Care of the jaundiced neonate

Care of the Jaundiced Neonate Notice Medicine is an ever-changing science As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy are required The authors and the publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is complete and generally in accord with the standards accepted at the time of publication However, in view of the possibility of human error or changes in medical sciences, neither the authors nor the publisher nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete, and they disclaim all responsibility for any errors or omissions or for the results obtained from use of the information contained in this work Readers are encouraged to confirm the information contained herein with other sources For example and in particular, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the information contained in this work is accurate and that changes have not been made in the recommended dose or in the contraindications for administration This recommendation is of particular importance in connection with new or infrequently used drugs Care of the Jaundiced Neonate David K Stevenson, MD Harold K Faber Professor of Pediatrics Department of Pediatrics Division of Neonatal and Developmental Medicine Stanford University School of Medicine Stanford, California M Jeffrey Maisels, MB BCh, DSc Physician in Chief, Beaumont Children’s Hospital Professor and Chair Department of Pediatrics Oakland University William Beaumont School of Medicine Royal Oak, Michigan Jon F Watchko, MD Professor of Pediatrics University of Pittsburgh School of Medicine Division of Newborn Medicine Magee-Womens Research Institute Pittsburgh, Pennsylvania New York Chicago San Francisco 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THE ACCURACY, ADEQUACY OR COMPLETENESS OF OR RESULTS TO BE OBTAINED FROM USING THE WORK, INCLUDING ANY INFORMATION THAT CAN BE ACCESSED THROUGH THE WORK VIA HYPERLINK OR OTHERWISE, AND EXPRESSLY DISCLAIM ANY WARRANTY, EXPRESS OR IMPLIED, INCLUDING BUT NOT LIMITED TO IMPLIED WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE McGraw-Hill and its licensors not warrant or guarantee that the functions contained in the work will meet your requirements or that its operation will be uninterrupted or error free Neither McGraw-Hill nor its licensors shall be liable to you or anyone else for any inaccuracy, error or omission, regardless of cause, in the work or for any damages resulting therefrom McGraw-Hill has no responsibility for the content of any information accessed through the work Under no circumstances shall McGraw-Hill and/or its licensors be liable for any indirect, incidental, special, punitive, consequential or similar damages that result from the use of or inability to use the work, even if any of them has been advised of the possibility of such damages This limitation of liability shall apply to any claim or cause whatsoever whether such claim or cause arises in contract, tort or otherwise Contributors Cristina Bellarosa, PhD Senior Researcher Italian Liver Foundation Trieste, Italy Glenn R Gourley, MD, AGAF Professor of Pediatrics University of Minnesota Minneapolis, Minnesota Vinod K Bhutani, MD, FAAP Professor Department of Pediatrics Stanford University School of Medicine Stanford, California Cathy Hammerman, MD Department of Neonatology Shaare Zedek Medical Center Professor of Pediatrics Faculty of Medicine of The Hebrew University Jerusalem, Israel Dag Bratlid, MD, PhD, MHA Professor of Pediatrics Department of Laboratory Medicine, Children’s and Women’s Health Faculty of Medicine, Norwegian University of Science and Technology Trondheim, Norway Dora Brites, PhD Senior Researcher and Full Professor Neuron Glia Biology in Health and Disease Faculty of Pharmacy, University of Lisbon Lisbon, Portugal Maria Alexandra Brito, PharmD, PhD Professor Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL) Faculty of Pharmacy, University of Lisbon Lisbon, Portugal Jane E Brumbaugh, MD Fellow, Neonatal-Perinatal Medicine Department of Pediatrics University of Minnesota Minneapolis, Minnesota Thor Willy Ruud Hansen, MD, PhD, MHA, FAAP Professor of Pediatrics Women & Children’s Division Oslo University Hospital, Rikshospitalet Oslo, Norway Michael Kaplan, MB, ChB Department of Neonatology Shaare Zedek Medical Center Professor of Pediatrics Faculty of Medicine of The Hebrew University Jerusalem, Israel Zhili Lin, MD, PhD Director Research and Development PerkinElmer Genetics, Inc Bridgeville, Pennsylvania M Jeffrey Maisels, MB BCh, DSc Physician in Chief, Beaumont Children’s Hospital Professor and Chair Department of Pediatrics Oakland University William Beaumont School of Medicine Royal Oak, Michigan ix To our families and to all others and their babies, most of whom become jaundiced for a while after birth This page intentionally left blank Contents Contributors ix Preface xi Acknowledgments xiii Chapter Genetics of Neonatal Jaundice Jon F Watchko and Zhili Lin Chapter Bilirubin Production and Its Measurement 29 David K Stevenson, Hendrik J Vreman, and Ronald J Wong Chapter Bilirubin and Its Various Fractions 41 Jane E Brumbaugh and Glenn R Gourley Chapter Bilirubin Metabolism and Transport 55 Cristina Bellarosa, Lucie Muchova, Libor Vitek, and Claudio Tiribelli Chapter Physiology of Neonatal Unconjugated Hyperbilirubinemia 65 Thor Willy Ruud Hansen and Dag Bratlid Chapter The Epidemiology of Neonatal Hyperbilirubinemia 97 M Jeffrey Maisels and Thomas B Newman Chapter Hemolytic Disorders and Their Management .145 Michael Kaplan and Cathy Hammerman Chapter Prevention, Screening, and Postnatal Management of Neonatal Hyperbilirubinemia 175 M Jeffrey Maisels and Thomas B Newman Chapter 10 Phototherapy and Other Treatments .195 M Jeffrey Maisels, David K Stevenson, Jon F Watchko, and Antony F McDonagh Chapter 11 Kernicterus 229 Steven M Shapiro Chapter 12 Public Policy to Prevent Severe Neonatal Hyperbilirubinemia 243 Vinod K Bhutani Chapter 13 Neonatal Jaundice in Low- and Middle-Income Countries .263 Tina M Slusher and Bolajoko O Olusanya Index 275 Chapter Bilirubin