Neonatology pp 611-620 | Cite as

Pathologic Unconjugated Hyperbilirubinemia, Isoimmunization, Abnormalities of Red Cells and Infections

  • Michael Kaplan
  • Ronald J. Wong
  • David K. Stevenson


Unconjugated hyperbilirubinemia in the newborn after birth is a normal phenomenon, transitional in nature, and harmless. It may be protective for the human neonate exposed to increased levels of oxygen and light in the environment outside the womb before antioxidant enzymatic defenses are fully upregulated. The phenomenon is called “physiologic neonatal jaundice” and the contributing biochemistry has been described in the preceding chapter (see  Chapter 81).


Exchange Transfusion G6PD Deficiency Hereditary Spherocytosis Direct Antiglobulin Test Neonatal Hyperbilirubinemia 
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  1. 1.
    Vreman HJ, Rodgers PA, Gale R, Stevenson DK (1989) Carbon monoxide excretion as an index of bilirubin production in rhesus monkeys. J Med Primatol 18: 449–460PubMedGoogle Scholar
  2. 2.
    Stevenson DK, Vreman HJ, Oh W, Fanaroff AA et al (1994) Bilirubin production in healthy term infants as measured by carbon monoxide in breath. Clin Chem 40: 1934–1939PubMedGoogle Scholar
  3. 3.
    Bhutani VK, Johnson L, Sivieri EM (1999) Predictive ability of a predischarge hour-specific serum bilirubin for subsequent significant hyperbilirubinemia in healthy term and near-term newborns. Pediatrics 103: 6–14PubMedCrossRefGoogle Scholar
  4. 4.
    Kaplan M, Muraca M, Hammerman C et al (2002) Imbalance between production and conjugation of bilirubin: A fundamental concept in the mechanism of neonatal jaundice. Pediatrics 110: e47Google Scholar
  5. 5.
    Stevenson DK, Bartoletti AL, Ostrander CR, Johnson JD (1979) Pulmonary excretion of carbon monoxide in the human infant as an index of bilirubin production. II. Infants of diabetic mothers. J Pediatr 94: 956–958Google Scholar
  6. 6.
    Stevenson DK, Ostrander CR, Hopper AO et al (1981) Pulmonary excretion of carbon monoxide as an index of bilirubin production. IIa. Evidence for possible delayed clearance of bilirubin in infants of diabetic mothers. J Pediatr 98: 822–824Google Scholar
  7. 7.
    Wong RJ, DeSandre GH, Sibley E, Stevenson DK (2006) Neonatal jaundice and liver disease. In: Fanaroff AA, Martin RJ, Walsh MC (eds) Neonatal-Perinatal Medicine: Diseases of the Fetus and Infant, 8th edn. Mosby, Philadelphia, pp 1419–1465Google Scholar
  8. 8.
    Shibahara S, Kitamuro T, Takahashi K (2002) Heme degradation and human disease: Diversity is the soul of life. Antioxid Redox Signal 4: 593–602Google Scholar
  9. 9.
    Hua L, Shi D, Bishop PR, Gosche J et al (2005) The role of UGT1A1*28 mutation in jaundiced infants with hypertrophic pyloric stenosis. Pediatr Res 58: 881–884PubMedCrossRefGoogle Scholar
  10. 10.
    Berardi A, Lugli L, Ferrari F et al (2006) Kernicterus associated with hereditary spherocytosis and UGT1A1 promoter polymorphism. Biol Neonate 90: 243–246PubMedCrossRefGoogle Scholar
  11. 11.
    Denschlag D, Marculescu R, Unfried G et al (2004) The size of a microsatellite polymorphism of the haem oxygenase 1 gene is associated with idiopathic recurrent miscarriage. Mol Hum Reprod 10: 211–214PubMedCrossRefGoogle Scholar
  12. 12.
    Beutler E, Gelbart T, Demina A (1998) Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism? Proc Natl Acad Sci 95: 8170–8174PubMedCrossRefGoogle Scholar
  13. 13.
    Bosma PJ, Chowdhury JR, Bakker C et al (1995) The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert’s syndrome. N Engl J Med 333: 1171–1175PubMedCrossRefGoogle Scholar
  14. 14.
