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Treatment of unconjugated hyperbilirubinemia in term and late preterm infants

Ronald J Wong, BA
Vinod K Bhutani, MD, FAAP
Section Editor
Steven A Abrams, MD
Deputy Editor
Melanie S Kim, MD


Almost all newborn infants develop neonatal hyperbilirubinemia (jaundice) with total serum or plasma bilirubin (TB) levels that exceed 1 mg/dL (17.1 micromol/L) the upper limit of normal for adults. Neonates with severe hyperbilirubinemia (defined as a TB >25 mg/dL [428 micromol/L]) are at risk for bilirubin-induced neurologic dysfunction (BIND) including kernicterus, which occurs when bilirubin crosses the blood-brain barrier and binds to brain tissue (figure 1). (See "Clinical manifestations of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Neurologic manifestations'.)

The treatment of neonatal unconjugated hyperbilirubinemia and prevention of severe hyperbilirubinemia are reviewed here. The clinical manifestations, evaluation, pathogenesis, and etiology of this disorder are discussed separately. (See "Clinical manifestations of unconjugated hyperbilirubinemia in term and late preterm infants" and "Evaluation of unconjugated hyperbilirubinemia in term and late preterm infants" and "Pathogenesis and etiology of unconjugated hyperbilirubinemia in the newborn".)


Neonatal hyperbilirubinemia in infants ≥35 weeks gestational age (GA) is defined as total serum or plasma bilirubin (TB) >95th percentile on the hour-specific Bhutani nomogram (figure 2) [1].

Severe neonatal hyperbilirubinemia, or "extreme hyperbilirubinemia," is defined as a TB >25 mg/dL (428 micromol/L). It is associated with an increased risk for bilirubin-induced neurologic dysfunction (BIND), which occurs when bilirubin crosses the blood-brain barrier and binds to brain tissue. (See "Clinical manifestations of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Neurologic manifestations'.)

Acute bilirubin encephalopathy (ABE) is used to describe the acute manifestations of BIND. (See "Clinical manifestations of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Acute bilirubin encephalopathy'.)


