Surg. 2006;30:700–5. https://doi.org/10.1016/j.ejcts.2006.08.021.

    Article  PubMed  Google Scholar 

  6. Axelrod DM, Chock VY, Reddy VM. Management of the preterm infant with congenital heart disease. Clin Perinatol. 2016;43:157–71. https://doi.org/10.1016/j.clp.2015.11.011.

    Article  PubMed  Google Scholar 

  7. Steurer MA, Baer RJ, Keller RL, Oltman S, Chambers CD, Norton ME, et al. Gestational age and outcomes in critical congenital heart disease. Pediatrics. 2017;140. https://doi.org/10.1542/peds.2017-0999.

  8. Chinn A, Fitzsimmons J, Shepard TH, Fantel AG. Congenital heart disease among spontaneous abortuses and stillborn fetuses: prevalence and associations. Teratology. 1989;40:475–82. https://doi.org/10.1002/tera.1420400510.

    Article  CAS  PubMed  Google Scholar 

  9. Matthiesen NB, Østergaard JR, Hjortdal VE, Henriksen TB. Congenital heart defects and the risk of spontaneous preterm birth. J Pediatr. 2021;229:168–74.e5. https://doi.org/10.1016/j.jpeds.2020.09.059.

    Article  PubMed  Google Scholar 

  10. Laas E, Lelong N, Thieulin AC, Houyel L, Bonnet D, Ancel PY, et al. Preterm birth and congenital heart defects: a population-based study. Pediatrics. 2012;130:e829–37. https://doi.org/10.1542/peds.2011-3279.

    Article  PubMed  Google Scholar 

  11. Nembhard WN, Salemi JL, Hauser KW, Kornosky JL. Are there ethnic disparities in risk of preterm birth among infants born with congenital heart defects? Birth Defects Res A Clin Mol Teratol. 2007;79:754–64. https://doi.org/10.1002/bdra.20411.

    Article  CAS  PubMed  Google Scholar 

  12. Chu PY, Li JS, Kosinski AS, Hornik CP, Hill KD. Congenital heart disease in premature infants 25-32 weeks’ gestational age. J Pediatr. 2017;181:37–41.e1. https://doi.org/10.1016/j.jpeds.2016.10.033.

    Article  PubMed  Google Scholar 

  13. Costello JM, Kim F, Polin R, Krishnamurthy G. Double jeopardy: prematurity and congenital heart disease-what’s known and why it’s important. World J Pediatr Congenit Heart Surg. 2022;13:65–71. https://doi.org/10.1177/21501351211062606.

    Article  PubMed  Google Scholar 

  14. Shin J. Risk factors for in-hospital mortality in premature infants with critical congenital heart disease. Clin Exp Pediatr. 2020;63:391–2. https://doi.org/10.3345/cep.2020.00444.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Stoll BJ, Hansen NI, Bell EF, Walsh MC, Carlo WA, Shankaran S, et al. Trends in care practices, morbidity, and mortality of extremely preterm neonates, 1993-2012. JAMA. 2015;314:1039–51. https://doi.org/10.1001/jama.2015.10244.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Janevic T, Zeitlin J, Auger N, Egorova NN, Hebert P, Balbierz A, et al. Association of race/ethnicity with very preterm neonatal morbidities. JAMA Pediatr. 2018;172:1061–9. https://doi.org/10.1001/jamapediatrics.2018.2029.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Yusuf K, Alshaikh B, da Silva O, Lodha AK, Wilson RD, Alvaro RE, et al. Neonatal outcomes of extremely preterm infants exposed to maternal hypertension and cigarette smoking. J Perinatol. 2018;38:1051–9. https://doi.org/10.1038/s41372-018-0111-1.

    Article  PubMed  Google Scholar 

  18. Steurer MA, Baer RJ, Chambers CD, Costello J, Franck LS, McKenzie-Sampson S, et al. Mortality and major neonatal morbidity in preterm infants with serious congenital heart disease. J Pediatr. 2021;239:110–16.e3. https://doi.org/10.1016/j.jpeds.2021.08.039.

    Article  PubMed  Google Scholar 

  19. Fisher JG, Bairdain S, Sparks EA, Khan FA, Archer JM, Kenny M, et al. Serious congenital heart disease and necrotizing enterocolitis in very low birth weight neonates. J Am Coll Surg. 2015;220:1018–26.e14. https://doi.org/10.1016/j.jamcollsurg.2014.11.026.

