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  • Review Article
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Management of severe hyperbilirubinemia in the cholestatic neonate: a review and an approach

Abstract

A review of the literature demonstrates that severe total hyperbilirubinemia (total serum bilirubin ≥ 20 mg/dL [340 µmol/L]) in some cholestatic term (≥37 weeks) and late-preterm (≥340/7–366/7 weeks) gestation neonates poses a risk for bilirubin-induced brain damage. When the direct bilirubin fraction is <50% of the total serum bilirubin this risk is associated with the total serum bilirubin alone and treatment decisions should be based on the total serum bilirubin. On the other hand, there are limited data on the risk of bilirubin-induced brain damage in the neonate with severe total hyperbilirubinemia and a direct bilirubin fraction that is equal to or exceeds 50% of the total serum bilirubin. When this rare combination occurs, efforts to keep the indirect bilirubin fraction from reaching severe levels might, nevertheless, be prudent.

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References

  1. Maisels MJ. The clinical approach to the jaundiced newborn. In: Maisels MJ, Watchko JF, editors. Neonatal jaundice. Harwood Academic Publishers: Amsterdam; 2000. p. 162–3.

  2. Claireaux AE, Cole PG, Lathe GH. Icterus of the brain in the newborn. Lancet. 1953;265:1226–30.

    Article  CAS  PubMed  Google Scholar 

  3. Diamond I, Schmid R. Experimental bilirubin encephalopathy. The mode of entry of bilirubin-14C into the central nervous system. J Clin Invest. 1966;45:678–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Schmid R. The role of protein interaction in the tissue uptake of bilirubin. In: Bouchier IAD, Billing BH, editors. Bilirubin metabolism. F.A. Davis Company: Philadelphia; 1967. p. 147–57.

  5. McDonagh AF. Bile pigments: bilatrienes and 5,15-biladienes. In: Dolphin D, editor. The porphyrins. Volume VI. Biochemistry, Part A. Academic Press: New York; 1979. p. 379–84.

  6. Stoll BJ, Kliegman RM. Digestive system disorders. In: Behrman RE, Kliegman RM, Jenson HB, editors. Nelson textbook of pediatrics. 17th Edition. Saunders: Philadelphia, 2004, 597.

  7. Barrett CT. Hemolytic disease of the newly born infant. In: Gellis SS, Kagan BM, editors. Current pediatric therapy 9. Saunders: Philadelphia; 1980. p. 735–38.

  8. Hsai DY, Patterson P, Allen FH Jr., Diamond LK, Gellis S. Prolonged obstructive jaundice in infancy. I. General survey of 156 cases. Pediatrics. 1952;10:243–52.

    Article  Google Scholar 

  9. Dunn PM. Obstructive jaundice and haemolytic disease of the newborn. Arch Dis Child. 1963;38:54–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Polacek K. Risk of kernicterus in newborn infants with a high level of conjugated bilirubin. Acta Paediatr Scand. 1966;55:401–4.

    Article  CAS  PubMed  Google Scholar 

  11. Grobler JM, Mercer MJ. Kernicterus associated with elevated predominantly direct reacting bilirubin. S Afr Med J. 1997;87:1146.

    CAS  PubMed  Google Scholar 

  12. Maisels MJ, Baltz RD, Bhutani VK, Newman TB, Palmer H, Rosenfeld W, et al. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114:297–316.

    Article  Google Scholar 

  13. Kaplan M, Merlob P, Regev R. Israeli guidelines for management of neonatal hyperbilirubinemia and prevention of kernicterus. J Perinatol. 2008;28:389–97.

    Article  CAS  PubMed  Google Scholar 

  14. Atkinson M, Budge H. Review of the NICE guidance on neonatal jaundice. Arch Dis Child Educ Pract Ed. 2011;96:136–40.

    Article  CAS  PubMed  Google Scholar 

  15. Bratlid D, Nakstad B, Hansen TWR. National guidelines for treatment of jaundice in the newborn. Acta Paediatr. 2011;100:499–505.

    Article  CAS  PubMed  Google Scholar 

  16. Bhutani VK, Johnson LH, Maisels MJ, Newman TB, Phibbs C, Stark AR, et al. Kernicterus: epidemiological strategies for its prevention through systems-based approaches. J Perinatol. 2004;24:650–62.

    Article  PubMed  Google Scholar 

  17. Davis AR, Rosenthal P, Escobar GJ, Newman TB. Interpreting conjugated bilirubin levels in newborns. J Pediatr. 2011;158:562–.e561.

