Advertisement

Neonatology pp 1169-1184 | Cite as

Kernicterus, Bilirubin-Induced Neurological Dysfunction, and New Treatments for Unconjugated Hyperbilirubinemia in Neonates

  • Christian V. Hulzebos
  • Claudio Tiribelli
  • Frans J. C. Cuperus
  • Petr H. Dijk
Reference work entry

Abstract

Severe hyperbilirubinemia occurs worldwide and threatens neurodevelopmental outcome of many infants. Acute kernicterus is an unambiguous clinical disorder in severely jaundiced newborn infants but may also occur in preterm infants at bilirubin levels below current treatment thresholds. Bilirubin-induced neurological dysfunction (BIND) consists of more subtle, but permanent, bilirubin encephalopathy and may present with auditory dysfunction and/or mild neurologic abnormalities such as mild impairment in neurologic and/or cognitive performance. Early prevention of severe hyperbilirubinemia is key to reduction of neurological sequelae and implies knowledge of maternal, perinatal, and neonatal risk factors. Subsequent recognition of neonates with perceived bilirubin neurotoxicity risk factors, of which hemolysis and sepsis are the most important, will enable categorization of neonates into high-, moderate-, or low-risk groups, with individualized screening and appropriate treatment. Phototherapy is the cornerstone of current treatment, and – if unsuccessful – exchange transfusion can be performed. Phototherapy does not always prevent bilirubin accumulation, and concerns exist about aggressive use in ELBW infants. Exchange transfusions are invasive procedures and associated with significant morbidity. It is highly conceivable that new treatments which either decrease bilirubin production, increase hepatic clearance, or decrease enterohepatic circulation will find their way in patients suffering severe hyperbilirubinemia and imminent BIND despite conventional treatment in the foreseeable future.

References

  1. Ahlfors CE, Parker AE (2005) Evaluation of a model for brain bilirubin uptake in jaundiced newborns. Pediatr Res 58(6):1175–1179CrossRefGoogle Scholar
  2. Ahlfors CE, Shapiro SM (2001) Auditory brainstem response and unbound bilirubin in jaundiced (jj) Gunn rat pups. Biol Neonate 80(2):158–162CrossRefGoogle Scholar
  3. Ahlfors CE, Wennberg RP (2004) Bilirubin-albumin binding and neonatal jaundice. Semin Perinatol 28(5):334–339CrossRefGoogle Scholar
  4. Ahlfors CE, Amin SB, Parker AE (2009) Unbound bilirubin predicts abnormal automated auditory brainstem response in a diverse newborn population. J Perinatol 29(4):305–309CrossRefGoogle Scholar
  5. American Academy of Pediatrics Subcommittee on Hyperbilirubinemia (2004) Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 114(1098–4275; 1):297–316Google Scholar
  6. Amin SB, Orlando MS, Dalzell LE, Merle KS, Guillet R (1999) Morphological changes in serial auditory brain stem responses in 24 to 32 weeks’ gestational age infants during the first week of life. Ear Hear 20(5):410–418CrossRefGoogle Scholar
  7. Amin SB, Ahlfors C, Orlando MS, Dalzell LE, Merle KS, Guillet R (2001) Bilirubin and serial auditory brainstem responses in premature infants. Pediatrics 107(4):664–670CrossRefGoogle Scholar
  8. Bhutani VK, Zipursky A, Blencowe H, Khanna R, Sgro M, Ebbesen F et al (2013) Neonatal hyperbilirubinemia and Rhesus disease of the newborn: incidence and impairment estimates for 2010 at regional and global levels. Pediatr Res 74(Suppl 1):86–100CrossRefGoogle Scholar