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Literature review current through: Mar 2017. | This topic last updated: Mar 30, 2017.
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  1. American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004; 114:297.
  2. Bhutani VK, Johnson L, Sivieri EM. Predictive ability of a predischarge hour-specific serum bilirubin for subsequent significant hyperbilirubinemia in healthy term and near-term newborns. Pediatrics 1999; 103:6.
  3. Bratlid D, Nakstad B, Hansen TW. National guidelines for treatment of jaundice in the newborn. Acta Paediatr 2011; 100:499.
  4. Garland JS, Alex C, Deacon JS, Raab K. Treatment of infants with indirect hyperbilirubinemia. Readmission to birth hospital vs nonbirth hospital. Arch Pediatr Adolesc Med 1994; 148:1317.
  5. Ahlfors CE. Criteria for exchange transfusion in jaundiced newborns. Pediatrics 1994; 93:488.
  6. Ahlfors CE, Wennberg RP, Ostrow JD, Tiribelli C. Unbound (free) bilirubin: improving the paradigm for evaluating neonatal jaundice. Clin Chem 2009; 55:1288.
  7. Lamola AA, Bhutani VK, Du L, et al. Neonatal bilirubin binding capacity discerns risk of neurological dysfunction. Pediatr Res 2015; 77:334.
  8. Johnson L, Bhutani VK. The clinical syndrome of bilirubin-induced neurologic dysfunction. Semin Perinatol 2011; 35:101.
  9. Gottstein R, Cooke RW. Systematic review of intravenous immunoglobulin in haemolytic disease of the newborn. Arch Dis Child Fetal Neonatal Ed 2003; 88:F6.
  10. Martinez JC, Maisels MJ, Otheguy L, et al. Hyperbilirubinemia in the breast-fed newborn: a controlled trial of four interventions. Pediatrics 1993; 91:470.
  11. Brown AK, Kim MH, Wu PY, Bryla DA. Efficacy of phototherapy in prevention and management of neonatal hyperbilirubinemia. Pediatrics 1985; 75:393.
  12. Ip S, Chung M, Kulig J, et al. An evidence-based review of important issues concerning neonatal hyperbilirubinemia. Pediatrics 2004; 114:e130.
  13. John E. Phototherapy in neonatal hyperbilirubinaemia. Aust Paediatr J 1975; 11:49.
  14. Maisels MJ, Kring E. Rebound in serum bilirubin level following intensive phototherapy. Arch Pediatr Adolesc Med 2002; 156:669.
  15. Holtrop PC, Madison K, Maisels MJ. A clinical trial of fiberoptic phototherapy vs conventional phototherapy. Am J Dis Child 1992; 146:235.
  16. Garg AK, Prasad RS, Hifzi IA. A controlled trial of high-intensity double-surface phototherapy on a fluid bed versus conventional phototherapy in neonatal jaundice. Pediatrics 1995; 95:914.
  17. Tan KL. Comparison of the efficacy of fiberoptic and conventional phototherapy for neonatal hyperbilirubinemia. J Pediatr 1994; 125:607.
  18. Newman TB, Kuzniewicz MW, Liljestrand P, et al. Numbers needed to treat with phototherapy according to American Academy of Pediatrics guidelines. Pediatrics 2009; 123:1352.
  19. Ennever JF, Costarino AT, Polin RA, Speck WT. Rapid clearance of a structural isomer of bilirubin during phototherapy. J Clin Invest 1987; 79:1674.
  20. Eggert P, Stick C, Schröder H. On the distribution of irradiation intensity in phototherapy. Measurements of effective irradiance in an incubator. Eur J Pediatr 1984; 142:58.
  21. Maisels MJ. Why use homeopathic doses of phototherapy? Pediatrics 1996; 98:283.
  22. Djokomuljanto S, Quah BS, Surini Y, et al. Efficacy of phototherapy for neonatal jaundice is increased by the use of low-cost white reflecting curtains. Arch Dis Child Fetal Neonatal Ed 2006; 91:F439.
  23. Vreman HJ, Wong RJ, Stevenson DK. Phototherapy: current methods and future directions. Semin Perinatol 2004; 28:326.
  24. Bhutani VK, Committee on Fetus and Newborn, American Academy of Pediatrics. Phototherapy to prevent severe neonatal hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2011; 128:e1046.
  25. Vreman HJ, Wong RJ, Stevenson DK, et al. Light-emitting diodes: a novel light source for phototherapy. Pediatr Res 1998; 44:804.
  26. Seidman DS, Moise J, Ergaz Z, et al. A new blue light-emitting phototherapy device: a prospective randomized controlled study. J Pediatr 2000; 136:771.
  27. Kumar P, Chawla D, Deorari A. Light-emitting diode phototherapy for unconjugated hyperbilirubinaemia in neonates. Cochrane Database Syst Rev 2011; :CD007969.
  28. Tridente A, De Luca D. Efficacy of light-emitting diode versus other light sources for treatment of neonatal hyperbilirubinemia: a systematic review and meta-analysis. Acta Paediatr 2012; 101:458.
