{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T15:21:43Z","timestamp":1788535303764,"version":"build-2803163510"},"reference-count":116,"publisher":"American Academy of Pediatrics (AAP)","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2006,2,1]]},"abstract":"<jats:p>PURPOSE. We sought to evaluate the sensitivity and specificity of total serum bilirubin concentration (TSB) and free (unbound) bilirubin concentration (Bf) as predictors of risk for bilirubin toxicity and kernicterus and to examine consistency between these findings and proposed mechanisms of bilirubin transport and brain uptake.<\/jats:p><jats:p>METHODS. A review of literature was undertaken to define basic principles of bilirubin transport and brain uptake leading to neurotoxicity. We then reviewed experimental and clinical evidence that relate TSB or Bf to risk for bilirubin toxicity and kernicterus.<\/jats:p><jats:p>RESULTS. There are insufficient published data to precisely define sensitivity and specificity of either TSB or Bf in determining risk for acute bilirubin neurotoxicity or chronic sequelae (kernicterus). However, available laboratory and clinical evidence indicate that Bf is better than TSB in discriminating risk for bilirubin toxicity in patients with severe hyperbilirubinemia. These findings are consistent with basic pharmacokinetic principles involved in bilirubin transport and tissue uptake.<\/jats:p><jats:p>CONCLUSIONS. Experimental and clinical data strongly suggest that measurement of Bf in newborns with hyperbilirubinemia will improve risk assessment for neurotoxicity, which emphasizes the need for additional clinical evaluation relating Bf and TSB to acute bilirubin toxicity and long-term outcome. We speculate that establishing risk thresholds for neurotoxicity by using newer methods for measuring Bf in minimally diluted serum samples will improve the sensitivity and specificity of serum indicators for treating hyperbilirubinemia, thus reducing unnecessary aggressive intervention and associated cost and morbidity.<\/jats:p>","DOI":"10.1542\/peds.2005-0395","type":"journal-article","created":{"date-parts":[[2006,2,1]],"date-time":"2006-02-01T19:21:17Z","timestamp":1138821677000},"page":"474-485","source":"Crossref","is-referenced-by-count":196,"title":["Toward Understanding Kernicterus: A Challenge to Improve the Management of Jaundiced Newborns"],"prefix":"10.1542","volume":"117","author":[{"given":"Richard P.","family":"Wennberg","sequence":"first","affiliation":[{"name":"Division of Neonatology, Department of Pediatrics, University of Washington, Seattle, Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles E.","family":"Ahlfors","sequence":"additional","affiliation":[{"name":"LW Ligand, LLC, Vashon, Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinod K.","family":"Bhutani","sequence":"additional","affiliation":[{"name":"Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lois H.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Section on Newborn Pediatrics, Pennsylvania Hospital, University of Pennsylvania Health System, Philadelphia, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven M.","family":"Shapiro","sequence":"additional","affiliation":[{"name":"Department of Neurology, Medical College of Virginia, Richmond, Virginia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"417","published-online":{"date-parts":[[2006,2,1]]},"reference":[{"key":"2021120820072861800_R1","doi-asserted-by":"crossref","unstructured":"Mollison PL, Walker W. Controlled trials of the treatment of hemolytic disease of the newborn. Lancet.\u20081952;1(9):429\u2013433","DOI":"10.1016\/S0140-6736(52)91949-1"},{"key":"2021120820072861800_R2","doi-asserted-by":"crossref","unstructured":"Hsia DY, Allen FH Jr, Gellis SS, Diamond LK. Erythroblastosis fetalis VIII: studies of serum bilirubin in relation to kernicterus. N Engl J Med.\u20081952;247:668\u2013671","DOI":"10.1056\/NEJM195210302471802"},{"key":"2021120820072861800_R3","doi-asserted-by":"crossref","unstructured":"American Academy of Pediatrics, Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation [published correction appears in Pediatrics. 2004;114:1138]. Pediatrics.\u20082004;114:297\u2013316","DOI":"10.1542\/peds.114.1.297"},{"key":"2021120820072861800_R4","doi-asserted-by":"crossref","unstructured":"Johnson LH, Bhutani VK, Brown AK. System-based approach to the management of neonatal jaundice and prevention of kernicterus. J Pediatr.