  9. Caldera R, Maynier M, Sender A, Brossard Y, Tortrat D, Galiay JC et al (1993) The effect of human albumin in association with intensive phototherapy in the management of neonatal jaundice. Arch Fr Pediatr 50(5):399–402PubMedGoogle Scholar
  10. Calligaris SD, Bellarosa C, Giraudi P, Wennberg RP, Ostrow JD, Tiribelli C (2007) Cytotoxicity is predicted by unbound and not total bilirubin concentration. Pediatr Res 62(5):576–580CrossRefGoogle Scholar
  11. Coda Zabetta CD, Iskander IF, Greco C, Bellarosa C, Demarini S, Tiribelli C et al (2013) Bilistick: a low-cost point-of-care system to measure total plasma bilirubin. Neonatology 103(3):177–181CrossRefGoogle Scholar
  12. Cuperus FJ, Hafkamp AM, Hulzebos CV, Verkade HJ (2009a) Pharmacological therapies for unconjugated hyperbilirubinemia. Curr Pharm Des 15(25):2927–2938CrossRefGoogle Scholar
  13. Cuperus FJ, Hafkamp AM, Havinga R, Vitek L, Zelenka J, Tiribelli C et al (2009b) Effective treatment of unconjugated hyperbilirubinemia with oral bile salts in Gunn rats. Gastroenterology 136(2):673–82.e1CrossRefGoogle Scholar
  14. Cuperus FJ, Iemhoff AA, van der Wulp M, Havinga R, Verkade HJ (2010) Acceleration of the gastrointestinal transit by polyethylene glycol effectively treats unconjugated hyperbilirubinaemia in Gunn rats. Gut 59(3):373–380CrossRefGoogle Scholar
  15. Cuperus FJ, Schreuder AB, van Imhoff DE, Vitek L, Vanikova J, Konickova R et al (2013) Beyond plasma bilirubin: the effects of phototherapy and albumin on brain bilirubin levels in Gunn rats. J Hepatol 58(1):134–140CrossRefGoogle Scholar
  16. Dennery PA, Seidman DS, Stevenson DK (2001) Neonatal hyperbilirubinemia. N Engl J Med 344(8):581–590CrossRefGoogle Scholar
  17. D’Silva S, Colah RB, Ghosh K, Mukherjee MB (2014) Combined effects of the UGT1A1 and OATP2 gene polymorphisms as major risk factor for unconjugated hyperbilirubinemia in Indian neonates. Gene 547(1):18–22CrossRefGoogle Scholar
  18. Forbes SJ, Gupta S, Dhawan A (2015) Cell therapy for liver disease: from liver transplantation to cell factory. J Hepatol 62(1 Suppl):S157–S169CrossRefGoogle Scholar
  19. Good WV, Hou C (2015) Visuocortical bilirubin-induced neurological dysfunction. Semin Fetal Neonatal Med 20(1):37–41CrossRefGoogle Scholar
  20. Gotink MJ, Benders MJ, Lavrijsen SW, Rodrigues Pereira R, Hulzebos CV, Dijk PH (2013) Severe neonatal hyperbilirubinemia in the Netherlands. Neonatology 104(2):137–142CrossRefGoogle Scholar
  21. Govaert P, Lequin M, Swarte R, Robben S, De Coo R, Weisglas-Kuperus N et al (2003) Changes in globus pallidus with (pre)term kernicterus. Pediatrics 112(6):1256–1263, 1098–4275CrossRefGoogle Scholar
  22. Groenendaal F, van der Grond J, de Vries LS (2004) Cerebral metabolism in severe neonatal hyperbilirubinemia. Pediatrics 114(1):291–294CrossRefGoogle Scholar
  23. Hansen TW (2000) Pioneers in the scientific study of neonatal jaundice and kernicterus. Pediatrics 106(2):E15CrossRefGoogle Scholar
  24. Hosono S, Ohno T, Kimoto H, Nagoshi R, Shimizu M, Nozawa M (2001) Effects of albumin infusion therapy on total and unbound bilirubin values in term infants with intensive phototherapy. Pediatr Int 43(1):8–11CrossRefGoogle Scholar
  25. Hosono S, Ohno T, Kimoto H, Nagoshi R, Shimizu M, Nozawa M et al (2002) Follow-up study of auditory brainstem responses in infants with high unbound bilirubin levels treated with albumin infusion therapy. Pediatr Int 44(5):488–492CrossRefGoogle Scholar