    Kaplan M, Hammerman C, Maisels MJ (2003) Bilirubin genetics for the nongeneticist: Hereditary defects of neonatal bilirubin conjugation. Pediatrics 111 (4 Part 1): 886–893PubMedCrossRefGoogle Scholar
  15. 15.
    Watchko JF, Daood MJ, Biniwale M (2002) Understanding neonatal hyperbilirubinaemia in the era of genomics. Semin Neonatol 7: 143–152PubMedCrossRefGoogle Scholar
  16. 16.
    Hsia DY, Allen FH Jr, Gellis SS, Diamond LK (1952) Erythroblastosis fetalis. VIII. Studies of serum bilirubin in relation to Kernicterus. N Engl J Med 247: 668–671Google Scholar
  17. 17.
    Newman TB, Maisels MJ (1990) Does hyperbilirubinemia damage the brain of healthy full-term infants? Clin Perinatal 17: 331–358Google Scholar
  18. 18.
    Watchko JF, Oski FA (1983) Bilirubin 20 mg/dL = vigintiphobia. Pediatrics 71: 660–663PubMedGoogle Scholar
  19. 19.
    Newman TB, Maisels MJ (1992) Response to commentaries re: Evaluation and treatment of jaundice in the term newborn: A kinder, gentler approach. Pediatrics 89 (5 Part 1): 831–833PubMedGoogle Scholar
  20. 20.
    Ozmert E, Erdem G, Topcu M et al (1996) Long-term follow-up of indirect hyperbilirubinemia in full-term Turkish infants. Acta Paediatr 85: 1440–1444PubMedCrossRefGoogle Scholar
  21. 21.
    Nilsen ST, Finne PH, Bergsjo P, Stamnes O (1984) Males with neonatal hyperbilirubinemia examined at 18 years of age. Acta Paediatr Scand 73: 176–180PubMedCrossRefGoogle Scholar
  22. 22.
    American Academy of Pediatrics (2004) Management of hyper-bilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 114: 297–316CrossRefGoogle Scholar
  23. 23.
    Maisels MJ, Newman TB (1995) Kernicterus in otherwise healthy, breastfed term newborns. Pediatrics 96 (4 Part 1): 730–733PubMedGoogle Scholar
  24. 24.
    Blanchette V, Dror Y, Chan A (2005) Hematology In: MacDonald MG, Mullett MD, Seschia MMK (eds) Avery’s Neonatology: Pathophysiology and management of the newborn. Lippincott, Williams and Wilkins, Philadelphia, pp 1169–1234Google Scholar
  25. 25.
    Stevenson DK, Fanaroff AA, Maisels MJ et al (2001) Prediction of hyperbilirubinemia in near-term and term infants. Pediatrics 108: 31–39PubMedCrossRefGoogle Scholar
  26. 26.
    Kaplan M, Herschel M, Hammerman C et al (2006) Studies in hemolysis in glucose-6-phosphate dehydrogenase-deficient African American neonates. Clin Chim Acta 365: 177–182PubMedCrossRefGoogle Scholar
  27. 27.
    Maisels MJ, Kring E (2006) The contribution of hemolysis to early jaundice in normal newborns. Pediatrics 118: 276–279PubMedCrossRefGoogle Scholar
  28. 28.
    Martin JA, Hamilton BE, Sutton PD et al (2003) Births: Final data for 2002. Natl Vital Stat Rep 52: 1–113PubMedGoogle Scholar
  29. 29.
    Moise KJ Jr (2008) Management of rhesus alloimmunization in pregnancy. Obstet Gynecol 112: 164–176PubMedCrossRefGoogle Scholar
  30. 30.
    Liley AW (1961) Liquor amnil analysis in the management of the pregnancy complicated by resus sensitization. Am J Obstet Gynecol 82: 1359–1370PubMedGoogle Scholar
  31. 31.
    Queenan JT, Tomai TP, Ural SH, King JC (1993) Deviation in amniotic fluid optical density at a wavelength of 450 nm in Rh-immunized pregnancies from 14 to 40 weeks’ gestation: A proposal for clinical management. Am J Obstet Gynecol 168: 1370–1376Google Scholar
  32. 32.
