Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Evaluation 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 a total serum or plasma bilirubin (TB) level greater than 1 mg/dL (17.1 micromol/L), which is the upper limit of normal for adults. As TB increases, it produces neonatal jaundice, the yellowish discoloration of the skin and/or conjunctiva (as visualized on the sclerae) caused by bilirubin deposition [1]. Neonates with severe hyperbilirubinemia (defined as a TB >25 mg/dL [428 micromol/L]) are at risk for bilirubin-induced neurologic dysfunction (BIND), which occurs when bilirubin crosses the blood-brain barrier and binds to brain tissue (figure 1). As a result, it is important to identify and manage infants who are at risk for developing hyperbilirubinemia. (See "Clinical manifestations of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Clinical manifestations'.)

The evaluation of neonatal unconjugated hyperbilirubinemia, including identifying at-risk infants is reviewed here. The pathogenesis, etiology, clinical manifestations, prevention, and treatment of hyperbilirubinemia are discussed separately. (See "Pathogenesis and etiology of unconjugated hyperbilirubinemia in the newborn" and "Clinical manifestations of unconjugated hyperbilirubinemia in term and late preterm infants" and "Treatment of unconjugated hyperbilirubinemia in term and late preterm infants".)


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 1) [2].

Severe neonatal 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 'Clinical 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'.)

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Dec 04, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Dennery PA, Seidman DS, Stevenson DK. Neonatal hyperbilirubinemia. N Engl J Med 2001; 344:581.
  2. American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004; 114:297.
  3. 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.
  4. Maisels MJ, Newman TB. Kernicterus in otherwise healthy, breast-fed term newborns. Pediatrics 1995; 96:730.
  5. AAP Subcommittee on Neonatal Hyperbilirubinemia. Neonatal jaundice and kernicterus. Pediatrics 2001; 108:763.
  6. Mah JK, Wirrell E. All is not well: the continual challenges of bilirubin encephalopathy. Can J Neurol Sci 2005; 32:273.
  7. Christensen RD, Lambert DK, Henry E, et al. Unexplained extreme hyperbilirubinemia among neonates in a multihospital healthcare system. Blood Cells Mol Dis 2013; 50:105.
  8. Bhutani VK, Johnson LH, Jeffrey Maisels M, et al. Kernicterus: epidemiological strategies for its prevention through systems-based approaches. J Perinatol 2004; 24:650.
  9. Watchko JF, Kaplan M, Stark AR, et al. Should we screen newborns for glucose-6-phosphate dehydrogenase deficiency in the United States? J Perinatol 2013; 33:499.
  10. Nock ML, Johnson EM, Krugman RR, et al. Implementation and analysis of a pilot in-hospital newborn screening program for glucose-6-phosphate dehydrogenase deficiency in the United States. J Perinatol 2011; 31:112.
  11. Johnson LH, Bhutani VK, Brown AK. System-based approach to management of neonatal jaundice and prevention of kernicterus. J Pediatr 2002; 140:396.
  12. Johnson L, Bhutani VK, Karp K, et al. Clinical report from the pilot USA Kernicterus Registry (1992 to 2004). J Perinatol 2009; 29 Suppl 1:S25.
  13. Watchko JF. Vigintiphobia revisited. Pediatrics 2005; 115:1747.
  14. Bhutani VK, Johnson L. Kernicterus in the 21st century: frequently asked questions. J Perinatol 2009; 29 Suppl 1:S20.
  15. Eggert LD, Wiedmeier SE, Wilson J, Christensen RD. The effect of instituting a prehospital-discharge newborn bilirubin screening program in an 18-hospital health system. Pediatrics 2006; 117:e855.
  16. Riskin A, Tamir A, Kugelman A, et al. Is visual assessment of jaundice reliable as a screening tool to detect significant neonatal hyperbilirubinemia? J Pediatr 2008; 152:782.
  17. Keren R, Tremont K, Luan X, Cnaan A. Visual assessment of jaundice in term and late preterm infants. Arch Dis Child Fetal Neonatal Ed 2009; 94:F317.
  18. Bertini G, Rubaltelli FF. Non-invasive bilirubinometry in neonatal jaundice. Semin Neonatol 2002; 7:129.
  19. Bhutani VK, Stark AR, Lazzeroni LC, et al. Predischarge screening for severe neonatal hyperbilirubinemia identifies infants who need phototherapy. J Pediatr 2013; 162:477.
  20. Schumacher RE. Transcutaneous bilirubinometry and diagnostic tests: "the right job for the tool". Pediatrics 2002; 110:407.