  26. Hulzebos CV, van Imhoff DE, Bos AF, Ahlfors CE, Verkade HJ, Dijk PH (2008) Usefulness of the bilirubin/albumin ratio for predicting bilirubin-induced neurotoxicity in premature infants. Arch Dis Child Fetal Neonatal Ed 93(5):F384–F388CrossRefGoogle Scholar
  27. Hulzebos CV, Dijk PH, van Imhoff DE, Bos AF, Lopriore E, Offringa M et al (2014) The bilirubin albumin ratio in the management of hyperbilirubinemia in preterm infants to improve neurodevelopmental outcome: a randomized controlled trial – BARTrial. PLoS One 9(6):e99466CrossRefGoogle Scholar
  28. Ip S, Chung M, Kulig J, O’Brien R, Sege R, Glicken S et al (2004) An evidence-based review of important issues concerning neonatal hyperbilirubinemia. Pediatrics 114(1):e130–e153CrossRefGoogle Scholar
  29. Iskander I, Gamaleldin R, El Houchi S, El Shenawy A, Seoud I, El Gharbawi N et al (2014) Serum bilirubin and bilirubin/albumin ratio as predictors of bilirubin encephalopathy. Pediatrics 134(5):e1330–e1339CrossRefGoogle Scholar
  30. Jangaard KA, Vincer MJ, Allen AC (2007) A randomized trial of aggressive versus conservative phototherapy for hyperbilirubinemia in infants weighing less than 1500 g: short- and long-term outcomes. Paediatr Child Health 12(10):853–858PubMedPubMedCentralGoogle Scholar
  31. Johnson L, Brown AK, Bhutani VK (1999) BIND – A clinical score for bilirubin-induced neurological dysfunction in newborns. Pediatrics 104:746Google Scholar
  32. Kaplan M, Bromiker R, Hammerman C (2014) Hyperbilirubinemia, hemolysis, and increased bilirubin neurotoxicity. Semin Perinatol 38(7):429–437CrossRefGoogle Scholar
  33. Kim MH, Yoon JJ, Sher J, Brown AK (1980) Lack of predictive indices in kernicterus: a comparison of clinical and pathologic factors in infants with or without kernicterus. Pediatrics 66(6):852–858PubMedGoogle Scholar
  34. Liu W, Liu H, Wang T, Tang X (2015) Therapeutic effects of probiotics on neonatal jaundice. Pak J Med Sci 31(5):1172–1175PubMedPubMedCentralGoogle Scholar
  35. Lucey JF (1972) Neonatal jaundice and phototherapy. Pediatr Clin North Am 19(4):827–839CrossRefGoogle Scholar
  36. Lunsing RJ (2014) Subtle bilirubin-induced neurodevelopmental dysfunction (BIND) in the term and late preterm infant: does it exist? Semin Perinatol 38(7):465–471CrossRefGoogle Scholar
  37. Maisels MJ, Watchko JF (2003) Treatment of jaundice in low birthweight infants. Arch Dis Child Fetal Neonatal Ed 88(6):F459–F463CrossRefGoogle Scholar
  38. Maisels MJ, Watchko JF, Bhutani VK, Stevenson DK (2012) An approach to the management of hyperbilirubinemia in the preterm infant less than 35 weeks of gestation. J Perinatol 32:660–664CrossRefGoogle Scholar
  39. Manning D, Todd P, Maxwell M, Platt MJ (2007) Prospective surveillance study of severe hyperbilirubinaemia in the newborn in the UK and Ireland. Arch Dis Child Fetal Neonatal Ed 92(5):F342–F346CrossRefGoogle Scholar
  40. Mishra S, Cheema A, Agarwal R, Deorari A, Paul V (2015) Oral zinc for the prevention of hyperbilirubinaemia in neonates. Cochrane Database Syst Rev 7:CD008432Google Scholar
  41. Morris BH, Oh W, Tyson JE, Stevenson DK, Phelps DL, O’Shea TM et al (2008) Aggressive vs. conservative phototherapy for infants with extremely low birth weight. N Engl J Med 359(18):1885–1896CrossRefGoogle Scholar
  42. National Institute for Health and Clinical Excellence (2010) Available at: http://www.nice.org.uk/CG98
  43. Newman TB, Klebanoff MA (1993) Neonatal hyperbilirubinemia and long-term outcome: another look at the Collaborative Perinatal Project. Pediatrics 92(5):651–657PubMedGoogle Scholar