    Article  CAS  PubMed  Google Scholar 

  18. Harpavat S, Garcia-Prats JA, Anaya C, Brandt ML, Lupo PJ, Finegold MJ, et al. Diagnostic yield of newborn screening for biliary atresia using direct or conjugated bilirubin measurements. JAMA. 2020;323:1141–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Greene DN, Liang J, Holmes DT, Resch A, Lorey TS. Neonatal total bilirubin measurements: Still room for harmonization. Clin Biochem. 2014;47:1112–5.

    Article  CAS  PubMed  Google Scholar 

  20. Oppe TE, Valaes T. Obstructive jaundice and haemolytic disease of the newborn. Lancet. 1959;1:536–9.

    Article  CAS  PubMed  Google Scholar 

  21. Dunn PM. Obstructive jaundice, liver damage and Rh haemolytic disease of the newborn. Jew Meml Hospital Bull. 1965;10:94–124.

    Google Scholar 

  22. Stempfel R, Broman B, Escardo FE, Zetterstrom R. Obstructive jaundice complicating hemolytic disease of the newborn. Pediatrics. 1956;17:471–81.

    Article  CAS  PubMed  Google Scholar 

  23. Bowman JM. Neonatal management. In: Queenan JT, editor. Modern management of the Rh problem. Harper & Row: New York; 1977. p. 200–39.

  24. Bowman JM. Alloimmune hemolytic disease of the neonate. In: Stockman JA, Pochedly C, editors. Developmental and neonatal hematology. Raven Press: New York; 1988. p. 223–48.

  25. Zuelzer WW, Brown AK. Neonatal jaundice. A review. Am J Dis Child. 1961;101:87–127.

    Article  CAS  PubMed  Google Scholar 

  26. Smits-Wintjens VEHJ, Rath MEA, Lindenburg ITM, Oepkes D, van Zwet EW, Walther FJ, et al. Cholestasis in neonates with red cell alloimmune hemolytic disease: incidence, risk factors and outcome. Neonatology. 2012;101:306–10.

    Article  PubMed  Google Scholar 

  27. Allgood C, Bolisetty S. Severe conjugated hyperbilirubinemia and neonatal hemolysis. Int J Clin Pract. 2006;60:1513–4.

    Article  CAS  PubMed  Google Scholar 

  28. McAdams RM, Dotzler SA, Winter LW, Kerecman JD. Severe hemolytic disease of the newborn from anti-e. J Perinatol. 2008;28:230–2.

    Article  CAS  PubMed  Google Scholar 

  29. Usman AS, Mustaffa R, Ramli N, Diggi SA. Hemolytic disease of the fetus and newborn caused by anti-E. Asian J Transfus Sci. 2013;7:84–85.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Smith G, Knott P, Rissik J, de la Fuente J, Win N. Anti-U and haemolytic disease of the fetus and newborn. Br J Obstet Gynaecol. 1998;105:1318–21.

    Article  CAS  PubMed  Google Scholar 

  31. Raju TNK, Javed DIS. Fetal intrahepatic cholestasis secondary to BO hemolytic disease. J Nat Med Assoc. 1981;73:747–49.

    CAS  Google Scholar 

  32. Najak Z, Kanto WP Jr., Carrillo PJ. ABO hemolytic disease of the newborn associated with direct reacting hyperbilirubinemia. J Med Assoc Ga 1982;71:267–71.

    CAS  PubMed  Google Scholar 

  33. Sivan Y, Merlob P, Nutman J, Reisner SH. Direct hyperbilirubinemia complicating ABO haemolytic disease of the newborn. Clin Pediatr. 1983;22:537–8.

    Article  CAS  Google Scholar 

  34. Zonneveld R, van der Meer-Kapelle L, Sylva M, Brand A, Zijstra M, Schonewille H. Severe fetal hemolysis and cholestasis due to high titer maternal IgG anti-A antibodies. Pediatrics. 2019;143:e20182859.

    Article  PubMed  Google Scholar 

  35. Kordes U, Richter A, Santer R, Schafer H, Singer D, Sonntag J, et al. Neonatal cholestasis and glucose-6-P-dehydrogenase deficiency. Pediatr Blood Cancer. 2010;54:758–60.

    Article  PubMed  Google Scholar 

  36. Raphael MF, Van Wijk R, Schweizer JJ, Schouten-van Meeteren NAY, Kindermann A, van Solinge WW, et al. Pyruvate kinase deficiency associated with severe liver dysfunction in the newborn. Am J Hematol. 2007;82:1025–8.