    Bowman JM (1988) The prevention of Rh immunization. Transfus Med Rev 2: 129–150PubMedCrossRefGoogle Scholar
  33. 33.
    Cherif-Zahar B, Mattéi MG, Le Van Kim C et al (1991) Localization of the human Rh blood group gene structure to chromosome region 1p34.3–1p36.1 by in situ hybridization. Hum Genet 86: 398–400PubMedCrossRefGoogle Scholar
  34. 34.
    Lo YM, Hjelm NM, Fidler C et al (1998) Prenatal diagnosis of fetal RhD status by molecular analysis of maternal plasma. N Engl J Med 339: 1734–1738PubMedCrossRefGoogle Scholar
  35. 35.
    Van den Veyver IB, Moise KJ Jr (1996) Fetal RhD typing by polymerase chain reaction in pregnancies complicated by rhesus alloimmunization. Obstet Gynecol 88: 1061–1067PubMedCrossRefGoogle Scholar
  36. 36.
    Mari G, Deter RL, Carpenter RL et al (2000) Noninvasive diagnosis by Doppler ultrasonography of fetal anemia due to maternal red-cell alloimmunization. Collaborative Group for Doppler Assessment of the Blood Velocity in Anemic Fetuses. N Engl J Med 342: 9–14Google Scholar
  37. 37.
    Oepkes D, Seaward PG, Vandenbussche FP et al (2006) Doppler ultrasonography versus amniocentesis to predict fetal anemia. N Engl J Med 355: 156–164PubMedCrossRefGoogle Scholar
  38. 38.
    De Boer IP Zeestraten EC, Lopriore E et al (2008) Pediatric out-come in Rhesus hemolytic disease treated with and without intrauterine transfusion. Am J Obstet Gynecol 198: 54 e51–e54Google Scholar
  39. 39.
    Van Kamp IL, Klumper FJ, Oepkes D et al (2005) Complications of intrauterine intravascular transfusion for fetal anemia due to maternal red-cell alloimmunization. Am J Obstet Gynecol 192: 171–177PubMedCrossRefGoogle Scholar
  40. 40.
    Smits-Wintjens VE, Walther FJ, Lopriore E (2008) Rhesus haemolytic disease of the newborn: Postnatal management, associated morbidity and long-term outcome. Semin Fetal Neonatal Med 13: 265–271Google Scholar
  41. 41.
    Rübo J, Albrecht K, Lasch P et al (1992) High-dose intravenous immune globulin therapy for hyperbilirubinemia caused by Rh hemolytic disease. J Pediatr 121: 93–97PubMedCrossRefGoogle Scholar
  42. 42.
    Alcock GS, Liley H (2002) Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates. Cochrane Database Syst Rev 3:CD003313Google Scholar
  43. 43.
    Hudon L, Moise KJ Jr, Hegemier SE et al (1998) Long-term neu- rodevelopmental outcome after intrauterine transfusion for the treatment of fetal hemolytic disease. Am J Obstet Gynecol 179: 858 - 863PubMedCrossRefGoogle Scholar
  44. 44.
    Grundbacher FJ (1980) The etiology of ABO hemolytic disease of the newborn. Transfusion 20: 563–568PubMedCrossRefGoogle Scholar
  45. 45.
    Ozolek JA, Watchko JF, Mimouni F (1994) Prevalence and lack of clinical significance of blood group incompatibility in mothers with blood type A or B. J Pediatr 125: 87–91PubMedCrossRefGoogle Scholar
  46. 46.
    Fallstrom SP, Bjure J (1968) Endogenous formation of carbon monoxide in newborn infants. 3. ABO incompatibility. Acta Paediatr Scand 57: 137–144Google Scholar
  47. 47.
    Uetani Y, Nakamura H, Okamoto O et al (1989) Carboxyhemoglobin measurements in the diagnosis of ABO hemolytic disease. Acta Paediatr Jpn 31: 171–176PubMedGoogle Scholar
  48. 48.
    Meberg A, Johansen KB (1998) Screening for neonatal hyperbilirubinaemia and ABO alloimmunization at the time of testing for phenylketonuria and congenital hypothyreosis. Acta Paediatr 87: 1269–1274PubMedCrossRefGoogle Scholar
  49. 49.