  44. Norman M, Aberg K, Holmsten K, Weibel V, Ekeus C (2015) Predicting nonhemolytic neonatal hyperbilirubinemia. Pediatrics 136(6):1087–1094CrossRefGoogle Scholar
  45. Oh W, Tyson JE, Fanaroff AA, Vohr BR, Perritt R, Stoll BJ et al (2003) Association between peak serum bilirubin and neurodevelopmental outcomes in extremely low birth weight infants. Pediatrics 112(4):773–779CrossRefGoogle Scholar
  46. Okumus N, Turkyilmaz C, Onal EE, Atalay Y, Serdaroglu A, Elbeg S et al (2008) Tau and S100B proteins as biochemical markers of bilirubin-induced neurotoxicity in term neonates. Pediatr Neurol 39(4):245–252CrossRefGoogle Scholar
  47. Okwundu CI, Okoromah CA, Shah PS (2012) Prophylactic phototherapy for preventing jaundice in preterm or low birth weight infants. Cochrane Database Syst Rev 1:CD007966PubMedGoogle Scholar
  48. Olusanya BO, Ogunlesi TA, Slusher TM (2014) Why is kernicterus still a major cause of death and disability in low-income and middle-income countries? Arch Dis Child 99(12):1117–1121CrossRefGoogle Scholar
  49. Olusanya BO, Osibanjo FB, Slusher TM (2015) Risk factors for severe neonatal hyperbilirubinemia in low and middle-income countries: a systematic review and meta-analysis. PLoS One 10(2):e0117229CrossRefGoogle Scholar
  50. Ostrow JD, Pascolo L, Shapiro SM, Tiribelli C (2003a) New concepts in bilirubin encephalopathy. Eur J Clin Invest 11(11):988–997, 0014-2972CrossRefGoogle Scholar
  51. Ostrow JD, Pascolo L, Tiribelli C (2003b) Reassessment of the unbound concentrations of unconjugated bilirubin in relation to neurotoxicity in vitro. Pediatr Res 54(1):98–104, 0031-3998CrossRefGoogle Scholar
  52. Ostrow JD, Pascolo L, Brites D, Tiribelli C (2004) Molecular basis of bilirubin-induced neurotoxicity. Trends Mol Med 10(2):65–70, 1471–4914CrossRefGoogle Scholar
  53. Pearlman MA, Gartner LM, Lee K, Eidelman AI, Morecki R, Horoupian DS (1980) The association of kernicterus with bacterial infection in the newborn. Pediatrics 65(1):26–29PubMedGoogle Scholar
  54. Radmacher PG, Groves FD, Owa JA, Ofovwe GE, Amuabunos EA, Olusanya BO et al (2015) A modified Bilirubin-induced neurologic dysfunction (BIND-M) algorithm is useful in evaluating severity of jaundice in a resource-limited setting. BMC Pediatr 15, 015-0355-2Google Scholar
  55. Ritter DA, Kenny JD, Norton HJ, Rudolph AJ (1982) A prospective study of free bilirubin and other risk factors in the development of kernicterus in premature infants. Pediatrics 69(3):260–266PubMedGoogle Scholar
  56. Scheidt PC, Graubard BI, Nelson KB, Hirtz DG, Hoffman HJ, Gartner LM et al (1991) Intelligence at six years in relation to neonatal bilirubin levels: follow-up of the National Institute of Child Health and Human Development Clinical Trial of Phototherapy. Pediatrics 87(6):797–805PubMedGoogle Scholar
  57. Schulz S, Wong RJ, Vreman HJ, Stevenson DK (2012) Metalloporphyrins – an update. Front Pharmacol 3:68CrossRefGoogle Scholar
  58. Shapiro SM (2003) Bilirubin toxicity in the developing nervous system. Pediatr Neurol 29(5):410–421, 0887-8994CrossRefGoogle Scholar
  59. Shapiro SM (2005) Definition of the clinical spectrum of kernicterus and bilirubin-induced neurologic dysfunction (BIND). J Perinatol 25(1):54–59, 0743-8346CrossRefGoogle Scholar
  60. Shapiro SM (2010) Chronic bilirubin encephalopathy: diagnosis and outcome. Semin Fetal Neonatal Med 15(3):157–163CrossRefGoogle Scholar
  61. Shapiro SM, Nakamura H (2001) Bilirubin and the auditory system. J Perinatol 21(Suppl 1):S52–S55, discussion S59–62CrossRefGoogle Scholar