    Article  PubMed  Google Scholar 

  20. Polito A, Piga S, Cogo PE, Corchia C, Carnielli V, da Frè M, et al. Increased morbidity and mortality in very preterm/VLBW infants with congenital heart disease. Intensive Care Med. 2013;39:1104–12. https://doi.org/10.1007/s00134-013-2887-y.

    Article  PubMed  Google Scholar 

  21. Hadzimuratovic E, Dinarevic SM, Hadzimuratovic A. Sepsis in premature newborns with congenital heart disease. Congenit Heart Dis. 2010;5:435–8. https://doi.org/10.1111/j.1747-0803.2010.00406.x.

    Article  PubMed  Google Scholar 

  22. Ortinau CM, Anadkat JS, Smyser CD, Eghtesady P. Intraventricular hemorrhage in moderate to severe congenital heart disease. Pediatr Crit Care Med. 2018;19:56–63. https://doi.org/10.1097/PCC.0000000000001374.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Pappas A, Shankaran S, Hansen NI, Bell EF, Stoll BJ, Laptook AR, et al. Outcome of extremely preterm infants with congenital heart defects from the National Institute of Child Health and Human Development Neonatal Research Network. Pediatr Cardiol. 2012;33:1415–26. https://doi.org/10.1007/s00246-012-0375-8.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Johns KJ, Johns JA, Feman SS, Dodd DA. Retinopathy of prematurity in infants with cyanotic congenital heart disease. Am J Dis Child. 1991;145:200–3. https://doi.org/10.1001/archpedi.1991.02160020092024.

    Article  CAS  PubMed  Google Scholar 

  25. Miller SP, McQuillen PS, Hamrick S, Xu D, Glidden DV, Charlton N, et al. Abnormal brain development in newborns with congenital heart disease. N Engl J Med. 2007;357:1928–38. https://doi.org/10.1056/NEJMoa067393.

    Article  CAS  PubMed  Google Scholar 

  26. Bellinger DC, Wypij D, duPlessis AJ, Rappaport LA, Jonas RA, Wernovsky G, et al. Neurodevelopmental status at eight years in children with dextro-transposition of the great arteries: the Boston Circulatory Arrest Trial. J Thorac Cardiovasc Surg. 2003;126:1385–96. https://doi.org/10.1016/s0022-5223(03)00711-6.

    Article  PubMed  Google Scholar 

  27. Karl TR, Hall S, Ford G, Kelly EA, Brizard CPR, Mee RBB, et al. Arterial switch with full-flow cardiopulmonary bypass and limited circulatory arrest: neurodevelopmental outcome. J Thorac Cardiovasc Surg. 2004;127:213–22. https://doi.org/10.1016/j.jtcvs.2003.06.001.

    Article  PubMed  Google Scholar 

  28. Bellinger DC, Jonas RA, Rappaport LA, Wypij D, Wernovsky G, Kuban KC, et al. Developmental and neurologic status of children after heart surgery with hypothermic circulatory arrest or low-flow cardiopulmonary bypass. N Engl J Med. 1995;332:549–55. https://doi.org/10.1056/NEJM199503023320901.

    Article  CAS  PubMed  Google Scholar 

  29. Limperopoulos C, Majnemer A, Shevell MI, Rosenblatt B, Rohlicek C, Tchervenkov C. Neurologic status of newborns with congenital heart defects before open heart surgery. Pediatrics. 1999;103:402–8. https://doi.org/10.1542/peds.103.2.402.

    Article  CAS  PubMed  Google Scholar 

  30. Calderon J, Stopp C, Wypij D, DeMaso DR, Rivkin M, Newburger JW, et al. Early-term birth in single-ventricle congenital heart disease after the Fontan procedure: neurodevelopmental and psychiatric outcomes. J Pediatr. 2016;179:96–103. https://doi.org/10.1016/j.jpeds.2016.08.084.