Toxicity 115 Dora Brites and Maria Alexandra Brito vii This page intentionally left blank NEONATAL JAUNDICE IN LOW- AND MIDDLE-INCOME COUNTRIES Ogunlesi T, Dedeke I, Adekanmbi A, Fetuga M, Ogunfowora O The incidence and outcome of bilirubin encephalopathy in Nigeria Niger J Med 2007;4: 354–359 10 Owa JA, Ogunlesi TA Why we are still doing so many exchange blood transfusion for neonatal jaundice in Nigeria World J Pediatr 2009;5:51–55 11 Eneh AU, Oruamabo RS Neonatal jaundice in a special care baby unit (SCBU) in Port Harcourt, Nigeria: a prospective study Port Harcourt Med J 2008;2:110–117 12 Slusher TM, Vreman HJ, McLaren DW, Lewison LJ, Brown AK, Stevenson DK Glucose-6-phosphate dehydrogenase deficiency and carboxyhemoglobin concentrations associated with bilirubin-related morbidity and death in Nigerian infants J Pediatr 1995;126:102–108 13 Owa JA, Osinaike AI Neonatal morbidity and mortality in Nigeria Indian J Pediatr 1998;65:441–449 14 Tikmani S, Warraich H, Abbasi F, Rizvi A, Darmstadt G, Zaidi A Incidence of neonatal hyperbilirubinemia: a population based prospective study in Pakistan Trop Med Int Health 2010;5:502–507 15 Sanpavat S Exchange transfusion and its morbidity in ten-year period at King Chulalongkorn Hospital J Med Assoc Thai 2005;88:588–592 16 Tiker F, Gulcan H, Kilicdag H, Tarcan A, Gurakan B Extreme hyperbilirubinemia in newborn infants Clin Pediatr (Phila) 2006;45:257–261 17 Ebbesen F, Andersson C, Verder H, et al Extreme hyperbilirubinaemia in term and near-term infants in Denmark Acta Paediatr 2005;1:59–64 18 Johnson L, Bhutani VK, Karp K, Sivieri EM, Shapiro SM Clinical report from the pilot USA Kernicterus Registry (1992 to 2004) J Perinatol 2009;29(suppl 1): S25–S45 19 Olusanya B, Akande A, Emokpae A, Olowe S Infants with severe neonatal jaundice in Lagos, Nigeria: incidence, correlates and hearing screening outcomes Trop Med Int Health 2009;3:301–310 20 Okechukwu A, Achonwa A Morbidity and mortality patterns of admissions into the special care baby unit of University of Abuja Teaching Hospital Niger J Clin Pract 2009;4:389–394 21 Ugwu R, Eneh A, Oruamabo R Mortality in the special care baby unit of the University of Port Harcourt Teaching Hospital (UPTH) Why and when newborns die? Niger J Paediatr 2006;3:133–134 22 Simiyu DE Morbidity and mortality of neonates admitted in general paediatric wards at Kenyatta National Hospital East Afr Med J 2003;80:611–616 23 Rahim F Pattern and outcome of admissions to neonatal unit of Khyber Teaching Hospital, Peshawar Pak J Med Sci 2007;23:249–253 271 24 Islam M Morbidity pattern and mortality of neonates admitted in a tertiary level teaching hospital in Bangladesh Mymensingh Med J 2010;19:159–162 25 da Silva LP, Queiros F, Lima I Etiology of hearing impairment in children and adolescents of a reference center APADA in the city of Salvador, state of Bahia Braz J Otorhinolaryngol 2006;72:33–36 26 Gordon AL, English M, Tumaini Dzombo J, Karisa M, Newton CR Neurological and developmental outcome of neonatal jaundice and sepsis in rural Kenya Trop Med Int Health 2005;10:1114–1120 27 Mukhopadhyay K, Chowdhary G, Singh P, Kumar P, Narang A Neurodevelopmental outcome of acute bilirubin encephalopathy J Trop Pediatr 2010;56:333–336 28 Banerjee TK, Hazra A, Biswas A, et al Neurological disorders in children and adolescents Indian J Pediatr 2009;76:139–146 29 Boo NY, Oakes M, Lye MS, Said H Risk factors associated with hearing loss in term neonates with hyperbilirubinaemia J Trop Pediatr 1994;40:194–197 30 Somefun OA, Lesi FE, Danfulani MA, Olusanya BO Communication disorders in Nigerian children Int J Pediatr Otorhinolaryngol 2006;70:697–702 31 Olusanya BO, Somefun AO Sensorineural hearing loss in infants with neonatal jaundice in Lagos: a communitybased study Ann Trop Paediatr 2009;29:119–128 32 Olusanya BO, Okolo AA Adverse perinatal conditions in hearing-impaired children in a developing country Paediatr Perinat Epidemiol 2006;20:366–371 33 Ozturk A, Demirci F, Yavuz T, et al Antenatal and delivery risk factors and prevalence of cerebral palsy in Duzce (Turkey) Brain Dev 2007;29:39–42 34 Wolf MJ, Wolf B, Beunen G, Casaer P Neurodevelop mental outcome at year in Zimbabwean neonates with extreme hyperbilirubinaemia Eur J Pediatr 1999; 158:111–114 35 Green SE “What you mean what’s wrong with her?”: stigma and the lives of families of children with disabilities Soc Sci Med 2003;57:1361–1374 36 Hibbard RA, Desch LW; American Academy of Pediatrics Committee on Child Abuse and Neglect, American Academy of Pediatrics Council on Children with Disabilities Maltreatment of children with disabilities Pediatrics 2007;119:1018–1025 37 Knutson JF, Johnson CR, Sullivan PM Disciplinary choices of mothers of deaf children and mothers of normally hearing children Child Abuse Negl 2004;28: 925–937 38 Kvam MH Sexual abuse of deaf children A retrospective analysis of the prevalence and characteristics of childhood sexual abuse among deaf adults in Norway Child Abuse Negl 2004;28:241–251 272 Chapter 13 39 Sullivan PM, Knutson JF Maltreatment and disabilities: a population-based epidemiological study Child Abuse Negl 2000;24:1257–1273 40 Togonu-Bickersteth F, Odebiyi AI Influence of Yoruba beliefs about abnormality on the socialization of deaf children: a research note J Child Psychol Psychiatry 1985;26:639–652 41 Dubowitz H, Bennett S Physical abuse and neglect of children Lancet 2007;369:1891–1899 42 Dube SR, Felitti VJ, Dong M, Giles WH, Anda RF The impact of adverse childhood experiences on health problems: evidence from four birth cohorts dating back to 1900 Prev Med 2003;37:268–277 43 Hildyard KL, Wolfe DA Child neglect: developmental issues and outcomes Child Abuse Negl 2002;26:679–695 44 Glaser D Child abuse and neglect and the brain—a review J Child Psychol Psychiatry 2000;41:97–116 45 Olusanya BO, Ruben RJ, Parving A Reducing the burden of communication disorders in the developing world: an opportunity for the millennium development project JAMA 2006;296:441–444 46 UNICEF State of the World’s Children 2006 New York: UNICEF, UNICEF House; 2005 47 Jamison DT