  62. Slusher TM, Owa JA, Painter MJ, Shapiro SM (2011) The kernicteric facies: facial features of acute bilirubin encephalopathy. Pediatr Neurol 44(2):153–154CrossRefGoogle Scholar
  63. Slusher TM, Olusanya BO, Vreman HJ, Brearley AM, Vaucher YE, Lund TC et al (2015) A randomized trial of phototherapy with filtered sunlight in African neonates. N Engl J Med 373(12):1115–1124CrossRefGoogle Scholar
  64. Soorani-Lunsing I, Woltil HA, Hadders-Algra M (2001) Are moderate degrees of hyperbilirubinemia in healthy term neonates really safe for the brain? Pediatr Res 12;50(6):701–705CrossRefGoogle Scholar
  65. Suresh GK, Martin CL, Soll RF (2003) Metalloporphyrins for treatment of unconjugated hyperbilirubinemia in neonates. Cochrane Database Syst Rev 2:1469–493 CD004207Google Scholar
  66. Turkel SB (1990) Autopsy findings associated with neonatal hyperbilirubinemia. Clin Perinatol 17(2):381–396CrossRefGoogle Scholar
  67. Van Der Veere CN, Sinaasappel M, McDonagh AF, Rosenthal P, Labrune P, Odievre M et al (1996) Current therapy for Crigler-Najjar syndrome type 1: report of a world registry. Hepatology 24(2):311–315, 0270-9139CrossRefGoogle Scholar
  68. van Dijk R, Beuers U, Bosma PJ (2015) Gene replacement therapy for genetic hepatocellular jaundice. Clin Rev Allergy Immunol 48(2 –3):243–253CrossRefGoogle Scholar
  69. van Imhoff DE, Dijk PH, Hulzebos CV, BARTrial study group, Netherlands Neonatal Research Network (2011) Uniform treatment thresholds for hyperbilirubinemia in preterm infants: background and synopsis of a national guideline. Early Hum Dev 87(8):521–525CrossRefGoogle Scholar
  70. Volpe JJ (2009) Bilirubin and brain damage. Neurology of the newborn, 5th edn. Saunders Elsevier, Philadelphia, pp 619–651Google Scholar
  71. Wallenstein MB, Bhutani VK (2013) Jaundice and kernicterus in the moderately preterm infant. Clin Perinatol 40(4):679–688CrossRefGoogle Scholar
  72. Watchko JF, Maisels MJ (2003) Jaundice in low birthweight infants: pathobiology and outcome. Arch Dis Child Fetal Neonatal Ed 88(6):F455–F458CrossRefGoogle Scholar
  73. Watchko JF, Maisels MJ (2014) The enigma of low bilirubin kernicterus in premature infants: why does it still occur, and is it preventable? Semin Perinatol 38(7):397–406CrossRefGoogle Scholar
  74. Watchko JF, Tiribelli C (2013) Bilirubin-induced neurologic damage – mechanisms and management approaches. N Engl J Med 369(21):2021–2030CrossRefGoogle Scholar
  75. Wennberg RP, Schwartz R, Sweet AY (1966) Early versus delayed feeding of low birth weight infants: effects on physiologic jaundice. J Pediatr 68(6):860–866CrossRefGoogle Scholar
  76. Wennberg RP, Ahlfors CE, Bhutani VK, Johnson LH, Shapiro SM (2006) Toward understanding kernicterus: a challenge to improve the management of jaundiced newborns. Pediatrics 117(2):474–485CrossRefGoogle Scholar
  77. Wong RJ, Stevenson DK (2015) Neonatal hemolysis and risk of bilirubin-induced neurologic dysfunction. Semin Fetal Neonatal Med 20(1):26–30CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Christian V. Hulzebos
    • 1
  • Claudio Tiribelli
    • 2
  • Frans J. C. Cuperus
    • 3
  • Petr H. Dijk
    • 1
  1. 1.Beatrix Children’s HospitalUniversity Medical Center GroningenGroningenThe Netherlands
  2. 2.Liver Research CentreUniversity of TriesteTriesteItaly
  3. 3.Department of Gastroenterology and HepatologyUniversity Medical Center GroningenGroningenThe Netherlands

Personalised recommendations