\u20082002;140:396\u2013403","DOI":"10.1067\/mpd.2002.123098"},{"key":"2021120820072861800_R5","unstructured":"Ip S, Glicken S, Kulig J, Obrien R, Sege R, Lau J. Management of Neonatal Hyperbilirubinemia. Rockville, MD: US Department of Health and Human Services, Agency for Healthcare Research and Quality;2003. AHRQ Publication 03-E011"},{"key":"2021120820072861800_R6","doi-asserted-by":"crossref","unstructured":"Bhutani VK, Johnson LH, Maisels MJ, et al. Kernicterus: epidemiological strategies for its prevention through systems-based approaches. J Perinatol.\u20082004;24:650\u2013662","DOI":"10.1038\/sj.jp.7211152"},{"key":"2021120820072861800_R7","doi-asserted-by":"crossref","unstructured":"Ip S, Chung M, Kulig J, et al. An evidence-based review of important issues concerning neonatal hyperbilirubinemia. Pediatrics.\u20082004;114(1). Available at: www.pediatrics.org\/cgi\/content\/full\/114\/1\/e130","DOI":"10.1542\/peds.114.1.e130"},{"key":"2021120820072861800_R8","doi-asserted-by":"crossref","unstructured":"Newman TB, Maisels MJ. Does hyperbilirubinemia damage the brain of full-term infants?Clin Perinatol.\u20081990;17:331\u2013338","DOI":"10.1016\/S0095-5108(18)30571-2"},{"key":"2021120820072861800_R9","doi-asserted-by":"crossref","unstructured":"Newman TB, Klebanoff MA. Neonatal hyperbilirubinemia and long-term outcome: another look at the Collaborative Perinatal Project. Pediatrics.\u20081993;92:651\u2013657","DOI":"10.1542\/peds.92.5.651"},{"key":"2021120820072861800_R10","doi-asserted-by":"crossref","unstructured":"Newman TB, Liljestrand P, Escobar GJ. Infants with bilirubin levels of 30 mg\/dL or more in a large managed care organization. Pediatrics.\u20082003;111:1303\u20131311","DOI":"10.1542\/peds.111.6.1303"},{"key":"2021120820072861800_R11","doi-asserted-by":"crossref","unstructured":"Jacobsen J. Binding of bilirubin to human serum albumin: determination of the dissociation constants. FEBS Lett.\u20081969;5:112\u2013114","DOI":"10.1016\/0014-5793(69)80307-8"},{"key":"2021120820072861800_R12","doi-asserted-by":"crossref","unstructured":"Brodersen R. Bilirubin: solubility and interaction with albumin and phospholipid. J Biol Chem.\u20081979;254:2364\u20132369","DOI":"10.1016\/S0021-9258(17)30230-2"},{"key":"2021120820072861800_R13","doi-asserted-by":"crossref","unstructured":"Hahm JS, Ostrow JD, Mukerjee P, Celic L. Ionization and self-association of unconjugated bilirubin, determined by rapid solvent partition from chloroform, with further studies of bilirubin solubility. J Lipid Res.\u20081992;33:1123\u20131137","DOI":"10.1016\/S0022-2275(20)40764-3"},{"key":"2021120820072861800_R14","doi-asserted-by":"crossref","unstructured":"Silverman WA, Andersen DG, Blanc WA, Crosier DN. A difference in mortality rate and incidence of kernicterus among premature infants allotted to two prophylactic antibacterial regimens. Pediatrics.\u20081956;18:614\u2013624","DOI":"10.1542\/peds.18.4.614"},{"key":"2021120820072861800_R15","doi-asserted-by":"crossref","unstructured":"Ritter DA, Kenny JD, Norton J, Rudolph AJ. A prospective study of free bilirubin and other risk factors in the development of kernicterus in premature infants. Pediatrics.\u20081982;69:260\u2013266","DOI":"10.1542\/peds.69.3.260"},{"key":"2021120820072861800_R16","doi-asserted-by":"crossref","unstructured":"Goessling W, Zucker SD. Role of apolipoprotein D in the transport of bilirubin in plasma. Am J Physiol Gastrointest Liver Physiol.\u20082000;279:G356\u2013G365","DOI":"10.1152\/ajpgi.2000.279.2.G356"},{"key":"2021120820072861800_R17","doi-asserted-by":"crossref","unstructured":"Levine RL, Fredericks WR, Rapoport S. Entry of bilirubin into brain due to opening of the blood-brain barrier. Pediatrics.\u20081982;69:255\u2013259","DOI":"10.1542\/peds.69.3.255"},{"key":"2021120820072861800_R18","doi-asserted-by":"crossref","unstructured":"Wennberg RP, Hance AJ. Experimental bilirubin encephalopathy: importance of total bilirubin, protein binding, and blood-brain barrier. Pediatr Res.\u20081986;20:789\u2013792","DOI":"10.1203\/00006450-198608000-00018"},{"key":"2021120820072861800_R19","doi-asserted-by":"crossref","unstructured":"Ives NK, Bolas NM, Gardiner RM. The effects of bilirubin on brain energy metabolism during hyperosmolar opening of the blood-brain barrier: an in vivo study using 31P nuclear magnetic resonance spectroscopy. Pediatr Res.\u20081989;26:356\u2013361","DOI":"10.1203\/00006450-198910000-00014"},{"key":"2021120820072861800_R20","doi-asserted-by":"crossref","unstructured":"Wennberg RP, Johanssen BB, Folbergrova J, Siesjo BK. Bilirubin-induced changes in brain energy metabolism after osmotic opening of the blood-brain barrier. Pediatr Res.