  21. Varvarigou A, Fouzas S, Skylogianni E, et al. Transcutaneous bilirubin nomogram for prediction of significant neonatal hyperbilirubinemia. Pediatrics 2009; 124:1052.
  22. Maisels MJ, Clune S, Coleman K, et al. The natural history of jaundice in predominantly breastfed infants. Pediatrics 2014; 134:e340.
  23. Maisels MJ. Screening and early postnatal management strategies to prevent hazardous hyperbilirubinemia in newborns of 35 or more weeks of gestation. Semin Fetal Neonatal Med 2010; 15:129.
  24. Maisels MJ, Kring E. Transcutaneous bilirubin levels in the first 96 hours in a normal newborn population of > or = 35 weeks' gestation. Pediatrics 2006; 117:1169.
  25. Newman TB, Liljestrand P, Escobar GJ. Combining clinical risk factors with serum bilirubin levels to predict hyperbilirubinemia in newborns. Arch Pediatr Adolesc Med 2005; 159:113.
  26. Gonçalves A, Costa S, Lopes A, et al. Prospective validation of a novel strategy for assessing risk of significant hyperbilirubinemia. Pediatrics 2011; 127:e126.
  27. Bromiker R, Bin-Nun A, Schimmel MS, et al. Neonatal hyperbilirubinemia in the low-intermediate-risk category on the bilirubin nomogram. Pediatrics 2012; 130:e470.
  28. Kuzniewicz MW, Escobar GJ, Newman TB. Impact of universal bilirubin screening on severe hyperbilirubinemia and phototherapy use. Pediatrics 2009; 124:1031.
  29. Mah MP, Clark SL, Akhigbe E, et al. Reduction of severe hyperbilirubinemia after institution of predischarge bilirubin screening. Pediatrics 2010; 125:e1143.
  30. Suresh GK, Clark RE. Cost-effectiveness of strategies that are intended to prevent kernicterus in newborn infants. Pediatrics 2004; 114:917.
  31. Darling EK, Ramsay T, Sprague AE, et al. Universal bilirubin screening and health care utilization. Pediatrics 2014; 134:e1017.
  32. Maisels MJ, Kring E. Transcutaneous bilirubinometry decreases the need for serum bilirubin measurements and saves money. Pediatrics 1997; 99:599.
  33. Bhutani VK, Gourley GR, Adler S, et al. Noninvasive measurement of total serum bilirubin in a multiracial predischarge newborn population to assess the risk of severe hyperbilirubinemia. Pediatrics 2000; 106:E17.
  34. US Preventive Services Task Force. Screening of infants for hyperbilirubinemia to prevent chronic bilirubin encephalopathy: US Preventive Services Task Force recommendation statement. Pediatrics 2009; 124:1172.
  35. Trikalinos TA, Chung M, Lau J, Ip S. Systematic review of screening for bilirubin encephalopathy in neonates. Pediatrics 2009; 124:1162.
  36. Maisels MJ, Bhutani VK, Bogen D, et al. Hyperbilirubinemia in the newborn infant > or =35 weeks' gestation: an update with clarifications. Pediatrics 2009; 124:1193.
  37. Newman TB, Xiong B, Gonzales VM, Escobar GJ. Prediction and prevention of extreme neonatal hyperbilirubinemia in a mature health maintenance organization. Arch Pediatr Adolesc Med 2000; 154:1140.
  38. Keren R, Luan X, Friedman S, et al. A comparison of alternative risk-assessment strategies for predicting significant neonatal hyperbilirubinemia in term and near-term infants. Pediatrics 2008; 121:e170.
  39. Maisels MJ, Coffey MP, Gendelman B, et al. Diagnosing Jaundice by Eye-Outpatient Assessment of Conjunctival Icterus in the Newborn. J Pediatr 2016; 172:212.
  40. Maisels MJ. What's in a name? Physiologic and pathologic jaundice: the conundrum of defining normal bilirubin levels in the newborn. Pediatrics 2006; 118:805.
  41. Vreman HJ, Verter J, Oh W, et al. Interlaboratory variability of bilirubin measurements. Clin Chem 1996; 42:869.
  42. Lo SF, Doumas BT, Ashwood ER. Performance of bilirubin determinations in US laboratories--revisited. Clin Chem 2004; 50:190.
  43. Kuzniewicz MW, Greene DN, Walsh EM, et al. Association Between Laboratory Calibration of a Serum Bilirubin Assay, Neonatal Bilirubin Levels, and Phototherapy Use. JAMA Pediatr 2016; 170:557.