  29. Morris BH, Tyson JE, Stevenson DK, et al. Efficacy of phototherapy devices and outcomes among extremely low birth weight infants: multi-center observational study. J Perinatol 2013; 33:126.
  30. CREMER RJ, PERRYMAN PW, RICHARDS DH. Influence of light on the hyperbilirubinaemia of infants. Lancet 1958; 1:1094.
  31. Slusher TM, Vreman HJ, Olusanya BO, et al. Safety and efficacy of filtered sunlight in treatment of jaundice in African neonates. Pediatrics 2014; 133:e1568.
  32. Slusher TM, Olusanya BO, Vreman HJ, et al. A Randomized Trial of Phototherapy with Filtered Sunlight in African Neonates. N Engl J Med 2015; 373:1115.
  33. Osborn LM, Bolus R. Breast feeding and jaundice in the first week of life. J Fam Pract 1985; 20:475.
  34. Amato M, Howald H, von Muralt G. Interruption of breast-feeding versus phototherapy as treatment of hyperbilirubinemia in full-term infants. Helv Paediatr Acta 1985; 40:127.
  35. Yetman RJ, Parks DK, Huseby V, et al. Rebound bilirubin levels in infants receiving phototherapy. J Pediatr 1998; 133:705.
  36. Chang PW, Kuzniewicz MW, McCulloch CE, Newman TB. A Clinical Prediction Rule for Rebound Hyperbilirubinemia Following Inpatient Phototherapy. Pediatrics 2017; 139.
  37. Kaplan M, Kaplan E, Hammerman C, et al. Post-phototherapy neonatal bilirubin rebound: a potential cause of significant hyperbilirubinaemia. Arch Dis Child 2006; 91:31.
  38. Mahé E, Beauchet A, Aegerter P, Saiag P. Neonatal blue-light phototherapy does not increase nevus count in 9-year-old children. Pediatrics 2009; 123:e896.
  39. Rubaltelli FF, Da Riol R, D'Amore ES, Jori G. The bronze baby syndrome: evidence of increased tissue concentration of copper porphyrins. Acta Paediatr 1996; 85:381.
  40. McDonagh AF. Bilirubin, copper-porphyrins, and the bronze-baby syndrome. J Pediatr 2011; 158:160.
  41. Tan KL, Jacob E. The bronze baby syndrome. Acta Paediatr Scand 1982; 71:409.
  42. Newman TB, Wickremasinghe AC, Walsh EM, et al. Retrospective Cohort Study of Phototherapy and Childhood Cancer in Northern California. Pediatrics 2016; 137.
  43. Wickremasinghe AC, Kuzniewicz MW, Grimes BA, et al. Neonatal Phototherapy and Infantile Cancer. Pediatrics 2016; 137.
  44. Wintermeier K, von Poblotzki M, Genzel-Boroviczény O, et al. Neonatal blue light phototherapy increases café-au-lait macules in preschool children. Eur J Pediatr 2014; 173:1519.
  45. Oláh J, Tóth-Molnár E, Kemény L, Csoma Z. Long-term hazards of neonatal blue-light phototherapy. Br J Dermatol 2013; 169:243.
  46. Messner KH, Maisels MJ, Leure-DuPree AE. Phototoxicity to the newborn primate retina. Invest Ophthalmol Vis Sci 1978; 17:178.
  47. Steiner LA, Bizzarro MJ, Ehrenkranz RA, Gallagher PG. A decline in the frequency of neonatal exchange transfusions and its effect on exchange-related morbidity and mortality. Pediatrics 2007; 120:27.
  48. Flaherman VJ, Kuzniewicz MW, Escobar GJ, Newman TB. Total serum bilirubin exceeding exchange transfusion thresholds in the setting of universal screening. J Pediatr 2012; 160:796.
  49. Bhutani VK, Meng NF, Knauer Y, et al. Extreme hyperbilirubinemia and rescue exchange transfusion in California from 2007 to 2012. J Perinatol 2016; 36:853.
  50. Ozmert E, Erdem G, Topçu M, et al. Long-term follow-up of indirect hyperbilirubinemia in full-term Turkish infants. Acta Paediatr 1996; 85:1440.
  51. Funato M, Teraoka S, Tamai H, Shimida S. Follow-up study of auditory brainstem responses in hyperbilirubinemic newborns treated with exchange transfusion. Acta Paediatr Jpn 1996; 38:17.
  52. Hung KL. Auditory brainstem responses in patients with neonatal hyperbilirubinemia and bilirubin encephalopathy. Brain Dev 1989; 11:297.
  53. Kuriyama M, Tomiwa K, Konishi Y, Mikawa H. Improvement in auditory brainstem response of hyperbilirubinemic infants after exchange transfusions. Pediatr Neurol 1986; 2:127.
  54. Nwaesei CG, Van Aerde J, Boyden M, Perlman M. Changes in auditory brainstem responses in hyperbilirubinemic infants before and after exchange transfusion. Pediatrics 1984; 74:800.
  55. Wong RJ, DeSandre GH, Sibley E, Stevenson DK. Neonatal jaundice and liver disease. In: Neonatal-Perinatal Medicine: Diseases of the Fetus and Infant, 8th ed, Martin RJ, Klaus MH, Fanaroff AA, Walsh MC (Eds), Mosby and Elsevier, Philadelphia 2006. p.1446.
  56. Keenan WJ, Novak KK, Sutherland JM, et al. Morbidity and mortality associated with exchange transfusion. Pediatrics 1985; 75:417.
  57. Hovi L, Siimes MA. Exchange transfusion with fresh heparinized blood is a safe procedure. Experiences from 1 069 newborns. Acta Paediatr Scand 1985; 74:360.