\u20081991;30:473\u2013478","DOI":"10.1203\/00006450-199111000-00015"},{"key":"2021120820072861800_R21","unstructured":"Wennberg, RP. The blood-brain barrier and bilirubin encephalopathy. Cell Mol Neurobiol.\u20082000;20:97\u2013109"},{"key":"2021120820072861800_R22","doi-asserted-by":"crossref","unstructured":"Ives NK, Gardiner RM. Blood-brain permeability to bilirubin in the rat studied using intracarotid bolus injection and in situ brain perfusion techniques. Pediatr Res.\u20081990;27:436\u2013441","DOI":"10.1203\/00006450-199005000-00004"},{"key":"2021120820072861800_R23","doi-asserted-by":"crossref","unstructured":"Robinson PJ, Rapoport SI. Binding effect of albumin on uptake of bilirubin by brain. Pediatrics.\u20081987;79:553\u2013558","DOI":"10.1542\/peds.79.4.553"},{"key":"2021120820072861800_R24","doi-asserted-by":"crossref","unstructured":"Ahlfors CE. Effect of serum dilution on apparent unbound bilirubin concentration as measured by the peroxidase method. Clin Chem.\u20081981;27:692\u2013696","DOI":"10.1093\/clinchem\/27.5.692"},{"key":"2021120820072861800_R25","doi-asserted-by":"crossref","unstructured":"Weisiger RA, Ostrow JD, Koehler RK, Webster CC, Mukerjee P, Pascolo L, Tiribeli C. Affinity of human serum albumin for bilirubin varies with albumin concentrations and buffer composition: results of a novel approach. J Biol Chem.\u20082001;276:29953\u201329960","DOI":"10.1074\/jbc.M104628200"},{"key":"2021120820072861800_R26","doi-asserted-by":"crossref","unstructured":"Ahlfors CE, Parker AE. Evaluation of a model for brain bilirubin uptake in jaundiced newborns. Pediatr Res.\u20082005;56:1175\u20131179","DOI":"10.1203\/01.pdr.0000185248.43044.cd"},{"key":"2021120820072861800_R27","unstructured":"Wennberg RP. Animal models of bilirubin encephalopathy. Adv Vet Sci Comp Med.\u20081993;37:87\u2013113"},{"key":"2021120820072861800_R28","doi-asserted-by":"crossref","unstructured":"Ahlfors CE, Bennett SH, Shoemaker CT, et al. Changes in the auditory brainstem response associated with intravenous infusion of unconjugated bilirubin into infant rhesus monkeys. Pediatr Res.\u20081986;20:511\u2013515","DOI":"10.1203\/00006450-198606000-00005"},{"key":"2021120820072861800_R29","doi-asserted-by":"crossref","unstructured":"Borst P, Evers R, Kool M, Wijnholds J. The multidrug resistance protein family. Biochim Biophys Acta.\u20081999;1461:347\u2013357","DOI":"10.1016\/S0005-2736(99)00167-4"},{"key":"2021120820072861800_R30","unstructured":"Gosland MP, Brophy NA, Duran GE, et al. Bilirubin: a physiological substrate for the multidrug transporter [abstract]. Proc Am Assoc Cancer Res.\u20081991;32:426"},{"key":"2021120820072861800_R31","doi-asserted-by":"crossref","unstructured":"Watchko JF, Daood MJ, Hansen TWR. Brain bilirubin content is increased in P-glycoprotein-deficient transgenic null mutant mice. Pediatr Res.\u20081998;44:763\u2013766","DOI":"10.1203\/00006450-199811000-00020"},{"key":"2021120820072861800_R32","doi-asserted-by":"crossref","unstructured":"Watchko JF, Daood MJ, Mahmood B, Vats K, Hart C, Ahdab-Barmada M. P-glycoprotein and bilirubin disposition. J Perinatol.\u20082001;21(suppl 1):S43\u2013S47; discussion S59\u2013S62","DOI":"10.1038\/sj.jp.7210633"},{"key":"2021120820072861800_R33","doi-asserted-by":"crossref","unstructured":"Hank\u00f8 E, Tommarello S, Watchko JF, Hansen TW. Administration of drugs known to inhibit P-glycoprotein increases brain bilirubin and alters the regional distribution of bilirubin in rat brain. Pediatr Res.\u20082003;54:441\u2013445","DOI":"10.1203\/01.PDR.0000085169.87948.B6"},{"key":"2021120820072861800_R34","doi-asserted-by":"crossref","unstructured":"Ostrow JD, Pascolo L, Brites D, Tiribelli C. Molecular basis of bilirubin-induced neurotoxicity. Trends Mol Med.\u20082004;10:65\u201370","DOI":"10.1016\/j.molmed.2003.12.003"},{"key":"2021120820072861800_R35","doi-asserted-by":"crossref","unstructured":"Rigato I, Pascolo L, Fernetti C, Ostrow JD, Tiribelli C. The human multidrug-resistance-associated protein MRP1 mediates ATP-dependent transport of unconjugated bilirubin. Biochem J.\u20082004;383:335\u2013341","DOI":"10.1042\/BJ20040599"},{"key":"2021120820072861800_R36","doi-asserted-by":"crossref","unstructured":"Gennuso F, Fernetti C, Tirolo C, et al. Bilirubin protects astrocytes from its own toxicity by inducing up-regulation and translocation of multidrug resistance-associated protein 1 (MRP1). Proc Natl Acad Sci USA.\u20082004;101:2470\u20132475","DOI":"10.1073\/pnas.0308452100"},{"key":"2021120820072861800_R37","doi-asserted-by":"crossref","unstructured":"Brodersen R, Bartels P. Enzymatic oxidation of bilirubin. Eur J Biochem.