World Bank Disease Control Priorities in Developing Countries New York: Oxford University Press; 1993 48 Lawn JE, Osrin D, Adler A, Cousens S Four million neonatal deaths: counting and attribution of cause of death Paediatr Perinat Epidemiol 2008;22:410–416 49 Bjerre JV, Petersen JR, Ebbesen F Surveillance of extreme hyperbilirubinaemia in Denmark A method to identify the newborn infants Acta Paediatr 2008;97:1030–1034 50 Manning D, Todd P, Maxwell M, Jane Platt M Prospective surveillance study of severe hyperbilirubinaemia in the newborn in the UK and Ireland Arch Dis Child Fetal Neonatal Ed 2007;92:F342–F346 51 Sgro M, Campbell D, Shah V Incidence and causes of severe neonatal hyperbilirubinemia in Canada CMAJ 2006;175:587–590 52 Lawn RE, Rudan I, Rubens C Four million newborn deaths: is the global research agenda evidence-based? Early Hum Dev 2008;84:809–814 53 Bryce J, Boschi-Pinto C, Shibuya K, Black RE WHO estimates of the causes of death in children Lancet 2005;365:1147–1152 54 Anker M, Black RE, Coldham C, et al A Standard Verbal Autopsy Method for Investigating Causes of Death in Infants and Children Geneva: World Health Organization; 1999 55 Ogunfowora OB, Daniel OJ Neonatal jaundice and its management: knowledge, attitude and practice of community health workers in Nigeria BMC Public Health 2006;6:19 56 Manzar S Cephalo-caudal progression of jaundice: a reliable, non-invasive clinical method to assess the degree of neonatal hyperbilirubinaemia J Trop Pediatr 1999;45:312–313 57 Hatzenbuehler L, Zaidi AK, Sundar S, et al Validity of neonatal jaundice evaluation by primary health-care workers and physicians in Karachi, Pakistan J Perinatol 2010;30:616–621 58 Darmstadt GL, Baqui AH, Choi Y, et al Validation of community health workers’ assessment of neonatal illness in rural Bangladesh Bull World Health Organ 2009;87:12–19 59 Kaplan M, Hammerman C Understanding and preventing severe neonatal hyperbilirubinemia: is bilirubin neurotoxicity really a concern in the developed world? Clin Perinatol 2004;31:555–575, x 60 Sodeinde O, Chan MC, Maxwell SM, Familusi JB, Hendrickse RG Neonatal jaundice, aflatoxins and naphthols: report of a study in Ibadan, Nigeria Ann Trop Paediatr 1995;15:107–113 61 Valaes T Severe neonatal jaundice associated with glucose-6-phosphate dehydrogenase deficiency: pathogenesis and global epidemiology Acta Paediatr Suppl 1994;394:58–76 62 Zipursky A, Paul VK The global burden of Rh disease Arch Dis Child Fetal Neonatal Ed 2011;96:F84–F85 63 Volpe J Bilirubin and brain injury In: Neurology of the Newborn 5th ed Philadelphia: Saunders Elsevier; 2008:635–637 64 Johnson L, Brown AK, Bhutani VK BIND—a clinical score for bilirubin induced neurologic dysfunction in newborns Pediatr Suppl 1999;104:746–747 65 Slusher T, Owa JA, Painter M, Shapiro S The kernicteric facies: facial features of acute bilirubin encephalopathy Pediatr Neurol 2011;44:153–154 66 Cline BK, Vreman HJ, Faber KL, et al Phototherapy device effectiveness in Nigeria: current irradiance levels and simple strategies for improvement E-PAS2011 2011;1450.540 67 Tan K Phototherapy for neonatal jaundice Clin Perinatol 1991;18:423–439 68 Slusher T, Faber K, Cline BK, et al Selectively filtered sunlight phototherapy: safe and effective for treatment of neonatal jaundice in Nigeria E-PAS2011 2011;2918.254 69 Malkin R, Anand V A novel phototherapy device: the design community approach for the developing world IEEE Eng Med Biol Mag 2010;29:37–43 70 Gomella TL, Cunningham MD, Eyal FG, Zenk KE Neonatology: Management, Procedures, On-Call Problems, Diseases, and Drugs New York: McGraw-Hill; 2004 71 Hosseinpour Sakha S, Gharehbaghi MM Exchange transfusion in severe hyperbilirubinemia: an experience in northwest Iran Turk J Pediatr 2010;52:367–371 NEONATAL JAUNDICE IN LOW- AND MIDDLE-INCOME COUNTRIES 72 Badiee Z Exchange transfusion in neonatal hyperbilirubinaemia: experience in Isfahan, Iran Singapore Med J 2007;48:421–423 73 Thomas JT, Muller P, Wilkinson C Antenatal phenobarbital for reducing neonatal jaundice after red cell isoimmunization Cochrane Database Syst Rev 2007:CD005541 74 Trevett TN Jr, Dorman K, Lamvu G, Moise KJ Jr Antenatal maternal administration of phenobarbital for the prevention of exchange transfusion in neonates with hemolytic 273 disease of the fetus and newborn Am J Obstet Gynecol 2005;192:478–482 75 Chawla D, Parmar V Phenobarbitone for prevention and treatment of unconjugated hyperbilirubinemia in preterm neonates: a systematic review and meta-analysis Indian Pediatr 2010;47:401–407 76 Stevenson DK, Wong RJ Metalloporphyrins in the management of neonatal hyperbilirubinemia Semin Fetal Neonatal Med 2010;15:164–168 This page intentionally left blank Index Page references followed by f indicate figures; those followed by t indicate tables A AAP See American Academy of Pediatrics (AAP) ABC See ATP binding cassette (ABC) family ABE See Acute bilirubin encephalopathy (ABE) ABO blood group immunization, 81 ABO hemolytic disease, 4, vs ABO setup, 154 Coombs’ test, 10 diagnosis of, 154 pathophysiology of, 153–154 ABO heterospecificity associated neonatal jaundice treatment, 156 definition, 152–153 newborn caused by, 152–156 ABO incompatibility, 98 ABR See Auditory brainstem response (ABR) N-Acetylcysteine (NAC), 121 Acute bilirubin encephalopathy (ABE), 47, 115, 229, 232, 245, 263 definitions, 232 major clinical features, 266t patient safety analysis for infant, example, 254t Adenosine triphosphate (ATP) adenosine-5′-triphosphate, 127 dependent mechanism, 68 formation of, 162 ADHD See Attention deficit hyperactivity disorder (ADHD) Advanced bilirubin encephalopathy, acute, 244f Aflatoxins, maternal ingestion provoke hemolysis in neonates with G6PD deficiency, 266t African American females, hyperbilirubinemia risk, African American newborns genesis of neonatal hyperbilirubinemia, Agency for Healthcare Research and Quality (AHRQ), 248 Aggressive/conservative phototherapy, 210 AhR See Aryl hydrocarbon receptor (AhR) AHRQ See Agency for Healthcare Research and Quality (AHRQ) Albumin-bound unconjugated bilirubin, 48 Ambient