Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

An approach to the management of hyperbilirubinemia in the preterm infant less than 35 weeks of gestation

Abstract

We provide an approach to the use of phototherapy and exchange transfusion in the management of hyperbilirubinemia in preterm infants of <35 weeks of gestation. Because there are limited data for evidence-based recommendations, these recommendations are, of necessity, consensus-based. The recommended treatment levels are based on operational thresholds for bilirubin levels and represent those levels beyond which it is assumed that treatment will likely do more good than harm. Long-term follow-up of a large population will be needed to evaluate whether or not these recommendations should be modified.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

References

  1. American Academy of Pediatrics. Subcommittee on hyperbilirubinemia. Clinical practice guideline: management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004; 114: 297–316.

    Article  Google Scholar 

  2. van Imhoff DE, Dijk PH, Hulzebos CV, BARTrial Study Group, Netherlands Neonatal Research Network. Uniform treatment thresholds for hyperbilirubinemia in preterm infants: background and synopsis of a national guideline. Early Hum Dev 2011; 87: 521–525.

    Article  PubMed  Google Scholar 

  3. Kaplan M, Merlob P, Regev R . Israel guidelines for the management of neonatal hyperbilirubinemia and prevention of kernicterus. J Perinatol 2008; 28: 389–397.

    CAS  Article  PubMed  Google Scholar 

  4. Rennie J, Burman-Roy S, Murphy MS . Neonatal jaundice: summary of NICE guidance. BMJ 2010; 340: 1190–1192.

    Article  Google Scholar 

  5. Bratlid D, Nakstad B, Hansen TWR . National guidelines for treatment of jaundice in the newborn. Acta Paediatr 2011; 100 (4): 499–505.

    CAS  Article  PubMed  Google Scholar 

  6. Canadian Paediatric Society. Guidelines for detection, management and prevention of hyperbilirubinemia in term and late preterm newborn infants (35 or more weeks’ gestation) - summary. Paediatr Child Health 2007; 12: 401–418.

    Article  Google Scholar 

  7. Horn AR, Kirsten GF, Kroon SM, Henning PA, Moller G, Pieper C et al. Phototherapy and exchange transfusion for neonatal hyperbilirubinaemia. S Afr Med J 2006; 96: 819–824.

    CAS  PubMed  Google Scholar 

  8. Maisels MJ, Watchko JF . Treatment of jaundice in low birthweight infants. Arch Dis Child Fetal Neonatal Ed 2003; 88: F459–F463.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. Rennie JM, Sehgal A, De A, Kendall GS, Cole TJ . Range of UK practice regarding thresholds for phototherapy and exchange transfusion in neonatal hyperbilirubinaemia. Arch Dis Child Fetal Neonatol Ed 2009; 94: F323–F327.

    CAS  Article  Google Scholar 

  10. Hansen TWR . Therapeutic approaches to neonatal jaundice: an international survey. Clin Pediatr 1996; 35: 309–316.

    CAS  Article  Google Scholar 

  11. National Institute for Health and Clinical Excellence. Neonatal Jaundice. National Institute for Health and Clinical Excellence, 2010, www.nice.org.uk/CG98.

  12. Bhutani VK . Survey of neonatologists in the Perinatal Section of the AAP (personal communication). 2011.

  13. Watchko JF, Maisels MJ . Jaundice in low birth weight infants - pathobiology and outcome. Arch Dis Child Fetal Neonatol Ed 2003; 88: F455–F459.

    CAS  Article  Google Scholar 

  14. Watchko JF, Oski FA . Kernicterus in preterm newborns: past, present and future. Pediatrics 1992; 90: 707–715.

    CAS  PubMed  Google Scholar 

  15. Shapiro SM . Chronic bilirubin encephalopathy: diagnosis and outcome. Semin Fetal Neonat Med 2010; 15: 157–163.

    Article  Google Scholar 

  16. Keenan WJ, Perlstein PH, Light IJ, Sutherland JM . kernicterus in small, sick, premature infants receiving phototherapy. Pediatrics 1972; 49: 652–655.

    CAS  PubMed  Google Scholar 

  17. Lipsitz PJ, Gartner LM, Bryla DA . Neonatal and infant mortality in relation to phototherapy. Pediatrics 1985; 75: 422–426.

    CAS  PubMed  Google Scholar 

  18. Govaert P, Lequin M, Swarte R, Robben S, De Coo R, Weisglas-Kuperus N et al. Changes in globus pallidus with (pre) term kernicterus. Pediatrics 2003; 112: 1256–1263.

    Article  PubMed  Google Scholar 

  19. Moll M, Goelz R, Naegele T, Wilke M, Poets CF . Are recommended phototherapy thresholds safe enough for extremely low birth weight (ELBW) infants? A report on 2 ELBW infants with kernicterus despite only moderate hyperbilirubinemia. Neonatology 2011; 99: 90–94.