\u20081969;10:468\u2013473","DOI":"10.1111\/j.1432-1033.1969.tb00712.x"},{"key":"2021120820072861800_R38","doi-asserted-by":"crossref","unstructured":"Hansen TWR, Allen JW. Bilirubin-oxidizing activity in rat brain. Biol Neonate.\u20081996;70:289\u2013295","DOI":"10.1159\/000244378"},{"key":"2021120820072861800_R39","doi-asserted-by":"crossref","unstructured":"Ostrow JD, Pascolo L, Shapiro SM, Tiribelli C. New concepts in bilirubin encephalopathy. Eur J Clin Invest.\u20082003;33:988\u2013997","DOI":"10.1046\/j.1365-2362.2003.01261.x"},{"key":"2021120820072861800_R40","doi-asserted-by":"crossref","unstructured":"Harris RC, Lucey JF, MacLean JR. Kernicterus in premature infants associated with low concentrations of bilirubin in plasma. Pediatrics.\u20081958;21:875\u2013883","DOI":"10.1542\/peds.21.6.875"},{"key":"2021120820072861800_R41","doi-asserted-by":"crossref","unstructured":"Shapiro SM. Acute brainstem auditory evoked potential abnormalities in jaundiced Gunn rats given sulfonamide. Pediatr Res.\u20081988;23:306\u2013310","DOI":"10.1203\/00006450-198803000-00015"},{"key":"2021120820072861800_R42","doi-asserted-by":"crossref","unstructured":"Hank\u00f8 E, Hansen TWR, Amaas R, Lindstad J, Rootwelt T. Bilirubin induces apoptosis and necrosis in human NT2-N neurons. Pediatr Res.\u20082005;57:179\u2013184","DOI":"10.1203\/01.PDR.0000148711.11519.A5"},{"key":"2021120820072861800_R43","doi-asserted-by":"crossref","unstructured":"Rodrigues CMP, Sola S, Brites D. Bilirubin induces apoptosis via the mitochondrial pathway in developing rat brain neurons. Hepatology.\u20082002;35:1186\u20131195","DOI":"10.1053\/jhep.2002.32967"},{"key":"2021120820072861800_R44","doi-asserted-by":"crossref","unstructured":"Keshavan P, Schwemberger SJ, Smith DL, Babcock GF, Zucker SD. Unconjugated bilirubin induces apoptosis in colon cancer cells by triggering mitochondrial depolarization. Int J Cancer.\u20082004;112:433\u2013445","DOI":"10.1002\/ijc.20418"},{"key":"2021120820072861800_R45","doi-asserted-by":"crossref","unstructured":"Brodersen R. Binding of bilirubin to albumin; implications for preventing bilirubin encephalopathy in the newborn. CRC Crit Rev Clin Lab Sci.\u20081979;11:305\u2013399","DOI":"10.3109\/10408368009105860"},{"key":"2021120820072861800_R46","doi-asserted-by":"crossref","unstructured":"Vohr BR, Kapr D, O'Dea C, et al. Behavioral changes correlated with brain-stem auditory evoked responses in term infants with moderate hyperbilirubinemia. J Pediatr.\u20081990;117:288\u2013291","DOI":"10.1016\/S0022-3476(05)80549-9"},{"key":"2021120820072861800_R47","doi-asserted-by":"crossref","unstructured":"Wennberg RP, Ahlfors CE, Bickers R, McMurtry CA, Shetter JL. Abnormal auditory brainstem response in a newborn infant with hyperbilirubinemia: improvement with exchange transfusion. J Pediatr.\u20081982;100:624\u2013626","DOI":"10.1016\/S0022-3476(82)80771-3"},{"key":"2021120820072861800_R48","doi-asserted-by":"crossref","unstructured":"Perlman M, Fainmesser P, Sohmer H, Tamari H, Wax Y, Pevsmer B. Auditory nerve-brainstem evoked responses in hyperbilirubinemic neonates. Pediatrics.\u20081983;72:658\u2013664","DOI":"10.1542\/peds.72.5.658"},{"key":"2021120820072861800_R49","doi-asserted-by":"crossref","unstructured":"Nakamura H, Takada S, Shimabuku R, Matsuo M, Matsuo T, Negishi H. Auditory nerve and brainstem responses in newborn infants with hyperbilirubinemia. Pediatrics.\u20081985;75:703\u2013708","DOI":"10.1542\/peds.75.4.703"},{"key":"2021120820072861800_R50","doi-asserted-by":"crossref","unstructured":"Funato M, Tamai H, Shimada S, Nakamura H. Vigintiphobia, unbound bilirubin, and auditory brainstem responses. Pediatrics.\u20081994;93:50\u201353","DOI":"10.1542\/peds.93.1.50"},{"key":"2021120820072861800_R51","doi-asserted-by":"crossref","unstructured":"Lenhardt ML, McArter R, Bryant B. Effects of neonatal hyperbilirubinemia on the brainstem electric response. J Pediatr.\u20081984;104:281\u2013284","DOI":"10.1016\/S0022-3476(84)81013-6"},{"key":"2021120820072861800_R52","doi-asserted-by":"crossref","unstructured":"Streletz LJ, Graziani LJ, Branca, Desai HJ, Travis SF, Mikaelian DO. Brainstem auditory evoked potentials in fullterm and preterm newborn with hyperbilirubinemia and hypoxemia. Neuropediatrics.\u20081986;17:66\u201371","DOI":"10.1055\/s-2008-1052503"},{"key":"2021120820072861800_R53","doi-asserted-by":"crossref","unstructured":"Gupta AK, Mann SB. Is auditory brainstem response a bilirubin toxicity marker?Am J Otolaryngol.