carbon monoxide, 145 American Academy of Pediatrics (AAP), 46, 73, 147, 175, 205, 232 criteria for exchange transfusion, 207 guideline, 245 clinical practice, recommendations, 177, 268 phototherapy level, 181 American College of Obstetrics and Gynecology (ACOG), 248 α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), 123 Amniotic fluid, 68 AMPA See α-Amino-3-hydroxy-5-methyl-4isoxazole propionic acid (AMPA) ANSD See Auditory neuropathy spectrum disorders (ANSD) Antenatal betamethasone, 99 Antioxidant, hyperbilirubinemia in adult diseases, 79 biochemical evidence, 78–80 in newborn, 80 Aryl hydrocarbon receptor (AhR), 59 ASD See Autism spectrum disorders (ASD) Asphyxia, 105 Association of Women’s Health, Obstetric and Neonatal Nurses (AWHONN), 254 A(TA)5 TAA allele, 15 ATP See Adenosine triphosphate (ATP) ATP binding cassette (ABC) family, 56, 129 cassette C (ABCC), 57 cassette transporter (ABCC3), 59 Attention deficit hyperactivity disorder (ADHD), 235 Auditory brainstem response (ABR), 48, 230 Auditory nervous system, 233 Auditory neuropathy/dyssynchrony, diagnosis of, 232 Auditory neuropathy spectrum disorders (ANSD), 230, 231, 232, 234, 237 Auditory system, 230 Auditory testing, in kernicterus, 230–232 Autism spectrum disorders (ASD), 86, 235 B Baclofen in dystonia treatment, 239 BAEPs See Brainstem auditory evoked potentials (BAEPs) Barbiturates, 99 BBB See Blood-brain barriers (BBB) BBBP See Bilirubin/BSP-binding protein (BBBP) BBS See Bronze baby syndrome (BBS) BCG vaccine tuberculosis, 265, 270 BCRP See Breast cancer resistance protein (BCRP) BE See Bilirubin encephalopathy (BE) Benzodiazepines in dystonia treatment, 239 Bf See Free bilirubin (Bf) BiliChek bilirubinometer, 46 BiliMed device, 47 Bilirubin, 68 ATP-dependent cellular export, 75 bilirubin-IXα, 66, 76 bilirubin-IXα glycosyl conjugates, 69 bilirubin-IXβ, 65 brain, phosphoglycoprotein and, 75f concentrations, 45 in serum, 80 conjugated, measurement of, 73 conjugates, 59 conjugating system, 68, 155 elimination, 29, 35 diagram of, 30 enterohepatic circulation, 103 excretion of, hyperbilirubinemia in fetus/ newborn, 67–70 275 276 Index Bilirubin (Cont.) fractions measurement of, 50 free bilirubin, 47–48, 48–50 high late, predischarge risk assessment to predict, 247t kernicterus, 47–48 photoisomers, 48–50 total serum bilirubin measurement, 41–45 transcutaneous bilirubinometry, 45–47 glucuronosylation, 59 heme, conversion of, 43f induced central nervous system (CNS) injury, intestinal reabsorption of, 103 levels, algorithm providing recommendations for management and follow-up, 186f–187f metabolism, 67 diagram of, 66f neurotoxicity, risk of, 79t, 147 nomenclature and chemical behavior, 42t photoproducts formation of, 199 production, 29, 36, 80 controlling, 35 diagram of, 30 estimates of, 31–34 fetus and newborn, 65–67 by heme catabolism, 65–66 hepatic bilirubin clearance in neonates, 6f HO-1, induction of, 82 hyperbilirubinemia risk, screening, 35–36 percent recovery heme, time, 32f phototherapy, potential toxicity, 34 source of, 29–31 solubility of, 41 species, historical recognition of, 44f stool bilirubin, 103f transcutaneous bilirubin levels, 106f 4Z, 15E -Bilirubin, 197 configurational and structural isomers, 198f formation, 198f Bilirubin–albumin complex, 48, 67 Bilirubin–brain interaction, 75–78, 77 bilirubin effects reversibility on brain, 78 bilirubin metabolism in brain, 77 blood–brain barrier, 76–77 brain blood flow, 77 infection/septicemia, role of, 77–78 neurotoxic bilirubin level, 78 Bilirubin/BSP-binding protein (BBBP), 55 Bilirubin elimination, sophisticated system of, 60 Bilirubin encephalopathy (BE), 164, 210 chronic, 229 hyperbilirubinemia signs, 263 chronic, definitions, 232–233 Bilirubin-induced neurological dysfunction (BIND), 36, 44, 76, 115, 229, 233, 243 ABE, development of, 78 BIND II score, 266, 267t brain region susceptibility to, 136 central auditory pathway dysfunction, 48 developing, potential risk for, 249 kernicterus, basic mechanism of, 78 mechanisms, 116 natural history of, 257 pathophysiology, 116 potential for, 244 risk for, 244 video documentary, 254 in vivo animal models of, 117 Bilirubin toxicity, 73, 79, 80, 85, 115–137 at different subcellular compartments endoplasmic reticulum and Golgi complex, 119–120 mitochondria, 118–119 nucleus, 120 experimental models to evaluate, 115–117 cell lines and primary cultures, 116 Gunn rat, 117 murine models, 117 organotypic slice cultures, 116–117 in vitro models, 115–117 in vivo animal models, 117 harmful effects on cell-to-cell adhesion, 123 inflammation and neurodevelopment stage as risk factors, 135–136 injury to neurons and glial cells, 123–135 astrocytes, 129–130 cell death and role of efflux pumps, 129–130 cell failure, determinants and modulators, 126–129 cytoskeleton dynamics, 125–126 in interplay between neurons and glia, 131–135 microglia, 131 neurogenesis, neuritogenesis, and synaptogenesis, 123–124 neurons, 123–129 oligodendrocytes, 131 signaling, reactivity, and immunosuppression, 129 synaptic plasticity, 125 interaction with plasma and intracellular membranes, 118 overview view on potential mechanisms, 121–123 accumulation of extracellular glutamate and excitotoxicity, 122–123 immunostimulation and immunotoxicity, 121–122 increased cytoplasmic calcium, 121 oxidative stress, 121 reversibility of, 79f treatment of cell and tissue cultures with bilirubin, 117–118 Bilirubin transport, 56 bilirubin conjugation, 57–59 brain bilirubin flux, 61–62 in fetus and newborn, 67–70 hyperbilirubinemia, fetus/newborn, 67–70 conjugation and excretion, 68–69 early feeding, 70 enterohepatic circulation, 69–70 glucuronyltransferase activity, 69 hepatic uptake, 67 intestinal malformations, 70 intrahepatic transport proteins, development, 69 and placenta, 67–68 total serum bilirubin values, 70f UGT activity, inducibility, 69 influx into brain, 62 metabolic disturbances, 61–62 overview of, 55 UCB blood–brain barriers, 60–61 cellular uptake, 55–56 factors affecting blood–brain transfer, 61 liver cell, 57–59 Biliverdin, 68 biliverdin-IXα, 66 nontoxic, 68 Biliverdin–bilirubin