    Article  PubMed  Google Scholar 

  31. Goff DA, Luan X, Gerdes M, Bernbaum J, D’Agostino JA, Rychik J, et al. Younger gestational age is associated with worse neurodevelopmental outcomes after cardiac surgery in infancy. J Thorac Cardiovasc Surg. 2012;143:535–42. https://doi.org/10.1016/j.jtcvs.2011.11.029.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Butler SC, Sadhwani A, Stopp C, Singer J, Wypij D, Dunbar-Masterson C, et al. Neurodevelopmental assessment of infants with congenital heart disease in the early postoperative period. Congenit Heart Dis. 2019;14:236–45. https://doi.org/10.1111/chd.12686.

    Article  PubMed  Google Scholar 

  33. Licht DJ, Wang J, Silvestre DW, Nicolson SC, Montenegro LM, Wernovsky G, et al. Preoperative cerebral blood flow is diminished in neonates with severe congenital heart defects. J Thorac Cardiovasc Surg. 2004;128:841–9. https://doi.org/10.1016/j.jtcvs.2004.07.022.

    Article  PubMed  Google Scholar 

  34. Mahle WT, Tavani F, Zimmerman RA, Nicolson SC, Galli KK, Gaynor JW, et al. An MRI study of neurological injury before and after congenital heart surgery. Circulation. 2002;106:I109–14.

    Article  PubMed  Google Scholar 

  35. Mulkey SB, Swearingen CJ, Melguizo MS, Schmitz ML, Ou X, Ramakrishnaiah RH, et al. Multi-tiered analysis of brain injury in neonates with congenital heart disease. Pediatr Cardiol. 2013;34:1772–84. https://doi.org/10.1007/s00246-013-0712-6.

    Article  PubMed  PubMed Central  Google Scholar 

  36. McQuillen PS, Hamrick SEG, Perez MJ, Barkovich AJ, Glidden DV, Karl TR, et al. Balloon atrial septostomy is associated with preoperative stroke in neonates with transposition of the great arteries. Circulation. 2006;113:280–5. https://doi.org/10.1161/CIRCULATIONAHA.105.566752.

    Article  PubMed  Google Scholar 

  37. Goff DA, Shera DM, Tang S, Lavin NA, Durning SM, Nicolson SC, et al. Risk factors for preoperative periventricular leukomalacia in term neonates with hypoplastic left heart syndrome are patient related. J Thorac Cardiovasc Surg. 2014;147:1312–8. https://doi.org/10.1016/j.jtcvs.2013.06.021.

    Article  PubMed  Google Scholar 

  38. Licht DJ, Shera DM, Clancy RR, Wernovsky G, Montenegro LM, Nicolson SC, et al. Brain maturation is delayed in infants with complex congenital heart defects. J Thorac Cardiovasc Surg. 2009;137:529–36. https://doi.org/10.1016/j.jtcvs.2008.10.025.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Childs AM, Ramenghi LA, Cornette L, Tanner SF, Arthur RJ, Martinez D, et al. Cerebral maturation in premature infants: quantitative assessment using MR imaging. Am J Neuroradiol. 2001;22:1577–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Lee FT, Seed M, Sun L, Marini D. Fetal brain issues in congenital heart disease. Transl Pediatr. 2021;10:2182–96. https://doi.org/10.21037/tp-20-224.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Morton SU, Quiat D, Seidman JG, Seidman CE. Genomic frontiers in congenital heart disease. Nat Rev Cardiol. 2022;19:26–42. https://doi.org/10.1038/s41569-021-00587-4.

    Article  PubMed  Google Scholar 

  42. Diab NS, Barish S, Dong W, Zhao S, Allington G, Yu X, et al. Molecular genetics and complex inheritance of congenital heart disease. Genes. 2021;12:1020. https://doi.org/10.3390/genes12071020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 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:e653–711. https://doi.org/10.1161/CIR.0000000000000606.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Homsy J, Zaidi S, Shen Y, Ware JS, Samocha KE, Karczewski KJ, et al. De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies. Science. 2015;350:1262–6. https://doi.org/10.1126/science.aac9396.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Jin SC, Homsy J, Zaidi S, Lu Q, Morton S, DePalma SR, et al. Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands. Nat Genet. 2017;49:1593–601. https://doi.org/10.1038/ng.3970.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Rollins CK, Ortinau CM, Stopp C, Friedman KG, Tworetzky W, Gagoski B, et al. Regional brain growth trajectories in fetuses with congenital heart disease. Ann Neurol. 2021;89:143–57. https://doi.org/10.1002/ana.25940.