    Article  CAS  PubMed  Google Scholar 

  37. Olivier F, Wieckowska A, Piedboeuf B, Alvarez F. Cholestasis and hepatic failure in a neonate: a case report of severe pyruvate kinase deficiency. Pediatrics. 2015;136:e1366–e1368.

    Article  PubMed  Google Scholar 

  38. Lane E, Murray KF. Neonatal cholestasis. Pediatr Clin N Am. 2017;64:621–39.

    Article  Google Scholar 

  39. Hamilton JR, Sass-Kortsak A. Jaundice associated with severe bacterial infection in young infants. J Pediatr. 1963;63:121–32.

    Article  CAS  PubMed  Google Scholar 

  40. Bech LF, Donneborg ML, Lund AM, Ebbesen F. Extreme neonatal hyperbilirubinemia, acute bilirubin encephalopathy, and kernicterus spectrum disorder in children with galactosemia. Pediatr Res. 2018;84:228–32.

    Article  CAS  PubMed  Google Scholar 

  41. Ryan TD, Dimmitt RA, Tubbs RS, Roberts OA, Choi H, Loukas M, et al. Contribution of surgical evacuation of a large subgaleal hematoma to the resolution of severe conjugated hyperbilirubinemia in a neonate. J Neurosurg. 2007;106:131–33.

    PubMed  Google Scholar 

  42. Singh A, Sachan R. Congenital cytomegalovirus infection presenting as severe conjugated hyperbilirubinemia in the first day of life. Int J Pediatr Res. 2018;4:035.

    Google Scholar 

  43. Copeland KC, Franks RC, Ramamurthy R. Neonatal hyperbilirubinemia and hypoglycemia in congenital hypopituitarism. Clin Pediatr. 1981;20:523–26.

    Article  CAS  Google Scholar 

  44. Drop SLS, Colle E, Guyda HJ. Hyperbilirubinemia and idiopathic hypopituitarism in the newborn period. Acta Paediatr Scand. 1979;68:277–80.

    Article  CAS  PubMed  Google Scholar 

  45. Oh KS, Bahmad HF, Brathwaite C, Sanchez AC, Recine M. Neonatal acute liver failure with pulmonary yellow hyaline membrane and kernicterus. Autops Case Rep. 2021;11:e2021268.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Romero Lopez MM, Pryce C, Maisels MJ. A newborn with a blueberry muffin rash, hepatosplenomegaly, thrombocytopenia and severe cholestatic Jaundice at birth. Clin Pediatr Oa. 2017;2:121.

    Article  Google Scholar 

  47. Makkar A, Mahmood B, Watchko JF. Severe hyperbilirubinemia in neonates during ECMO: important role of hemolysis. J Invest Med. 2016;64:612.

    Google Scholar 

  48. Perlman JM, Volpe JJ. Bilirubin. In: Volpe JJ, Inder TI, Barras DT, de Vries LS, du Plessis AJ, Neil JJ, Perlman JM, editors. Volpe’s neurology of the newborn. 6th edition. Elsevier: Philadelphia; 2018. p. 730-62.

  49. Boon WH. Kernicterus not associated with haemolytic disease. Arch Dis Child. 1957;32:85–90.

    Article  CAS  PubMed Central  Google Scholar 

  50. Valaes T, Fessas P, Doxiadis SA. Kernicterus in full-term infants without isoimmunization (4 cases). Proc R Soc Med. 1961;54:331–3.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Doxiadis SA, Valaes T. The clinical picture of glucose 6-phosphate dehydrogenase deficiency in early infancy. Arch Dis Child. 1964;39:545–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Naiman JL, Kosoy MH. Red cell glucose-6-phosphate dehydrogenase deficiency—a newly recognized cause of neonatal jaundice and kernicterus in Canada. Can Med Assoc J. 1964;91:1243–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Johnston WH, Angara V, Baumal R, Hawke WA, Johnson RH, Keet S, et al. Erythroblastosis fetalis and hyperbilirubinemia. A five-year follow-up with neurological, psychological, and audiological evaluation. Pediatrics. 1967;39:88–92.

    Article  CAS  PubMed  Google Scholar 

  54. Walker W, Ellis MI, Ellis E, Curry A, Savage RD, Sawyer R. A follow-up study of survivors of Rh-haemolytic disease. Dev Med Child Neurol. 1974;16:592–611.