shuttle, 30 Biliverdin reductase A (BLVRA), 12 BIND See Bilirubin-induced neurological dysfunction (BIND) Bioluminescence imaging (BLI) technology, 35 BLI technology See Bioluminescence imaging (BLI) technology Blood–brain barriers (BBB), 60, 76, 135, 198 schematic representation, 60f unconjugated bilirubin (UCB), 60–61 Blood–brain transfer unconjugated bilirubin, factors affecting, 61 Blood–cerebrospinal fluid barrier schematic representation, 60f Blood group incompatibility and DAT positivity, 153 Index BLVRA See Biliverdin reductase A (BLVRA) Botox injections, 239 Brain capillaries endothelial cells of, 60 Brainstem auditory-evoked potentials (BAEPs), 122, 230 Brainstem auditory evoked responses (BAERs), 230 Brainstem auditory nuclei, 233 Brainstem auditory pathways, 235 Breast cancer resistance protein (BCRP), 58f, 59 Breast-feeding, 101, 102 jaundice pathogenesis, 102–105, 102t bilirubin, intestinal reabsorption of, 103–104 caloric intake, 102–103 β-glucuronidase, 104 meconium passage, 104 urobilinogen formation, 104 risk of subsequent hyperbilirubinemia in newborns, 102t weight loss and intake, 103t Breast milk associated jaundice, 70, 74 feeding, neonatal jaundice, 18 Breast-nonfeeding jaundice, 102 Bronze baby syndrome (BBS), 83, 211–212 Bupivacaine, 99 C California Perinatal Quality Care Collaborative (CPQCC), 254 Canadian Paediatric Society, 175 CAP See College of American Pathologists (CAP) CAR See Constitutive androstane receptor (CAR) Carbon monoxide (CO) beta-agonists used for tocolysis, 99 endogenous sources, 31 end-tidal, 32f, 33f excretion, 212 flow-through system, 31f nonenzymatic sources, 31 physiological roles of, 31f total body bilirubin formation, 31 Carboxyhemoglobin (COHb) determinations, 145 levels, 33, 220 Carboxyhemoglobin corrected for ambient carbon monoxide (COHbc), 33 Casein hydrolysate See Nutramigen Caspase-1, 129 CDC See Centers for Disease Control and Prevention (CDC) Cell-free fetal DNA determination, 151 Cell lines, advantages of, 116 Centers for Disease Control and Prevention (CDC), 247 Central nervous system (CNS), 60, 115, 209, 229 disorders, pathogenesis of, 129 Central venous pressure (CVP), 152 Cerebral palsy (CP) cases, 229 CFTR See Cystic fibrosis conductance transmembrane regulator (CFTR) cGMP production See 3′,5′-Cyclic guanosine monophosphate (cGMP) production Chloral hydrate, use of hyperbilirubinemia, 105 2-Chlorophenoxy-2-methylpropionic acid, 220 Cholestatic jaundice in newborn, 83 Citrate-phosphate-dextrose (CPD), 216 Clinician–community partnership to prevent adverse newborn outcomes, 257t CMPI See Cow’s milk protein intolerance (CMPI) CM recordings See Cochlear microphonic (CM) recordings CNS See Central nervous system (CNS) CO See Carbon monoxide (CO) measurements of endogenous formation of, 154 Cochlear microphonic (CM) recordings, 231 COHb See Carboxyhemoglobin (COHb) COHbc See Carboxyhemoglobin corrected for ambient carbon monoxide (COHbc) Collaborative Perinatal Project (CPP), 105, 147 College of American Pathologists (CAP), 44 bilirubin concentrations, 45t Community health workers, 264 Configurational (Z→E) isomerization, 196–198, 198f Configurational isomers, 198 Congenital erythropoietic porphyria, 211 Congenital nonhemolytic unconjugated hyperbilirubinemia syndromes, 15t Constitutive androstane receptor (CAR), 59 Coombs’ test, 34, 81, 149, 178, 207 Cow’s milk protein intolerance (CMPI), 85 in neonatal hyperbilirubinemia, 85 CP See Cerebral palsy (CP) CPD See Citrate-phosphate-dextrose (CPD) CPP See Collaborative Perinatal Project (CPP) 277 CPQCC See California Perinatal Quality Care Collaborative (CPQCC) Crash-cart approach, 161 Crigler–Najjar syndrome, 69, 211, 213, 218 definitive therapy for, 214 patients, 56 type I (CN-I), 13, 59, 82 type II, 82–83 patients, 120 Critical to quality (CTQ) index, 245 CTQ index See Critical to quality (CTQ) index Cued Speech, 239 Curvilinear regression analysis, 146f CVP See Central venous pressure (CVP) 3′,5′-Cyclic guanosine monophosphate (cGMP) production, 122 Cystic fibrosis conductance transmembrane regulator (CFTR), 56 Cytochrome P450 system, 29 D DAT See Direct antiglobulin (agglutination) test (DAT) DBS See Deep brain stimulation (DBS) Deep brain stimulation (DBS), 239 Delta-bilirubin, 42 Dental enamel dysplasia, 233 Department of Health and Human Services, 248 Department of Public Health, 248 Dermal jaundice, zones of, 71f Desynchronization, 230 Diazepam, 99 in dystonia treatment, 239 Diazo method, 42 Dieter’s nucleus, 230 Direct antiglobulin (agglutination) test (DAT), 81, 146, 149, 178, 207 Direct Coombs’ test, 162 2,3-Disphosphoglycerate (2,3-DPG), 162 DNA mutagenic consequences, 120 oxidation, 120 Polymorphism Discovery Resource, 164 Doppler assessment, 151 Double volume exchange, 216 2,3-DPG See 2,3-Disphosphoglycerate (2,3-DPG) Dubin–Johnson syndrome, 59 Dyslexia, 235 Dystonia baclofen, 239 benzodiazepines, 239 diazepam, 239 treatment of, 239 278 Index by oxidation, 47 theory, 77 use, 48 E ELBW See Extremely low birth weight (ELBW) Electroencephalogram, 230 Embden–Meyerhof pathway, 162 Endoplasmic reticulum (ER), 56 End-tidal CO concentration corrected for ambient carbon monoxide (ETCOc), 33, 148 values for, 148f Enterohepatic circulation, 69, 70 ER See Endoplasmic reticulum (ER) EROR See Exaggerated rate of rise (EROR) Erythroblastosis, 150 clinical manifestations of, 152 Erythrocycte osmotic fragility, 213 ETCOc See End-tidal CO concentration corrected for ambient carbon monoxide (ETCOc) ET criteria See Exchange transfusion (ET) criteria Exaggerated rate of rise (EROR), 182 Excessive hyperbilirubinemia treatment, 229 Exchange transfusion (ET) criteria, 215–218, 263 complications, 216–218, 269 indications, 216 technique, 215–216 Expressive speech problems, 236 Extravascular hemolysis, 153 Extremely low birth weight (ELBW), 34 Extreme neonatal hyperbilirubinemia, 159–160 F FABP1 See Fatty acid-binding protein (FABP1) Fatty acid–binding protein (FABP1), 57 Fava beans, maternal ingestion provoke hemolysis in neonates with G6PD deficiency, 266t Favism, 159 FDA See Food and Drug Administration (FDA) Fetal hemolytic disease, 65 Fetal surveillance protocols, 156 Fiber-optic systems, 202 development of, 214 Fluorescent systems, 202 Food and Drug Administration (FDA), 46 Four-way stopcock assembly, 215f Free bilirubin (Bf), 42t, 47–48, 50, 55, 67, 73, 77, 229, 231, 238 concentrations, 67 fraction, 47 measurement, 48, 50 in newborn, 231 G Gene–environment interactions, 19 Gene replacement, 82 Genetic variations in bilirubin conjugation, 82 Gilbert nonsynonymous coding sequence variants, 16 Gilbert phenotype, 17 Gilbert’s genotype, 98 Gilbert’s syndrome, 5, 13–15, 17, 59, 60, 69, 80, 83, 97, 98, 102 See also Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) frequency of polymorphic U GT1A1 allele, 16t U GT1A1 gene variants report, 16t Glial cells, 123 interplay between neurons, 136f Global Prevention of Kernicterus Network, 264 Globus pallidus externa (GPe), 234 Globus pallidus interna (GPi), 234 Glucocorticoid-receptor response elements (GRE1), 17 Glucose-6-phosphate dehydrogenase (G6PD) deficiency, 4, 6, 35, 82, 98, 123, 147, 175, 218, 243, 251, 266 biochemical screening/testing, 160–161 commonly encountered mutation types, 159t deficiency and hemolysis, 159–160 dose-dependent genetic interaction, enzyme activity, erythrocytes stained cytochemically for, 159f ethnicity, 6t extreme neonatal hyperbilirubinemia, 159–160 favism, 159 frequency among UD military recruits, 252t function of, 157 genetics of, genotype vs phenotype, 157–158 genotypes, 158t Gilbert disease, 35 hyperbilirubinemia Taiwanese male neonates, 9f UGT1A1*28 promoter genotype, 8f life-threatening neonatal manifestations, 252 moderate neonatal hyperbilirubinemia, 160 molecular screening methods, 161 mutations, 158–159 neonates, overrepresentation, 157t risk, 269 role of enzyme, 158f screening for, 161, 251, 257 testing for, 160–161 β-Glucuronidase, 101, 104 Glutathione S-transferase (GST), 67 G6PD deficiency See Glucose-6-phosphate dehydrogenase (G6PD) deficiency deficient RBCs, 18, 19 GPe See Globus pallidus externa (GPe) GPi See Globus pallidus interna (GPi) GRE1 See Glucocorticoid-receptor response elements (GRE1) GST See Glutathione S-transferase (GST) G680T mutation, Gunn rat model, 48, 56 H Harvard Life Bridge Program, 255 HCFA See Healthcare Financing Administration (HCFA) HDN See Hemolytic disease of the newborn (HDN) Healthcare Financing Administration (HCFA), 255 Health care professional, 254 Health care providers, 253 Health care system, 245 Healthy Beginnings Initiative, 258 HEK293 cells, 56 Heme catabolic pathway, 29, 219f degradation pathway, 30 Heme oxygenase (HO), 5, 29, 65 activity, 66–67 functional isoforms, 66 inhibitors, 270 Hemin See Iron protoporphyrin Hemoglobin H disease, 11 Hemolysis, 213 incorporating endogenous formation studies of carbon monoxide, 154 Hemolytic disease of the newborn (HDN), 81, 150 Hemolytic disorders in bilirubin-induced neurotoxicity, hemolysis role in, 145–148 AAP recommendations regarding hemolyzing babies, 148 hemolyzing babies, 147–148 imbalance b/w bilirubin production and elimination, 145–146 possible increased risk associated with hemolysis, 146–147 Index classification of, 149t genetic interactions between hemolytic conditions and UGT1A1 polymorphisms, 163–165 heritable, 5–6 G6PD mutations, 6–9 hemoglobinopathies, 11 pyruvate kinase (PK) deficiency, 9–10 RBC membrane defects, 10–11 RBC metabolism, management of, 145–165 neonatal jaundice and, 145–148 AAP recommendations regarding hemolyzing babies, 148 hemolyzing babies, 147–148 imbalance b/w bilirubin production and elimination, 145–146 possible increased risk associated with hemolysis, 146–147 nonimmune hemolytic disease glucose-6-phosphate dehydrogenase deficiency, 157–161 hereditary elliptocytosis, 163 hereditary ovalocytosis, 163 hereditary pyropoikilocytosis, 163 hereditary spherocytosis, 162–163 hereditary stomatocytosis, 163 pyruvate kinase deficiency, 161–162 unstable hemoglobinopathies, 163 specific hemolytic conditions, 149–156 ABO blood group heterospecificity, definition, 152–153 ABO hemolytic disease, pathophysiology of, 153–154 ABO heterospecificity–associated neonatal jaundice treatment, 156 ABO setup vs ABO hemolytic disease, 154 blood group incompatibility and DAT positivity, 153 direct antiglobulin (agglutination) test, 149 hemolysis incorporating endogenous formation studies of carbon monoxide, 154 hyperbilirubinemia in ABO disease, predicting the severity, 155–156 hyperbilirubinemia incidence in ABO heterospecific neonates, 154–155 immune hemolytic conditions, 149 immunization due to antibodies other than RhD and ABO, 156 immunization process, 150 management of pregnancy, 150–151 in neonate, 153 newborn caused by ABO heterospecificity, 152–156 postnatal management of newborn, 152 Rh isoimmune hemolytic disease, 149–152 Henna provoke hemolysis in neonates with G6PD deficiency, 266t Hepa 1c1c7 cells, 120 Hereditary elliptocytosis, 10, 163 Hereditary ovalocytosis, 163 Hereditary pyropoikilocytosis, 163 Hereditary spherocytosis (HS), 10, 162–163 clinical features, 163 diagnosis of, 162–163 mutations responsible, 162 Hereditary stomatocytosis, 163 Heroin-addicted mothers, 99 High-intensity blue light phototherapy use of, 215 High-performance liquid chromatography (HPLC), 44 HO See Heme oxygenase (HO) Home phototherapy, 202, 209, 214 use of, 209 Homozygous α−thalassemia, 11 Hour-specific bilirubin levels receiver operating characteristic (ROC) curve, 249f Hour-specific bilirubin nomograms, 33f, 248 See also Receiver operating characteristic (ROC) curve HPLC See High-performance liquid chromatography (HPLC) HS See Hereditary spherocytosis (HS) HSA See Human serum albumin (HSA) Human serum albumin (HSA), 61, 115, 211 Hyperbilirubinemia, 214, 246 See also Neonatal hyperbilirubinemia AAP guideline for management, 250 in ABO disease, predicting the severity, 155–156 bilirubin as antioxidant in adult diseases, 79 biochemical evidence, 78–79 in newborn, 80 bilirubin–brain interaction, 75–78 bilirubin effects reversibility on brain, 78 bilirubin metabolism in brain, 77 blood–brain barrier, 77 brain blood flow, 77 