\u20081998;19:232\u2013236","DOI":"10.1016\/S0196-0709(98)90123-5"},{"key":"2021120820072861800_R54","doi-asserted-by":"crossref","unstructured":"Shapiro SM. Reversible brainstem auditory evoked potential abnormalities in jaundiced Gunn rats given sulfonamide. Pediatr Res.\u20081993;34:629\u2013633","DOI":"10.1203\/00006450-199311000-00014"},{"key":"2021120820072861800_R55","doi-asserted-by":"crossref","unstructured":"Shapiro SM. Brainstem auditory evoked potentials in an experimental model of bilirubin neurotoxicity. Clin Pediatr (Phila).\u20081994;33:460\u2013467","DOI":"10.1177\/000992289403300803"},{"key":"2021120820072861800_R56","doi-asserted-by":"crossref","unstructured":"Shapiro SM. Somatosensory and brainstem auditory evoked potentials in the Gunn rat model of acute bilirubin neurotoxicity. Pediatr Res.\u20082002;52:844\u2013849","DOI":"10.1203\/00006450-200212000-00006"},{"key":"2021120820072861800_R57","doi-asserted-by":"crossref","unstructured":"Gu\u0308rses D, Ilknur K, Tu\u0308rker S. Effects of hyperbilirubinemia on cerebrocortical electrical activity in newborns. Pediatr Res.\u20082002;52:125\u2013130","DOI":"10.1203\/00006450-200207000-00023"},{"key":"2021120820072861800_R58","doi-asserted-by":"crossref","unstructured":"Amin SB, Ahlfors C, Orlando MS, Dalzell LE, Merle KS, Guillet R. Bilirubin and serial auditory brainstem responses in premature infants. Pediatrics.\u20082001;107:664\u2013670","DOI":"10.1542\/peds.107.4.664"},{"key":"2021120820072861800_R59","doi-asserted-by":"crossref","unstructured":"Shapiro SM. Definition of the clinical spectrum of kernicterus and bilirubin-induced neurologic dysfunction (BIND). J Perinatol.\u20082005;25:54\u201359","DOI":"10.1038\/sj.jp.7211157"},{"key":"2021120820072861800_R60","doi-asserted-by":"crossref","unstructured":"de Vries LS, Lary S, Dubowitz LMS. Relationship of serum bilirubin levels to ototoxicity and deafness in high-risk low-birth-weight infants. Pediatrics.\u20081985;76:351\u2013354","DOI":"10.1542\/peds.76.3.351"},{"key":"2021120820072861800_R61","doi-asserted-by":"crossref","unstructured":"Amin SB. Clinical assessment of bilirubin-induced neurotoxicity in premature infants. Semin Perinatol.\u20082004;28:340\u2013347","DOI":"10.1053\/j.semperi.2004.09.005"},{"key":"2021120820072861800_R62","doi-asserted-by":"crossref","unstructured":"Starr A, Picton TW, Sininger Y, Hood LJ, Berlin CI. Auditory neuropathy. Brain.\u20081996;119:741\u2013753","DOI":"10.1093\/brain\/119.3.741"},{"key":"2021120820072861800_R63","unstructured":"Berlin CI, Hood L, Rose K. On renaming auditory neuropathy as auditory dys-synchrony. Aud Today.\u20082002;13:15\u201317"},{"key":"2021120820072861800_R64","doi-asserted-by":"crossref","unstructured":"Berlin CI, Morlet T, Hood LJ. Auditory neuropathy\/dyssynchrony: its diagnosis and management. Pediatr Clin North Am.\u20082003;50:331\u2013340","DOI":"10.1016\/S0031-3955(03)00031-2"},{"key":"2021120820072861800_R65","doi-asserted-by":"crossref","unstructured":"Rapin I, Gravel J. \u201cAuditory neuropathy\u201d: physiologic and pathologic evidence calls for more diagnostic specificity. Int J Pediatr Otorhinolaryngol.\u20082003;67:707\u2013728","DOI":"10.1016\/S0165-5876(03)00103-4"},{"key":"2021120820072861800_R66","doi-asserted-by":"crossref","unstructured":"Chisin R, Perlman M, Sohmer H. Cochlear and brain stem responses in hearing loss following neonatal hyperbilirubinemia. Ann Otol Rhinol Laryngol.\u20081979;88:352\u2013257","DOI":"10.1177\/000348947908800310"},{"key":"2021120820072861800_R67","doi-asserted-by":"crossref","unstructured":"Berlin CI, Hood L, Morlet T, Rose K, Brashears S. Auditory neuropathy\/dys-synchrony: diagnosis and management. Ment Retard Dev Disabil Res Rev.\u20082003;9:225\u2013231","DOI":"10.1002\/mrdd.10084"},{"key":"2021120820072861800_R68","doi-asserted-by":"crossref","unstructured":"Rance G, Beer DE, Cone-Wesson B, et al. Clinical findings for group of infants and young children with auditory neuropathy. Ear Hear.\u20081999;20:238\u2013252","DOI":"10.1097\/00003446-199906000-00006"},{"key":"2021120820072861800_R69","unstructured":"Sininger Y. Overview of auditory neuropathy. Audiology Online. July 8,2004"},{"key":"2021120820072861800_R70","doi-asserted-by":"crossref","unstructured":"Simmons JL, Beauchaine KL. Auditory neuropathy: case study with hyperbilirubinemia. J Am Acad Audiol.\u20082000;11:337\u2013347","DOI":"10.1055\/s-0042-1748063"},{"key":"2021120820072861800_R71","doi-asserted-by":"crossref","unstructured":"Taipia MC, Alemenar Latorre A, Lirola M, Moro Serrano M. Auditory neuropathy [in Spanish]. An Esp Pediatr.