    CAS  Article  PubMed  Google Scholar 

  20. Sugama S, Soeda A, Eto Y . Magnetic resonance imaging in three children with kernicterus. Pediatr Neurol 2001; 25: 328–331.

    CAS  Article  PubMed  Google Scholar 

  21. Mazeiras G, Roze J-C, Ancel P-Y, Caillaux G, Frondas-Chauty A, Denizot S et al. Hyperbilirubinemia and neurodevelopmental outcome of very low birthweight infants: results from the LIFT cohort. PLoS ONE 2012; 7 (1): 1–8.

    Article  Google Scholar 

  22. Oh W, Tyson JE, Fanaroff AA, Vohr BR, Perritt R, Stoll BJ et al. Association between peak serum bilirubin and neurodevelopmental outcomes in extremely low birth weight infants. Pediatrics 2003; 112: 773–779.

    Article  PubMed  Google Scholar 

  23. O’Shea TM, Dillard RG, Klinepeter KL, Goldstein DJ . Serum bilirubin levels, intracranial hemorrhage, and the risk of developmental problems in very low birth weight infants. Pediatrics 1992; 90: 888–892.

    PubMed  Google Scholar 

  24. Yeo KL, Perlman M, Hao Y, Mullaney P . Outcomes of extremely premature infants related to their peak serum bilirubin concentrations and exposure to phototherapy. Pediatrics 1998; 102 (6): 1426–1431.

    CAS  Article  PubMed  Google Scholar 

  25. Morris BH, Oh W, Tyson JE, Stevenson D, Phelps DL, O’Shea TM et al. Aggressive vs. conservative phototherapy for infants with extremely low birth weight. New Engl J Med 2008; 359: 1885–1896.

    CAS  Article  PubMed  Google Scholar 

  26. Brodersen R . Binding of bilirubin to albumin. CRC Crit Rev Clin Lab Sci 1980; 11: 305–399.

    CAS  PubMed  Google Scholar 

  27. McDonagh AF, Maisels MJ . Bilirubin unbound: deja vu all over again? Pediatrics 2006; 117: 523–525.

    Article  PubMed  Google Scholar 

  28. Wennberg RP, Ahlfors CE, Bhutani V, Johnson LH, Shapiro SM . Toward understanding kernicterus: a challenge to improve the management of jaundiced newborns. Pediatrics 2006; 117: 474–485.

    Article  PubMed  Google Scholar 

  29. Cashore WJ, Oh W . Unbound bilirubin and kernicterus in low birthweight infants. Pediatrics 1982; 69: 481–485.

    CAS  PubMed  Google Scholar 

  30. Nakamura H, Yonetani M, Uetani Y, Funato M, Lee Y . Determination of serum unbound bilirubin for prediction of kernicterus in low birth weight infants. Acta Paediatr Jpn 1992; 54: 642–647.

    Article  Google Scholar 

  31. Oh W, Stevenson DK, Tyson JE, Morris BH, Ahlfors CE, Bender GJ et al. Influence of clinical status on the association between plasma total and unbound bilirubin and death or adverse neurodevelopmental outcomes in extremely low birth weight infants. Acta Paediatr 2010; 99: 673–678.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. Ahlfors CE . Criteria for exchange transfusion in jaundiced newborns. Pediatrics 1994; 93: 488–494.

    CAS  PubMed  Google Scholar 

  33. Watchko JF . Kernicterus and the molecular mechanisms of bilirubin-induced CNS injury in newborns. NeuroMolecular Med 2006; 8: 513–529.

    CAS  Article  PubMed  Google Scholar 

  34. Wennberg RP . Cellular basis of bilirubin toxicity. NY State J Med 1991; 91: 493–496.

    CAS  Google Scholar 

  35. 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. Pediatrcs 2007; 120: 27–32.

    Article  Google Scholar 

  36. Maisels MJ . Phototherapy - traditional and nontraditional. J Perinatol 2001; 21: S93–S97.

    Article  PubMed  Google Scholar 

  37. Bryla DA, Brown A, Gartner L, Lipsitz P . Phototherapy for neonatal hyperbilirubinemia. Pediatrics 1986; 78 (1): 180–181.

    Google Scholar 

  38. Tozzi E, Tozzi-Ciancarelli MG, Di Giulio A, D’Alfonso A, Farello G, Spennati GF et al. In vitro and in vivo effects of erythrocyte phototherapy in newborns. Biol Neonate 1989; 56 (4): 204–209.

    CAS  Article  PubMed  Google Scholar 

  39. Vreman HJ, Wong RJ, Stevenson DK . Phototherapy: current methods and future directions. Semin Perinatol 2004; 28: 326–333.