    Article  CAS  PubMed  Google Scholar 

  55. Clark CF, Torii S, Hamamoto Y, Kaito H. The “bronze baby” syndrome: postmortem data. J Pediatr. 1976;88:461–64.

    Article  CAS  PubMed  Google Scholar 

  56. Johnson L. Hyperbilirubinemia in the term infant: when to worry, when to treat. NY State J Med. 1991;91:483–9.

    CAS  Google Scholar 

  57. Penn AA, Enzmann DR, Hahn JS, Stevenson DK. Kernicterus in a full term infant. Pediatrics. 1994;93:1003–6.

    Article  CAS  PubMed  Google Scholar 

  58. Maisels MJ, Newman TB. Kernicterus in otherwise healthy, breast-fed term newborns. Pediatrics. 1995;96:730–3.

    Article  CAS  PubMed  Google Scholar 

  59. Washington EC, Ector W, Abboud M, Ohning B, Holden K. Hemolytic jaundice due to G6PD deficiency causing kernicterus in a female newborn. South Med J. 1995;88:776–79.

    Article  CAS  PubMed  Google Scholar 

  60. Ebbesen F. Recurrence of kernicterus in term and near-term infants in Denmark. Acta Paediatr. 2000;89:1213–7.

    Article  CAS  PubMed  Google Scholar 

  61. Bertini G, Dani C, Fonda C, Zorzi C, Rubaltelli FF. Bronze baby syndrome and the risk of kernicterus. Acta Paediatr. 2005;94:968–71.

    Article  PubMed  Google Scholar 

  62. Castilho TR, Vargas MS, Pinsuti A, Rocha MA, D’Bertagnon JR. Bilirubin encephalopathy due to Rh incompatibility. Einstein. 2011;9:220–3.

    Article  PubMed  Google Scholar 

  63. Iskander I, Gamaleldin R, El Houchi S, El Shenawy A, Seoud I, El Gharbawi, et al. Serum bilirubin and bilirubin/albumin ratio as predictors of bilirubin encephalopathy. Pediatrics. 2014;134:e1330–9.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Sahoo T, Thukral A, Agarwal R, Sankar MJ. Galactosemia: an unusual cause of chronic bilirubin encephalopathy. BMJ Case Rep. 2015;bcr-2014-206852.

  65. Oh KS, Bahmad HF, Brathwaite C, Sanchez AC, Recine M. Neonatal acute liver failure with pulmonary yellow hyaline membrane and kernicterus. Autops Case Rep. 2021;11:e2021268.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Hsai DY, Walker FA. Variability in the clinical manifestations of galactosemia. J Pediatr. 1961;59:872–83.

    Article  Google Scholar 

  67. Hertel PM, Hawthorne K, Kim S, Finegold MJ, Shneider BL, Squires JE, et al. Presentation and outcomes of infants with idiopathic cholestasis: a multi-center prospective study. J Pediatr Gastroenterol Nutr. 2021; Aug 2, online ahead of print.

  68. Sundaram SS, Alonso EM, Narkewicz MR, Zhang S, Squires RH, Pediatric Acute Liver Failure Study Group. Characterization and outcomes of young infants with acute liver failure. J Pediatr. 2011;159:813–8.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Peinado-Acevedo JS, Chacon-Valenzuela E, Rodriguez-Moncada LL. Tan baby syndrome, an unpredictable complication of phototherapy. Biomedica. 2018;38:15–18.

    Article  PubMed  Google Scholar 

  70. A-Kadar HH, Balistreri WF. Unconjugated hyperbilirubinemia. In: Burg FD, Ingelfinger JR, Wald ER, editors. Current pediatric therapy, 14th Edition, WB Saunders: Philadelphia; 1993. p. 218–9.

  71. Porter MI, Dennis BL. Hyperbilirubinemia in the term newborn. Am Fam Physician. 2002;65:599–606.

    PubMed  Google Scholar 

  72. Kopelman AE, Brown RS, Odell GB. The “bronze” baby syndrome: a complication of phototherapy. J Pediatr. 1972;81:466–72.

    Article  CAS  PubMed  Google Scholar 

  73. Rubaltelli FF, Jori G, Reddi E. Bronze baby syndrome: a new porphyrin-related disorder. Pediatr Res. 1983;17:327–30.

    Article  CAS  PubMed  Google Scholar 

  74. Rubaltelli FF, Da Riol R, D’Amore E, Jori G. The bronze baby syndrome: evidence of increased tissue concentration of copper porphyrins. Acta Paediatr. 1996;85:381–4.

    Article  CAS  PubMed  Google Scholar 

  75. McDonagh AF. Bilirubin, copper-porphyrins, and the bronze-baby syndrome. J Pediatr. 2011;158:160–4.

    Article  PubMed  Google Scholar 

  76. Meisel P, Jahrig D, Theel L, Ordt AM, Jahrig K. The bronze baby syndrome: consequence of impaired excretion of photobilirubin? Photobiochem Photobiophys. 1982;3:345–52.