  58. Patra K, Storfer-Isser A, Siner B, et al. Adverse events associated with neonatal exchange transfusion in the 1990s. J Pediatr 2004; 144:626.
  59. Jackson JC. Adverse events associated with exchange transfusion in healthy and ill newborns. Pediatrics 1997; 99:e7 www.pediatrics.org/cgi/content/full/99/5/e7 (Accessed on July 14, 2007).
  60. Jackson JC. Adverse events associated with exchange transfusion in healthy and ill newborns. Pediatrics 1997; 99:E7.
  61. Alpay F, Sarici SU, Okutan V, et al. High-dose intravenous immunoglobulin therapy in neonatal immune haemolytic jaundice. Acta Paediatr 1999; 88:216.
  62. Dağoğlu T, Ovali F, Samanci N, Bengisu E. High-dose intravenous immunoglobulin therapy for rhesus haemolytic disease. J Int Med Res 1995; 23:264.
  63. Hammerman C, Kaplan M, Vreman HJ, Stevenson DK. Intravenous immune globulin in neonatal ABO isoimmunization: factors associated with clinical efficacy. Biol Neonate 1996; 70:69.
  64. Alcock GS, Liley H. Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates. Cochrane Database Syst Rev 2002; :CD003313.
  65. Smits-Wintjens VE, Walther FJ, Rath ME, et al. Intravenous immunoglobulin in neonates with rhesus hemolytic disease: a randomized controlled trial. Pediatrics 2011; 127:680.
  66. Santos MC, Sá C, Gomes SC Jr, et al. The efficacy of the use of intravenous human immunoglobulin in Brazilian newborns with rhesus hemolytic disease: a randomized double-blind trial. Transfusion 2013; 53:777.
  67. Louis D, More K, Oberoi S, Shah PS. Intravenous immunoglobulin in isoimmune haemolytic disease of newborn: an updated systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed 2014; 99:F325.
  68. Honar N, Ghashghaei Saadi E, Saki F, et al. Effect of Ursodeoxycholic Acid on Indirect Hyperbilirubinemia in Neonates Treated With Phototherapy. J Pediatr Gastroenterol Nutr 2016; 62:97.
  69. Reinisch JM, Sanders SA, Mortensen EL, Rubin DB. In utero exposure to phenobarbital and intelligence deficits in adult men. JAMA 1995; 274:1518.
  70. Yaffe SJ, Dorn LD. Effects of prenatal treatment with phenobarbital. Dev Pharmacol Ther 1990; 15:215.
  71. Kappas A, Drummond GS, Valaes T. A single dose of Sn-mesoporphyrin prevents development of severe hyperbilirubinemia in glucose-6-phosphate dehydrogenase-deficient newborns. Pediatrics 2001; 108:25.
  72. Kappas A, Drummond GS, Henschke C, Valaes T. Direct comparison of Sn-mesoporphyrin, an inhibitor of bilirubin production, and phototherapy in controlling hyperbilirubinemia in term and near-term newborns. Pediatrics 1995; 95:468.
  73. Martinez JC, Garcia HO, Otheguy LE, et al. Control of severe hyperbilirubinemia in full-term newborns with the inhibitor of bilirubin production Sn-mesoporphyrin. Pediatrics 1999; 103:1.
  74. Kappas A, Drummond GS. Control of heme metabolism with synthetic metalloporphyrins. J Clin Invest 1986; 77:335.
  75. Reddy P, Najundaswamy S, Mehta R, et al. Tin-mesoporphyrin in the treatment of severe hyperbilirubinemia in a very-low-birth-weight infant. J Perinatol 2003; 23:507.
  76. Valaes T, Petmezaki S, Henschke C, et al. Control of jaundice in preterm newborns by an inhibitor of bilirubin production: studies with tin-mesoporphyrin. Pediatrics 1994; 93:1.
  77. Suresh GK, Martin CL, Soll RF. Metalloporphyrins for treatment of unconjugated hyperbilirubinemia in neonates. Cochrane Database Syst Rev 2003; :CD004207.
  78. Wong RJ, Bhutani VK, Vreman HJ, et al. Tin mesoporphyrin for the prevention of severe neonatal hyperbilirubinemia. NeoReviews 2007; 8:e77.
  79. Bhutani VK, Poland R, Meloy LD, et al. Clinical trial of tin mesoporphyrin to prevent neonatal hyperbilirubinemia. J Perinatol 2016; 36:533.
  80. Heady JA, Morris JN, Oliver MF. WHO clofibrate/cholesterol trial: clarifications. Lancet 1992; 340:1405.
  81. Newman TB, Liljestrand P, Jeremy RJ, et al. Outcomes among newborns with total serum bilirubin levels of 25 mg per deciliter or more. N Engl J Med 2006; 354:1889.
  82. Kuzniewicz M, Newman TB. Interaction of hemolysis and hyperbilirubinemia on neurodevelopmental outcomes in the collaborative perinatal project. Pediatrics 2009; 123:1045.
  83. Jangaard KA, Fell DB, Dodds L, Allen AC. Outcomes in a population of healthy term and near-term infants with serum bilirubin levels of >or=325 micromol/L (>or=19 mg/dL) who were born in Nova Scotia, Canada, between 1994 and 2000. Pediatrics 2008; 122:119.
  84. Vandborg PK, Hansen BM, Greisen G, et al. Follow-up of neonates with total serum bilirubin levels ≥ 25 mg/dL: a Danish population-based study. Pediatrics 2012; 130:61.