    Article  PubMed  Google Scholar 

  40. Vreman HJ, Knauer Y, Wong RJ, Chan M-L, Stevenson DK . Dermal carbon monoxide excretion in neonatal rats during light exposure. Pediatr Res 2009; 66: 66–69.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. Zuniga-Gonzalez G, Gomez-Meda BC, Lemus-Varela M, Zamora-Perez AL, Armendariz-Borunda J, Barros-Hernandez A et al. Micronucleated erythrocytes in preterm newborns exposed to phototherapy and/or oxygentherapy. Photochem Photobiol 2012; 107: 79–83.

    CAS  Article  Google Scholar 

  42. Maisels MJ, McDonagh AF . Phototherapy for neonatal jaundice. N Engl J Med 2008; 358: 920–928.

    CAS  Article  PubMed  Google Scholar 

  43. Bhutani VK, Committee on Fetus and Newborn. Technical Report: phototherapy to prevent severe neonatal hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2011; 128: e1046–e1052.

    Article  PubMed  Google Scholar 

  44. Watchko JF . Exchange transfusion in the management of neonatal hyperbilirubinemia In: Maisels MJ, Watchko JF (eds). Neonatal Jaundice 2000, pp 169–176.

  45. Jackson JC . Adverse events associated with exchange transfusion in healthy and ill newborns. Pediatrics 1997; 99: e7.

    CAS  Article  PubMed  Google Scholar 

  46. Patra K, Storfer-Isser A, Siner B, Moore J, Hack M . Adverse events associated with neonatal exchange transfusion in the 1990 s. J Pediatr 2004; 144: 626–631.

    Article  PubMed  Google Scholar 

  47. Bowman JM . RhD hemolytic disease of the newborn. New Engl J Med 1998; 339: 1775–1777.

    CAS  Article  PubMed  Google Scholar 

  48. Keenan WJ, Novak KK, Sutherland JM, Bryla DA, Fetterly KL . Morbidity and mortality associated with exchange transfusion. Pediatrics (Suppl) 1985; 75: 417–421.

    CAS  Google Scholar 

  49. Grobler JM, Mercer MJ . Kernicterus associated with elevated predominantly direct-reacting bilirubin. S Afr Med J 1997; 87: 146.

    Google Scholar 

  50. Clark CF, Torii S, Hamamoto Y, Kaito H . The ‘bronze baby’ syndrome: postmortem data. J Pediatr 1976; 88: 461–464.

    CAS  Article  PubMed  Google Scholar 

  51. 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: 415–420.

    CAS  Article  PubMed  Google Scholar 

  52. Bertini G, Dani C, Fonda C, Zorzi C, Rubaltelli F . Bronze baby syndrome and the risk of kernicterus. Acta Paediatr 2005; 94: 968–971.

    Article  PubMed  Google Scholar 

  53. Rübo J, Albrecht K, Lasch P, Laufkötter E, Leititis J, Marsan D et al. High-dose intravenous immune globulin therapy for hyperbilirubinemia caused by Rh hemolytic disease. J Pediatr 1992; 121: 93–97.

    Article  PubMed  Google Scholar 

  54. Sato K, Hara T, Kondo T, Iwao H, Honda S, Ueda K . High-dose intravenous gammaglobulin therapy for neonatal immune haemolytic jaundice due to blood group incompatibility. Acta Paediatr Scand 1991; 80: 163–166.

    CAS  Article  PubMed  Google Scholar 

  55. Alpay F, Sarici SÜ, Okutan V, Erdem G, Özcan O, Gökçay E . High-dose intravenous immunoglobin therapy in neonatal immune haemolytic jaundice. Acta Paediatr 1999; 88: 216–219.

    CAS  Article  PubMed  Google Scholar 

  56. Smits-Wintjens VEHJ, Walther FJ, Rath MEA, Lindenburg ITM, te Pas AB, Kramer CM et al. Intravenous immunoglobulin in neonates with rhesus hemolytic disease: a randomized controlled trial. Pediatrics 2011; 127: 680–686.

    Article  PubMed  Google Scholar 

  57. Hammerman C, Kaplan M, Vreman HJ, Stevenson DK . Intravenous immune globulin in neonatal ABO isoimmunization: factors associated with clinical efficacy. Biol Neonate 1996; 70: 69–74.

    CAS  Article  PubMed  Google Scholar 

  58. Sackett DL, Haynes RB, Guyatt GH, Tugwell P . Clinical Epidemiology: A Basic Science for Clinical Medicine. 2nd edn. Little, Brown and Co: Boston, 1991.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M J Maisels.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Maisels, M., Watchko, J., Bhutani, V. et al. An approach to the management of hyperbilirubinemia in the preterm infant less than 35 weeks of gestation. J Perinatol 32, 660–664 (2012). https://doi.org/10.1038/jp.2012.71

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/jp.2012.71

Keywords

  • hyperbilirubinemia
  • jaundice
  • phototherapy
  • exchange transfusion

Further reading

Search

Quick links