    CAS  Google Scholar 

  77. Onishi S, Itoh S, Isobe K, Togari H, Kitoh H, Nishimura Y. Mechanism of development of bronze baby syndrome in neonates treated with phototherapy. Pediatrics. 1982;69:273–6.

    Article  CAS  PubMed  Google Scholar 

  78. Itoh S, Okada H, Kuboi T, Kusaka T. Phototherapy for neonatal hyperbilirubinemia. Pediatr Int. 2017;59:959–66.

    Article  CAS  PubMed  Google Scholar 

  79. Ebbesen F. Low reserve albumin for binding of bilirubin in neonates with deficiency of bilirubin excretion and bronze baby syndrome. Acta Paediatr Scand. 1982;71:415–20.

    Article  CAS  PubMed  Google Scholar 

  80. Tan KL, Jacob E. The bronze baby syndrome. Acta Paediatr Scand. 1982;71:409–14.

    Article  CAS  PubMed  Google Scholar 

  81. McDonagh AF. Controversies in bilirubin biochemistry and their clinical relevance. Semin Fetal Neo Med. 2010;15:141–47.

    Article  Google Scholar 

  82. Schmid R. Direct-reacting bilirubin, bilirubin glucuronide, in serum, bile, and urine. Science. 1956;124:76–77.

    Article  CAS  PubMed  Google Scholar 

  83. Ullrich D, Tischler T, Sieg A, Fevery J. Renal clearance of bilirubin conjugates in newborns of different gestational age. Eur J Pediatr. 1993;152:837–39.

    Article  CAS  PubMed  Google Scholar 

  84. Priolisi A. Does conjugated bilirubin displace unconjugated bilirubin from albumin? Arch Dis Child. 1976;51:990–1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Venigalla S, Gourley GR. Neonatal cholestasis. Semin Perinatol. 2004;28:348–55.

    Article  PubMed  Google Scholar 

  86. Nassabeh-Montazami S. Phototherapy. In: MacDonald MG, Ramasethu J, Rais-Bahrami K, editors. Atlas of procedures in neonatology. Lippincott Williams & Wilkens: Philadelphia; 2013. p. 357–60.

  87. Maisels MJ, Stevenson DK, Watchko JF, McDonagh AF. Phototherapy and other treatments. In: Stevenson DK, Maisels MJ, Watchko JF, editors. Care of the jaundiced neonate. McGraw-Hill: New York; 2012. p. 195–227.

  88. Kaplan M, Muraca M, Hammerman C, Vilei MT, Rubaltelli FF. Unconjugated and conjugated bilirubin pigments during perinatal development. V. Effect of phototherapy on serum conjugated bilirubin in hyperbilirubinemic neonates. Biol Neonate. 1998;73:155–60.

    Article  CAS  PubMed  Google Scholar 

  89. Maisels MJ, Bhutani VK, Bogen D, Newman TB, Stark AR, Watchko JF. Hyperbilirubinemia in the newborn infant > or =35 weeks’ gestation: an update with clarifications. Pediatrics. 2009;124:1193–8.

    Article  PubMed  Google Scholar 

  90. American Academy of Pediatrics. Steering Committee on Quality Improvement and Management. Classifying recommendations for clinical practice guidelines. Pediatrics. 2004;114:874–7.

    Article  Google Scholar 

  91. Newman TB. Universal bilirubin screening, guidelines, and evidence. Pediatrics. 2009;124:1199–202.

    Article  PubMed  Google Scholar 

  92. Christensen RD, Yaish HM. Hemolytic disorders causing severe neonatal hyperbilirubinemia. Clin Perinatol. 2015;42:515–27.

    Article  PubMed  Google Scholar 

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Acknowledgements

The authors gratefully acknowledge the generous assistance of Carrie Everstine of the Magee-Womens Hospital medical library.

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JF Watchko conceptualized the review, carried out the literature search, drafted the initial manuscript, and reviewed and revised the manuscript. MJ Maisels critically reviewed the manuscript for important intellectual content, played an important role in interpreting the literature findings, and reviewed and revised the manuscript. Both authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

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Correspondence to Jon F. Watchko.

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Both authors report serving as a consultant in medico-legal cases related to kernicterus.

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Watchko, J.F., Maisels, M.J. Management of severe hyperbilirubinemia in the cholestatic neonate: a review and an approach. J Perinatol 42, 695–701 (2022). https://doi.org/10.1038/s41372-022-01330-8

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