infection/septicemia, role of, 77–78 neurotoxic bilirubin level, 78 definitions, 154, 248 development, 97 risk factors for, 98t, 181, 181t drugs for, 220 etiologies for, 233 279 fetus/newborn, bilirubin production, 65 by heme catabolism, 65–66 heme oxygenase activity, 66–67 fetus/newborn, bilirubin transport/ excretion, 67–70 conjugation and excretion, 68–69 early feeding, 70 enterohepatic circulation, 69–70 glucuronyltransferase activity, 69 hepatic uptake, 67 intestinal malformations, 70 intrahepatic transport proteins, development, 69 and placenta, 67–68 total serum bilirubin values (TSB), 70f UGT activity, inducibility, 69 gestation, effect of, 100t hazardous, 253 infant jaundice pharmacological pitfalls treatment, drugs role, 74–75 incidence of, 155f, 164f, 165f in ABO heterospecific neonates, 154–155 infant development, probability, 185f infant jaundice clinical/laboratory evaluation at discharge assessment, 73–74 clinical/laboratory evaluation readmitted for, 74 jaundice treatment in infant, pharmacological pitfalls drug therapy, 75 herbal/traditional medicine roles, 75 key elements in the AAP guideline on management, 177t management, strategies for system-wide approach in, 255 neonatal, association of, 83 cow’s milk intolerance, 85 development of asthma, 85 diabetes type 1, 85 neuropsychiatric and cognitive disabilities, 85–86 in neonatal period jaundice cholestatic jaundice in newborn, 83 Crigler–Najjar syndrome type I, 82 Crigler–Najjar syndrome type II, 82–83 genetic variations in bilirubin conjugation, 82 Gilbert syndrome, 83 immune hemolytic disease, 81–82 nonimmune hemolytic disorders, 82 prolonged jaundice, causes of, 83 prolonged neonatal jaundice, 82 sign of infection, 82 280 Index Hyperbilirubinemia (Cont.) neurodevelopmental problems, 238t in newborn jaundice, clinical/laboratory evaluation bilirubin measurement, 72–73 initial assessment of, 72 physiological jaundice, 71–72 in newborn jaundice presentation jaundice development, 70–71 physiological versus nonphysiological jaundice, 70–71 phototherapy use and frequency management, 258 studies effect of universal bilirubin screening on, 189t placenta, heme oxygenase activity, 66–67 premature infant, jaundice, 80–81 prevention, 218 risk, African American females, severity, 243 treatment of, 163, 253 Hyperbilirubinemic, 85 Hyperbilirubinemic Gunn rats, 59 Hypoxia, 77 I ICAM-1 See Intercellular adhesion molecule-1 (ICAM-1) ICE See IL-1β-converting enzyme (ICE) ICH mouse model See Intracerebral hemorrhage (ICH) mouse model IDM See Insulin-dependent diabetic mothers (IDM) IL-1β-converting enzyme (ICE), 129 Immune hemolytic conditions, 149 Immune-mediated hemolytic disease, 11 Immunization process, 150 due to antibodies other than RhD and ABO, 156 Inadequate breastfeeding, 178 Infants exchange transfusion, potential complications, 218t guidelines for exchange transfusion in, 217f serum bilirubin, 188f Infra red (IR) light, 269 Insulin-dependent diabetic mothers (IDM), 98, 100, 101 Intensive phototherapy, 204, 268 Intercellular adhesion molecule-1 (ICAM-1), 122 Interleukin (IL)-1β and -6, 122 inflammatory signaling pathways, 130f International Committee for Standardization in Haematology, 160 Interwave interval (IWI), 230 Intracerebral hemorrhage (ICH) mouse model, 122 Intravenous immune globulin (IVIG) administration of, 152 drugs increasing conjugation of bilirubin, 220 prophylactic administration, 152 use of, 152 In vivo cell-to-cell interactions advantage, 116 Iron protoporphyrin, 35 Irradiance, 199–200 Isoimmune hemolytic disease, 220 IVIG See Intravenous immune globulin (IVIG) IWI See Interwave interval (IWI) J Jaundice diagnosis of, 72 in infants, clinical/laboratory evaluation at discharge, assessment, 73 readmitted for, 74 in infants, end-tidal carbon monoxide levels, 32f lactation/nutrition history, 74 in neonatal period cholestatic jaundice in newborn, 83 Crigler–Najjar syndrome type I, 82 Crigler–Najjar syndrome type II, 82–83 genetic variations in bilirubin conjugation, 82 Gilbert syndrome, 83 immune hemolytic disease, 81–82 nonimmune hemolytic disorders, 82 prolonged jaundice, causes of, 83 prolonged neonatal jaundice, 82 sign of infection, 82 in newborn, clinical/laboratory evaluation bilirubin measurement, 72–73 initial assessment of, 72 physiological jaundice, 71–72 physiologic, 105 risk profiles, 35, 35f treatment in infant, pharmacological pitfalls drugs role, 74–75 drug therapy, 75 herbal/traditional medicine roles, 75 visual identification of, 72f Jendrassik–Grof procedure, 44 Joint Commission on Accreditation of Healthcare Organizations (JCAHO) Sentinel Alert, 246–247, 254 K Kernicteric facies, 267, 268f Kernicterus, 229–239, 243 chronic hyperbilirubinemia signs, 263 clinicopathological correlations, 230–232 auditory testing, 230–232 neuroimaging, 230 definitions, 232–233, 232–234 acute bilirubin encephalopathy, 232 chronic bilirubin encephalopathy, 232–233 research definitions, 237t subtle kernicterus, 233 incidence, population-based estimates of, 176t national incidence, 245 neurodevelopmental problems due to hyperbilirubinemia, 238 pathology, 229–230 subtype classification of, 234–237 by certainty of kernicterus, 237 classification by location, 235t possible sequelae, 235 by severity of symptoms, 236–237, 236t subtype relation with neurodevelopmental age of exposure, 237–238 treatment of, 238–239 Kernicterus spectrum disorders (KSDs), 244 category, 234 Kramer scale, 265, 265f KSDs See Kernicterus spectrum disorders (KSDs) L Labor/delivery, in hyperbilirubinemia anesthesia and analgesia, 99 delivery mode, 99 drugs, 98–99 induction and augmentation, 98–99 oxytocin, use of, 98 phenobarbital, 99 placental transfusion, 99–100 umbilical cord clamping timing, 100 vacuum extraction, 99 vaginally and cesarean section mean breast milk transfer, 99t Large for gestation (LGA), 98 LBW See Low birth weight (LBW) LEDs See Light-emitting diodes (LEDs) LGA See Large for gestation (LGA) Ligandin, 69 polymorphisms, 13 Light-emitting diodes (LEDs), 34 development of, 214 technology, 204 disadvantage, 204 Index Light spectrum, 198–199 