  44. Grohmann K, Roser M, Rolinski B, et al. Bilirubin measurement for neonates: comparison of 9 frequently used methods. Pediatrics 2006; 117:1174.
  45. Barko HA, Jackson GL, Engle WD. Evaluation of a point-of-care direct spectrophotometric method for measurement of total serum bilirubin in term and near-term neonates. J Perinatol 2006; 26:100.
  46. De Luca D, Romagnoli C, Tiberi E, et al. Skin bilirubin nomogram for the first 96 h of life in a European normal healthy newborn population, obtained with multiwavelength transcutaneous bilirubinometry. Acta Paediatr 2008; 97:146.
  47. Engle WD, Lai S, Ahmad N, et al. An hour-specific nomogram for transcutaneous bilirubin values in term and late preterm Hispanic neonates. Am J Perinatol 2009; 26:425.
  48. Sanpavat S, Nuchprayoon I, Smathakanee C, Hansuebsai R. Nomogram for prediction of the risk of neonatal hyperbilirubinemia, using transcutaneous bilirubin. J Med Assoc Thai 2005; 88:1187.
  49. Bental YA, Shiff Y, Dorsht N, et al. Bhutani-based nomograms for the prediction of significant hyperbilirubinaemia using transcutaneous measurements of bilirubin. Acta Paediatr 2009; 98:1902.
  50. Fouzas S, Mantagou L, Skylogianni E, et al. Transcutaneous bilirubin levels for the first 120 postnatal hours in healthy neonates. Pediatrics 2010; 125:e52.
  51. Yu ZB, Dong XY, Han SP, et al. Transcutaneous bilirubin nomogram for predicting neonatal hyperbilirubinemia in healthy term and late-preterm Chinese infants. Eur J Pediatr 2011; 170:185.
  52. Akahira-Azuma M, Yonemoto N, Mori R, et al. An hour-specific transcutaneous bilirubin nomogram for Mongolian neonates. Eur J Pediatr 2015; 174:1299.
  53. Han S, Yu Z, Liu L, et al. A Model for Predicting Significant Hyperbilirubinemia in Neonates From China. Pediatrics 2015; 136:e896.
  54. Bromiker R, Goldberg A, Kaplan M. Israel transcutaneous bilirubin nomogram predicts significant hyperbilirubinemia. J Perinatol 2017; 37:1315.
  55. Slusher TM, Angyo IA, Bode-Thomas F, et al. Transcutaneous bilirubin measurements and serum total bilirubin levels in indigenous African infants. Pediatrics 2004; 113:1636.
  56. Fine KL, Carey WA, Schuster JAW, et al. Defining the limitations of transcutaneous bilirubin measurement in late preterm newborns. J Perinatol 2017; 37:658.
  57. De Luca D, Jackson GL, Tridente A, et al. Transcutaneous bilirubin nomograms: a systematic review of population differences and analysis of bilirubin kinetics. Arch Pediatr Adolesc Med 2009; 163:1054.
  58. Ebbesen F, Vandborg PK, Trydal T. Comparison of the transcutaneous bilirubinometers BiliCheck and Minolta JM-103 in preterm neonates. Acta Paediatr 2012; 101:1128.
  59. Taylor JA, Burgos AE, Flaherman V, et al. Discrepancies between transcutaneous and serum bilirubin measurements. Pediatrics 2015; 135:224.
  60. Casnocha Lucanova L, Matasova K, Zibolen M, Krcho P. Accuracy of transcutaneous bilirubin measurement in newborns after phototherapy. J Perinatol 2016; 36:858.
  61. Wainer S, Rabi Y, Parmar SM, et al. Impact of skin tone on the performance of a transcutaneous jaundice meter. Acta Paediatr 2009; 98:1909.
  62. Samiee-Zafarghandy S, Feberova J, Williams K, et al. Influence of skin colour on diagnostic accuracy of the jaundice meter JM 103 in newborns. Arch Dis Child Fetal Neonatal Ed 2014; 99:F480.
  63. Olusanya BO, Imosemi DO, Emokpae AA. Differences Between Transcutaneous and Serum Bilirubin Measurements in Black African Neonates. Pediatrics 2016; 138.
  64. Engle WD, Jackson GL, Sendelbach D, et al. Assessment of a transcutaneous device in the evaluation of neonatal hyperbilirubinemia in a primarily Hispanic population. Pediatrics 2002; 110:61.
  65. Engle WD, Jackson GL, Stehel EK, et al. Evaluation of a transcutaneous jaundice meter following hospital discharge in term and near-term neonates. J Perinatol 2005; 25:486.