    Article  PubMed  Google Scholar 

  47. Sadhwani A, Wypij D, Rofeberg V, Gholipour A, Mittleman M, Rohde J, et al. Fetal brain volume predicts neurodevelopment in congenital heart disease. Circulation. 2022;145:1108–19. https://doi.org/10.1161/CIRCULATIONAHA.121.056305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Rychik J, Goff D, McKay E, Mott A, Tian Z, Licht DJ, et al. Characterization of the placenta in the newborn with congenital heart disease: distinctions based on type of cardiac malformation. Pediatr Cardiol. 2018;39:1165–71. https://doi.org/10.1007/s00246-018-1876-x.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Segar DE, Zhang J, Yan K, Reid A, Frommelt M, Cohen S. The relationship between placental pathology and neurodevelopmental outcomes in complex congenital heart disease. Pediatr Cardiol. 2022. https://doi.org/10.1007/s00246-022-03018-4.

  50. Fenster L, Schaefer C, Mathur A, Hiatt RA, Pieper C, Hubbard AE, et al. Psychologic stress in the workplace and spontaneous abortion. Am J Epidemiol. 1995;142:1176–83. https://doi.org/10.1093/oxfordjournals.aje.a117576.

    Article  CAS  PubMed  Google Scholar 

  51. Kurki T, Hiilesmaa V, Raitasalo R, Mattila H, Ylikorkala O. Depression and anxiety in early pregnancy and risk for preeclampsia. Obstet Gynecol. 2000;95:487–90. https://doi.org/10.1016/s0029-7844(99)00602-x.

    Article  CAS  PubMed  Google Scholar 

  52. Paarlberg KM, Vingerhoets AJJM, Passchier J, Dekker GA, van Geijn HP. Psychosocial factors and pregnancy outcome: a review with emphasis on methodological issues. J Psychosom Res. 1995;39:563–95. https://doi.org/10.1016/0022-3999(95)00018-6.

    Article  CAS  PubMed  Google Scholar 

  53. Wu Y, Kapse K, Jacobs M, Niforatos-Andescavage N, Donofrio MT, Krishnan A, et al. Association of maternal psychological distress with in utero brain development in fetuses with congenital heart disease. JAMA Pediatr. 2020;174:e195316. https://doi.org/10.1001/jamapediatrics.2019.5316.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Tacy TA, Kasparian NA, Karnik R, Geiger M, Sood E. Opportunities to enhance parental well-being during prenatal counseling for congenital heart disease. Semin Perinatol. 2022;46:151587. https://doi.org/10.1016/j.semperi.2022.151587.

    Article  PubMed  Google Scholar 

  55. Butler S, Als H. Individualized developmental care improves the lives of infants born preterm. Acta Paediatr. 2008;97:1173–5. https://doi.org/10.1111/j.1651-2227.2008.00916.x.

    Article  PubMed  Google Scholar 

  56. Lisanti AJ, Vittner D, Medoff-Cooper B, Fogel J, Wernovsky G, Butler S. Individualized family-centered developmental care: an essential model to address the unique needs of infants with congenital heart disease. J Cardiovasc Nurs. 2019;34:85–93. https://doi.org/10.1097/JCN.0000000000000546.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Als H. Toward a synactive theory of development: promise for the assessment and support of infant individuality. Infant Ment Health J. 1982;3:229–43. https://doi.org/10.1002/1097-0355(198224)3:4<229::AID-IMHJ2280030405>3.0.CO;2-H.

    Article  Google Scholar 

  58. NICHD Neonatal Research Network (NRN). Extremely preterm birth outcome data. https://www.nichd.nih.gov/about/org/der/branches/ppb/programs/epbo/Pages/epbo_case.aspx. Accessed 4/1/2023.

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T-32 Neonatal Research Training Program 5T32HD098061 (JAK), Farb Family Fund (JWN).

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Katz, J.A., Levy, P.T., Butler, S.C. et al. Preterm congenital heart disease and neurodevelopment: the importance of looking beyond the initial hospitalization. J Perinatol 43, 958–962 (2023). https://doi.org/10.1038/s41372-023-01687-4

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