\u20082000;53:399\u2013404","DOI":"10.1016\/S1695-4033(00)78619-X"},{"key":"2021120820072861800_R72","doi-asserted-by":"crossref","unstructured":"Yilmaz Y, Degirmenci S, Akdas F, et al. Prognostic value of auditory brainstem response for neurologic outcome in patients with neonatal indirect hyperbilirubinemia. J Child Neurol.\u20082001;16:772\u2013775","DOI":"10.1177\/088307380101601014"},{"key":"2021120820072861800_R73","doi-asserted-by":"crossref","unstructured":"Madden C, Hilbert L, Rutter M, Greinwald J, Choo D. Pediatric cochlear implantation in auditory neuropathy. Otol Neurotol.\u20082002;23:163\u2013168","DOI":"10.1097\/00129492-200203000-00011"},{"key":"2021120820072861800_R74","doi-asserted-by":"crossref","unstructured":"Newman TB, Maisels MJ. Evaluation and treatment of jaundice in the term newborn: a kinder, gentler approach. Pediatrics.\u20081982;89:809\u2013818","DOI":"10.1542\/peds.89.5.809"},{"key":"2021120820072861800_R75","doi-asserted-by":"crossref","unstructured":"American Academy of Pediatrics, Provisional Committee for Quality Improvement and Subcommittee on Hyperbilirubinemia. Practice parameter: management of hyperbilirubinemia in the healthy term infant [published correction appears in Pediatrics. 1995;95:458\u2013461]. Pediatrics.\u20081994;94:558\u2013561","DOI":"10.1542\/peds.94.4.558"},{"key":"2021120820072861800_R76","doi-asserted-by":"crossref","unstructured":"Grimmer I, Berger-Jones K, Bu\u0308hrer C, Brandl U, Obladen M. Later neurological sequelae of non-hemolytic hyperbilirubinemia of healthy term neonates. Acta Paediatr.\u20081999;88:661\u2013663","DOI":"10.1111\/j.1651-2227.1999.tb00018.x"},{"key":"2021120820072861800_R77","doi-asserted-by":"crossref","unstructured":"Soorani-Lunsing I, Woltil HA, Hadders-Algra M. Are moderate degrees of hyperbilirubinemia in healthy term neonates really safe for the brain?Pediatr Res.\u20082001;50:701\u2013705","DOI":"10.1203\/00006450-200112000-00012"},{"key":"2021120820072861800_R78","doi-asserted-by":"crossref","unstructured":"Ahlfors CE, Herbsman O. Unbound bilirubin in a term newborn with kernicterus. Pediatrics.\u20082003;111:1110\u20131112","DOI":"10.1542\/peds.111.5.1110"},{"key":"2021120820072861800_R79","doi-asserted-by":"crossref","unstructured":"Harris MC, Bernbaum JC, Polin JR, Zimmerman R, Polin RA. Developmental follow-up of breastfed term and near-term infants with marked hyperbilirubinemia. Pediatrics.\u20082001;107:1075\u20131080","DOI":"10.1542\/peds.107.5.1075"},{"key":"2021120820072861800_R80","unstructured":"Johnson L, Brown AK. A pilot registry for acute and chronic kernicterus in term and near-term infants [abstract]. Pediatrics.\u20081999;104(suppl):736"},{"key":"2021120820072861800_R81","doi-asserted-by":"crossref","unstructured":"Odell GB. Studies in kernicterus: I. The protein binding of bilirubin. J Clin Invest.\u20081959;38:823\u2013833","DOI":"10.1172\/JCI103864"},{"key":"2021120820072861800_R82","doi-asserted-by":"crossref","unstructured":"Odell GB, Cohen SN, Kelly PC. Studies in kernicterus: II. The determination of the saturation of serum albumin with bilirubin. J Pediatr.\u20081969;74:214\u2013230","DOI":"10.1016\/S0022-3476(69)80069-7"},{"key":"2021120820072861800_R83","doi-asserted-by":"crossref","unstructured":"Porter EG, Waters WJ. A rapid micromethod for measuring the reserve albumin binding capacity in serum from newborn infants with hyperbilirubinemia. J Lab Clin Med.\u20081966;67:660\u2013668","DOI":"10.1016\/S0022-3476(65)81954-0"},{"key":"2021120820072861800_R84","unstructured":"Kaufmann NA, Simeha AJ, Blondheim SH. The uptake of bilirubin by blood cells from plasma and its relationship to the criteria for exchange transfusion. Clin Sci.\u20081967;33:201\u2013208"},{"key":"2021120820072861800_R85","doi-asserted-by":"crossref","unstructured":"Bratlid D. Bilirubin binding by human erythrocytes. Scand J Clin Lab Invest.\u20081972;29:91\u201397","DOI":"10.3109\/00365517209081060"},{"key":"2021120820072861800_R86","doi-asserted-by":"crossref","unstructured":"Jirsova V, Jirsa M, Heringova A, Kodovsky O, Weirichova J. The use and possible diagnostic significance of Sephadex gel filtration of serum from icteric newborn. Biol Neonat.\u20081967;11:204\u2013208","DOI":"10.1159\/000240067"},{"key":"2021120820072861800_R87","doi-asserted-by":"crossref","unstructured":"Kaufmann NA, Kapitulnik J, Blondheim SH. Bilirubin binding affinity of serum: comparison of qualitative and quantitative Sephadex gel filtration methods. Clin Chem.\u20081973;19:1276\u20131279","DOI":"10.1093\/clinchem\/19.11.1276"},{"key":"2021120820072861800_R88","doi-asserted-by":"crossref","unstructured":"Robertson AF, Karp WB, Brodersen R. Comparison of bilirubin concentration and bilirubin\/albumin ratio with the bilirubin-binding ability in neonatal serum. J Pediatr.