    Bhutani VK, Johnson LH, Jeffrey Maisels M et al (2004) Kernicterus: epidemiological strategies for its prevention through systems-based approaches. J Perinatol 24: 650–662PubMedCrossRefGoogle Scholar
  50. 50.
    Sgro M, Campbell D, Shah V (2006) Incidence and causes of severe neonatal hyperbilirubinemia in Canada. CMAJ 175: 587–590PubMedCrossRefGoogle Scholar
  51. 51.
    Kaplan M, Hammerman C, Renbaum P et al (2000) Gilbert’s syndrome and hyperbilirubinaemia in ABO-incompatible neonates. Lancet 356: 652–653PubMedCrossRefGoogle Scholar
  52. 52.
    Moise KJ (2005) Red blood cell alloimmunization in pregnancy. Semin Hematol 42: 169–178PubMedCrossRefGoogle Scholar
  53. 53.
    Hackney DN, Knudtson EJ, Rossi KQ et al (2004) Management of pregnancies complicated by anti-c isoimmunization. Obstet Gynecol 103: 24–30PubMedCrossRefGoogle Scholar
  54. 54.
    Joy SD, Rossi KQ, Krugh D, O’Shaughnessy RW (2005) Management of pregnancies complicated by anti-E alloimmunization. Obstet Gynecol 105: 24–28PubMedCrossRefGoogle Scholar
  55. 55.
    McKenna DS, Nagaraja HN, O’Shaughnessy R (1999) Management of pregnancies complicated by anti-Kell isoimmunization. Obstet Gynecol 93 (5 Part 1): 667–673PubMedCrossRefGoogle Scholar
  56. 56.
    Vaughan JI, Warwick R, Letsky E et al (1994) Erythropoietic suppression in fetal anemia because of Kell alloimmunization. Am J Obstet Gynecol 171: 247–252PubMedGoogle Scholar
  57. 57.
    Beutler E (1994) G6PD deficiency. Blood 84: 3613–3636PubMedGoogle Scholar
  58. 58.
    WHO Working Group (1989) Glucose-6-phosphate dehydrogenase deficiency. Bull World Health Organ 67: 601–611Google Scholar
  59. 59.
    Kaplan M, Hammerman C (2004) Glucose-6-phosphate dehydrogenase deficiency: A hidden risk for kernicterus. Semin Perinatol 28: 356–364Google Scholar
  60. 60.
    Valaes T (1994) Severe neonatal jaundice associated with glucose-6-phosphate dehydrogenase deficiency: Pathogenesis and global epidemiology. Acta Paediatr Suppl 394: 58–76PubMedCrossRefGoogle Scholar
  61. 61.
    Manning D, Todd P, Maxwell M, Jane Platt M (2007) Prospective surveillance study of severe hyperbilirubinaemia in the newborn in the UK and Ireland. Arch Dis Child Fetal Neonatal Ed 92: F342–F346PubMedCrossRefGoogle Scholar
  62. 62.
    Necheles TF, Rai US, Valaes T (1976) The role of haemolysis in neonatal hyperbilirubinaemia as reflected in carboxyhaemoglobin levels. Acta Paediatr Scand 65: 361–367PubMedCrossRefGoogle Scholar
  63. 63.
    Slusher TM, Vreman HJ, McLaren DW et al (1995) Glucose-6-phosphate dehydrogenase deficiency and carboxyhemoglobin concentrations associated with bilirubin-related morbidity and death in Nigerian infants. J Pediatr 126: 102–108PubMedCrossRefGoogle Scholar
  64. 64.
    Kaplan M, Herschel M, Hammerman C et al (2004) Hyperbilirubinemia among African American, glucose-6-phosphate dehydrogenase-deficient neonates. Pediatrics 114: e213–e219PubMedCrossRefGoogle Scholar
  65. 65.
    Kaplan M, Vreman HJ, Hammerman C et al (1996) Contribution of haemolysis to jaundice in Sephardic Jewish glucose-6-phosphate dehydrogenase deficient neonates. Br J Haematol 93: 822–827PubMedCrossRefGoogle Scholar
  66. 66.