  66. Grabenhenrich J, Grabenhenrich L, Bührer C, Berns M. Transcutaneous bilirubin after phototherapy in term and preterm infants. Pediatrics 2014; 134:e1324.
  67. Maisels MJ. Use TcB as a screening tool for jaundiced newborns. AAP News 2004; 25:9.
  68. Taylor JA, Burgos AE, Flaherman V, et al. Utility of Decision Rules for Transcutaneous Bilirubin Measurements. Pediatrics 2016; 137.
  69. Kaplan M, Shchors I, Algur N, et al. Visual screening versus transcutaneous bilirubinometry for predischarge jaundice assessment. Acta Paediatr 2008; 97:759.
  70. Mishra S, Chawla D, Agarwal R, et al. Transcutaneous bilirubinometry reduces the need for blood sampling in neonates with visible jaundice. Acta Paediatr 2009; 98:1916.
  71. Wainer S, Parmar SM, Allegro D, et al. Impact of a transcutaneous bilirubinometry program on resource utilization and severe hyperbilirubinemia. Pediatrics 2012; 129:77.
  72. van den Esker-Jonker B, den Boer L, Pepping RM, Bekhof J. Transcutaneous Bilirubinometry in Jaundiced Neonates: A Randomized Controlled Trial. Pediatrics 2016; 138.
  73. Maisels MJ, Engle WD, Wainer S, et al. Transcutaneous bilirubin levels in an outpatient and office population. J Perinatol 2011; 31:621.
  74. Wickremasinghe AC, Karon BS, Cook WJ. Accuracy of neonatal transcutaneous bilirubin measurement in the outpatient setting. Clin Pediatr (Phila) 2011; 50:1144.
  75. Stevenson DK, Fanaroff AA, Maisels MJ, et al. Prediction of hyperbilirubinemia in near-term and term infants. Pediatrics 2001; 108:31.
  76. Stevenson DK, Vreman HJ. Carbon monoxide and bilirubin production in neonates. Pediatrics 1997; 100:252.
  77. Bartoletti AL, Stevenson DK, Ostrander CR, Johnson JD. Pulmonary excretion of carbon monoxide in the human infant as an index of bilirubin production. I. Effects of gestational and postnatal age and some common neonatal abnormalities. J Pediatr 1979; 94:952.
  78. Vreman HJ, Stevenson DK, Oh W, et al. Semiportable electrochemical instrument for determining carbon monoxide in breath. Clin Chem 1994; 40:1927.
  79. Stevenson DK, Vreman HJ, Oh W, et al. Bilirubin production in healthy term infants as measured by carbon monoxide in breath. Clin Chem 1994; 40:1934.
  80. Bhutani VK, Srinivas S, Castillo Cuadrado ME, et al. Identification of neonatal haemolysis: an approach to predischarge management of neonatal hyperbilirubinemia. Acta Paediatr 2016; 105:e189.
  81. Castillo Cuadrado ME, Bhutani VK, Aby JL, et al. Evaluation of a new end-tidal carbon monoxide monitor from the bench to the bedside. Acta Paediatr 2015; 104:e279.
  82. Christensen RD, Lambert DK, Henry E, et al. End-tidal carbon monoxide as an indicator of the hemolytic rate. Blood Cells Mol Dis 2015; 54:292.
  83. Maisels MJ, Kring E. The contribution of hemolysis to early jaundice in normal newborns. Pediatrics 2006; 118:276.
  84. Amin SB, Wang H, Laroia N, Orlando M. Unbound Bilirubin and Auditory Neuropathy Spectrum Disorder in Late Preterm and Term Infants with Severe Jaundice. J Pediatr 2016; 173:84.
  85. Wennberg RP, Ahlfors CE. A different view on bilirubin binding. Pediatrics 2006; 118:846.
  86. Ahlfors CE. Criteria for exchange transfusion in jaundiced newborns. Pediatrics 1994; 93:488.
  87. Cashore WJ. Free bilirubin concentrations and bilirubin-binding affinity in term and preterm infants. J Pediatr 1980; 96:521.
  88. Iskander I, Gamaleldin R, El Houchi S, et al. Serum bilirubin and bilirubin/albumin ratio as predictors of bilirubin encephalopathy. Pediatrics 2014; 134:e1330.
  89. Kaplan M, Hammerman C, Bhutani VK. Parental education and the WHO neonatal G-6-PD screening program: a quarter century later. J Perinatol 2015; 35:779.