\u20081998;132:343\u2013344","DOI":"10.1016\/S0022-3476(98)70457-3"},{"key":"2021120820072861800_R89","doi-asserted-by":"crossref","unstructured":"Lamola AA, Eisinger J, Blumberg WE, Patel SC, Flores J. Fluorometric study of the partition of bilirubin among blood components: basis for rapid microassays of bilirubin and bilirubin binding capacity in whole blood. Anal Biochem.\u20081979;100:25\u201342","DOI":"10.1016\/0003-2697(79)90105-2"},{"key":"2021120820072861800_R90","doi-asserted-by":"crossref","unstructured":"Jacobsen J, Wennberg RP. Determination of unbound bilirubin in the serum of newborns. Clin Chem.\u20081974;33:783\u2013789","DOI":"10.1093\/clinchem\/20.7.783"},{"key":"2021120820072861800_R91","doi-asserted-by":"crossref","unstructured":"Cashore WJ, Monin JP, Oh W. Serum bilirubin binding capacity and free bilirubin concentration: A comparison between Sephadex G-25 filtration and peroxidase oxidation techniques. Pediatr Res.\u20081978;12:195\u2013198","DOI":"10.1203\/00006450-197803000-00006"},{"key":"2021120820072861800_R92","doi-asserted-by":"crossref","unstructured":"Kapitulnik J, Valaes T, Kaufmann NA, Blondheim SH. Clinical evaluation of Sephadex gel filtration in estimation of bilirubin binding in serum in neonatal jaundice. Arch Dis Child.\u20081974;49:886\u2013894","DOI":"10.1136\/adc.49.11.886"},{"key":"2021120820072861800_R93","doi-asserted-by":"crossref","unstructured":"Zamet P, Nakamura H, Perez-Robles S, Larroche JC, Minkowski A. The use of critical levels of birth weight and \u201cfree bilirubin\u201d as an approach for prevention of kernicterus. Biol Neonate.\u20081975;26:274\u2013282","DOI":"10.1159\/000240739"},{"key":"2021120820072861800_R94","unstructured":"Valaes T, Kapitulnik J, Kaufmann NA, Blondheim SH. Experience with Sephadex gel filtration in assessing the risk of bilirubin encephalopathy in neonatal jaundice. Birth Defects Orig Artic Ser.\u20081976;12(2):215\u2013228"},{"key":"2021120820072861800_R95","doi-asserted-by":"crossref","unstructured":"Odell GB, Storey GNB, Rosenberg LA. Studies in kernicterus: 3. The saturation of serum proteins with bilirubin during neonatal life and its relationship to brain damage at five years. J Pediatr.\u20081970;76:12\u201321","DOI":"10.1016\/S0022-3476(70)80124-X"},{"key":"2021120820072861800_R96","unstructured":"Johnson L, Boggs TR. Bilirubin-dependent brain damage: incidence and indication for treatment. In: Odell GB, Schaffer R, Simopoulous AP, eds. Phototherapy in the Newborn: An Overview. Washington, DC: National Academy of Sciences;1974:122\u2013149"},{"key":"2021120820072861800_R97","doi-asserted-by":"crossref","unstructured":"Nelson T, Jacobsen J, Wennberg RP. Effect of pH on the interaction of bilirubin with albumin and tissue culture cells. Pediatr Res.\u20081974;8:963\u2013967","DOI":"10.1203\/00006450-197412000-00010"},{"key":"2021120820072861800_R98","doi-asserted-by":"crossref","unstructured":"Mediavilla MG, Pascolo L, Rodriguez JV, Guibert EE, Ostrow JD, Tiribelli C. Uptake of [(3)H]bilirubin in freshly isolated rat hepatocytes: role of free bilirubin concentration. FEBS Lett.\u20081999;463:143\u2013145","DOI":"10.1016\/S0014-5793(99)01606-3"},{"key":"2021120820072861800_R99","doi-asserted-by":"crossref","unstructured":"Ostrow JD, Pascolo L, Tiribelli C. Reassessment of the unbound concentrations of unconjugated bilirubin in relation to neurotoxicity in vitro. Pediatr Res.\u20082003;54:98\u2013104","DOI":"10.1203\/01.PDR.0000067486.79854.D5"},{"key":"2021120820072861800_R100","doi-asserted-by":"crossref","unstructured":"Ahlfors CE, Shapiro SM. Auditory brainstem response and unbound bilirubin in jaundiced (jj) Gun rat pups. Biol Neonate.\u20082001;80:158\u2013162","DOI":"10.1159\/000047136"},{"key":"2021120820072861800_R101","doi-asserted-by":"crossref","unstructured":"Ahlfors CE. Unbound bilirubin associated with kernicterus: a historical approach. J Pediatr.\u20082000;137:540\u2013544","DOI":"10.1067\/mpd.2000.108566"},{"key":"2021120820072861800_R102","unstructured":"Murki S, Kumar P, Majumdar S, Marwaha N, Narang A. Risk factors for kernicterus in term babies with non-hemolytic jaundice. Indian Pediatr.\u20082001;38:757\u2013762"},{"key":"2021120820072861800_R103","doi-asserted-by":"crossref","unstructured":"Cashore WJ, Oh W. Unbound bilirubin and kernicterus in low-birth-weight infants. Pediatrics.