    Kaplan M, Rubaltelli FF, Hammerman C et al (1996) Conjugated bilirubin in neonates with glucose-6-phosphate dehydrogenase deficiency. J Pediatr 128 (5 Part 1): 695–697PubMedGoogle Scholar
  67. 67.
    Kaplan M, Renbaum P Levy-Lahad E et al (1997) Gilbert syndrome and glucose-6-phosphate dehydrogenase deficiency: a dose-dependent genetic interaction crucial to neonatal hyperbilirubinemia. Proc Natl Acad Sci USA 94: 12128–12132PubMedCrossRefGoogle Scholar
  68. 68.
    Huang CS, Chang PF, Huang MJ et al (2002) Glucose-6-phosphate dehydrogenase deficiency, the UDP-glucuronosyl transferase 1A1 gene, and neonatal hyperbilirubinemia. Gastroenterology 123: 127133Google Scholar
  69. 69.
    Kaplan M, Hammerman C, Feldman R, Brisk R (2000) Predischarge bilirubin screening in glucose-6-phosphate dehydrogenase-deficient neonates. Pediatrics 105 (3 Part 1): 533–537PubMedCrossRefGoogle Scholar
  70. 70.
    Fairbanks VF, Fernandez MN (1969) The identification of metabolic errors associated with hemolytic anemia. JAMA 208: 316–320PubMedCrossRefGoogle Scholar
  71. 71.
    Herschel M, Ryan M, Gelbart T, Kaplan M (2002) Hemolysis and hyperbilirubinemia in an African American neonate heterozygous for glucose-6-phosphate dehydrogenase deficiency. J Perinatol 22: 577–579PubMedCrossRefGoogle Scholar
  72. 72.
    Kaplan M, Beutler E, Vreman HJ et al (1999) Neonatal hyperbilirubinemia in glucose-6-phosphate dehydrogenase-deficient heterozygotes. Pediatrics 104 (1 Part 1): 68–74PubMedCrossRefGoogle Scholar
  73. 73.
    Kaplan M, Hammerman C, Vreman HJ et al (2001) Acute hemolysis and severe neonatal hyperbilirubinemia in glucose-6-phosphate dehydrogenase-deficient heterozygotes. J Pediatr 139: 137–140PubMedCrossRefGoogle Scholar
  74. 74.
    Herschel M, Beutler E (2001) Low glucose-6-phosphate dehydrogenase enzyme activity level at the time of hemolysis in a male neonate with the African type of deficiency. Blood Cells Mol Dis 27: 918–923PubMedCrossRefGoogle Scholar
  75. 75.
    Mentzer WC (1998) Pyruvate kinase deficiency and disorders of glycolysis. In: Nathan DG, Orkin SH (eds) Nathan and Oski’s Hematology of infancy and childhood. WB Saunders Company, Philadelphia, pp 665–703Google Scholar
  76. 76.
    Zanella A, Bianchi P, Fermo E (2007) Pyruvate kinase deficiency. Haematologica 92: 721–723PubMedCrossRefGoogle Scholar
  77. 77.
    Zanella A, Fermo E, Bianchi P et al (2007) Pyruvate kinase deficiency: The genotype-phenotype association. Blood Rev 21: 217–231Google Scholar
  78. 78.
    Iolascon A, Miraglia del Giudice E, Perrotta S et al (1998) Hereditary spherocytosis: From clinical to molecular defects. Haematologica 83: 240–257Google Scholar
  79. 79.
    Steiner LA, Gallagher PG (2007) Erythrocyte disorders in the perinatal period. Semin Perinatol 31: 254–261PubMedCrossRefGoogle Scholar
  80. 80.
    Fernandes A, Silva RF, Falcao AS et al (2004) Cytokine production, glutamate release and cell death in rat cultured astrocytes treated with unconjugated bilirubin and LPS. J Neuroimmunol 153: 64–75PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia 2012

Authors and Affiliations

  • Michael Kaplan
    • 1
    • 2
  • Ronald J. Wong
  • David K. Stevenson
  1. 1.Department of NeonatologyShaare Zedek Medical CenterIsrael
  2. 2.The Faculty of MedicineThe Hebrew UniversityJerusalemIsrael

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