\u20081982;69:481\u2013485","DOI":"10.1542\/peds.69.4.481"},{"key":"2021120820072861800_R104","doi-asserted-by":"crossref","unstructured":"Nakamura H, Yonetani M, Uetani Y, Funato M, Lee Y. Determination of serum unbound bilirubin for prediction of kernicterus in low birthweight infants. Acta Paediatr Jpn.\u20081992;34:642\u2013647","DOI":"10.1111\/j.1442-200X.1992.tb01024.x"},{"key":"2021120820072861800_R105","doi-asserted-by":"crossref","unstructured":"Ahlfors CE. Measurement of plasma unbound unconjugated bilirubin. Anal Biochem.\u20082000;279:130\u2013135","DOI":"10.1006\/abio.2000.4485"},{"key":"2021120820072861800_R106","doi-asserted-by":"crossref","unstructured":"Cashore WJ. Free bilirubin concentration and bilirubin-binding affinity in term and preterm infants. J Pediatr.\u20081980;96:521\u2013527","DOI":"10.1016\/S0022-3476(80)80860-2"},{"key":"2021120820072861800_R107","unstructured":"Brown AK, Johnson L. Loss of concern about jaundice and the re-emergence of kernicterus in full-term infants in the era of managed care. In: Fanaroff AA, Klaus MH, eds. The Yearbook of Neonatal and Perinatal Medicine. St Louis, MO: Mosby;1996:17\u201328"},{"key":"2021120820072861800_R108","doi-asserted-by":"crossref","unstructured":"Newman TB, Escobar GJ, Gonzales VM, Armstrong MA, Gardner MN, Folck BF. Frequency of neonatal bilirubin testing and hyperbilirubinemia in a large health maintenance organization. Pediatrics.\u20081999;104:1198\u20131203","DOI":"10.1542\/peds.104.S6.1198"},{"key":"2021120820072861800_R109","doi-asserted-by":"crossref","unstructured":"Ahlfors CE, Wennberg RP. Bilirubin-albumin binding and neonatal jaundice. Semin Perinatol.\u20082004;28:334\u2013339","DOI":"10.1053\/j.semperi.2004.09.002"},{"key":"2021120820072861800_R110","doi-asserted-by":"crossref","unstructured":"Jackson JC. Adverse events associated with exchange transfusion in healthy and ill newborns. Pediatrics.\u20081997;99(5). Available at: www.pediatrics.org\/cgi\/content\/full\/99\/5\/e7","DOI":"10.1542\/peds.99.5.e7"},{"key":"2021120820072861800_R111","doi-asserted-by":"crossref","unstructured":"Patra K, Storfer-Isser A, Siner B, Moore J, Hack M. Adverse events associated with neonatal exchange transfusion in the 1990s. J Pediatr.\u20082004;144:626\u2013631","DOI":"10.1016\/j.jpeds.2004.01.054"},{"key":"2021120820072861800_R112","unstructured":"Chima RS, Johnson LH, Bhutani BK. Evaluation of adverse events due to exchange transfusion in term and near-term newborns [abstract]. Pediatr Res.\u20082001;49:324"},{"key":"2021120820072861800_R113","doi-asserted-by":"crossref","unstructured":"Blackmon LR, Fanaroff AA, Raju TNK. Research on prevention of bilirubin-induced brain injury and kernicterus: National Institute of Child Health and Human Development Conference Executive Summary. Pediatrics.\u20082004;114:229\u2013233","DOI":"10.1542\/peds.114.1.229"},{"key":"2021120820072861800_R114","unstructured":"Newman T, Liljestrand P, Ferriero D, Hudes E, Jeremy R, Escobar G. 5-year neurodevelopmental outcome of newborns with total serum bilirubin levels \u226525 mg\/dL [abstract]. Pediatr Res.\u20082004;55:461A"},{"key":"2021120820072861800_R115","doi-asserted-by":"crossref","unstructured":"Govaert P, Lequin M, Swarte R, et al. Changes in globus pallidus with (pre)term kernicterus. Pediatrics.\u20082003;112:1256\u20131263","DOI":"10.1542\/peds.112.6.1256"},{"key":"2021120820072861800_R116","doi-asserted-by":"crossref","unstructured":"Oh W, Tyson JE, Fanaroff AA, et al. Association between peak serum bilirubin and neurodevelopmental outcomes in extremely low birth weight infants. Pediatrics.\u20082003;112:773\u2013779","DOI":"10.1542\/peds.112.4.773"}],"container-title":["Pediatrics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/publications.aap.org\/pediatrics\/article-pdf\/117\/2\/474\/1012498\/zpe00206000474.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/publications.aap.org\/pediatrics\/article-pdf\/117\/2\/474\/1012498\/zpe00206000474.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,6]],"date-time":"2023-05-06T10:44:15Z","timestamp":1683369855000},"score":1,"resource":{"primary":{"URL":"https:\/\/publications.aap.org\/pediatrics\/article\/117\/2\/474\/68489\/Toward-Understanding-Kernicterus-A-Challenge-to"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2006,2,1]]},"references-count":116,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2006,2,1]]},"published-print":{"date-parts":[[2006,2,1]]}},"URL":"https:\/\/doi.org\/10.1542\/peds.2005-0395","relation":{},"ISSN":["0031-4005","1098-4275"],"issn-type":[{"value":"0031-4005","type":"print"},{"value":"1098-4275","type":"electronic"}],"subject":[],"published":{"date-parts":[[2006,2,1]]}}}