Lipopolysaccharide (LPS), 127 Liver cell unconjugated bilirubin, 57–59 Liver transplantation, 82 Liver X receptor (LXR), 58f LMICs See Low-middle-income countries (LMICs) Locally made phototherapy device assembling, 268f Long-term depression (LTD), 125 Long-term potentiation (LTP), 125 Low birth weight (LBW), 204 infants, 100, 216 Low-middle-income countries (LMICs), 263 list of priorities in, 264 LPS See Lipopolysaccharide (LPS) LTD See Long-term depression (LTD) LTP See Long-term potentiation (LTP) LXR See Liver X receptor (LXR) Lysine, 67 M Magnetic resonance imaging (MRI), 48, 68, 230, 266 hyperintense signals on, 230 hyperintensities in globus pallidus, 231f Making Advances Against Jaundice in Infant Care (MAJIC), 255 Malaysian randomized trial, 205 MAP See Microtubule-associated protein (MAP) MAPK activation See Mitogen-activated protein kinase (MAPK) activation Maternal Child Health Bureau (MCH), 255 Maternal–child health care systems, 256 Matrix metalloproteinases (MMPs), 122 MCHC See Mean corpuscular hemoglobin concentration (MCHC) MDI See Mental Development Index (MDI) Mean corpuscular hemoglobin concentration (MCHC), 10 Mean corpuscular volume (MCV) α−thalassemia syndromes, 11 Meconium, 70 Medical Advisory Board, 255 Membrane receptors inefficiency, 118 Mendelian trait, Mental Development Index (MDI), 34 Mentholated rub/dusting powder provoke hemolysis in neonates with G6PD deficiency, 266t Metabolic acidosis, 152 Metalloporphyrins, 35, 219 structure, 218f N-Methyl-D-aspartate (NMDA) receptor, 122 Microglia role of, 131 Microtubule-associated protein (MAP), 125 Mitogen-activated protein kinase (MAPK) activation, 122 MMPs See Matrix metalloproteinases (MMPs) Moderate neonatal hyperbilirubinemia, 160 Molecular mechanisms, 121 Molecular screening methods, 161 Monoglucuronide, 69 Mother’s immune system, 150 Motor-predominant kernicterus, 234 Motor symptoms severity of, 236 Movement disorders athetosis, 232 dystonia, 232 MRI See Magnetic resonance imaging (MRI) findings, 135 MRPs See Multidrug resistance proteins (MRPs) Multidrug resistance proteins (MRPs), 56 protein-1 (MRP1), 129 protein (MRP2), 57 protein (MRP3), 57 N NAC See N–Acetylcysteine (NAC) NADPH/biliverdin reductase, 78 Naphthalene provoke hemolysis in neonates with G6PD deficiency, 266t National Academy of Clinical Biochemistry (NACB), 47 National Association of Neonatal Nurses (NANN), 255 National Human Genome Research Institute, 164 National Institute for Health and Clinical Excellence (NICE), 195 guideline, 179 National Institutes of Child Health and Human Development (NICHD), 201 neonatal research network trial initiating phototherapy and exchange transfusions criteria for, 210t National Institutes of Health (NIH), 255 NDI See Neurodevelopmental impairment (NDI) Negative predictive value (NPV), 155 Neonatal bilirubin cycle C (NB-C), 45 measurement of, 45 281 Neonatal brain injury cellular mechanisms, 136 Neonatal hyperbilirubinemia, 231, 264 adverse outcomes, reducing risk progress in, 246–247 association of, 83 cow’s milk intolerance, 85 development of asthma, 85 diabetes type 1, 85 neuropsychiatric and cognitive disabilities, 85–86 background, 244–246 statement of problem, 244–246 community-based toolkit to track progression, 246t definitions for severity, 244t epidemiology of (See Neonatal hyperbilirubinemia, epidemiology of) estimated occurrence, 2t follow-up, sunlight exposure, 185 genetic load vs environmental effect, 2f genetics of, gestation, effect of, 100t infants, patient race, 3f intervention in breastfeeding jaundiced newborn, 186 jaundiced newborn identification, 178–179 cephalocaudal progression of jaundice, 179 nursing protocols, 178 visual estimates of jaundice, 178–179 maternal child health care infrastructure and public policy, 256–257 outcome of, 232 pharmacologic prevention of, 185 physiologic and pathologic jaundice, 175–178 normal bilirubin value, 177 terminology, 177–178 practitioner help to implement guidelines, 185 prevention approaches, recent changes in, 246 ensuring successful breastfeeding, 178 primary, screening for isoimmunization, 178 screening, and postnatal management of, 175–189 severe, policy issues to birthing facility care, 257–258 severe, policy issues to emergency readmission care, 258–259 severe, policy issues to follow-up office-based care, 258 severe, policy issues to home care, 258 282 Index Neonatal hyperbilirubinemia, prevention (Cont.) severe, policy issues to triage for jaundiced newborn arriving at emergency room, 258–259 severe, public policy to, 243–259 societal role, 253–256 transcutaneous bilirubin measurements, 180–181 clinical application of, 180–181 effect of phototherapy, 181 factors affecting, 180–181 preterm and low birth weight infants, 180 site of sampling, 181 skin pigmentation and gestation, 180 TSB level effect, 180 and treatment, 259 useful policies and their access, 259 web sites, 259 recent multinational reviews assessing neonatal G6PD deficiency through public policy initiatives, 251–252 economic consequences of public policy initiatives, 252–253 effective use of phototherapy, 249–250 predischarge risk assessment, 248–249 promotion of breastfeeding, 248 reducing the need for exchange transfusion, 250–251 research needs, 257 risk assessment cephalocaudal progre, 181–182 clinical risk factors, 181 combining gestation with predischarge bilirubin level, 183 gestation, 100, 182 predischarge measurement of bilirubin level, 182 risk of, 17 Neonatal hyperbilirubinemia, epidemiology of altitude, 105 drugs administration, 105 ethnic and familial factors, 97 extravascular blood, 104–105 free radical production, 105 genetic factors, 97–98 during labor and delivery delivery mode, 99 drugs, 98–99 placental transfusion, 99–100 umbilical cord clamping timing, 100 vacuum extraction, 99 maternal factors, 98 diabetes, 98 smoking, 98 neonatal bilirubinemia, natural history, 107 neonatal factors birth weight, 100–101 breastfeeding and jaundice, 101–102 breastfeeding and jaundice pathogenesis, 102–105 caloric intake/weight loss, 101 diet, type of, 101 gender, 101 gestation, 100 normal bilirubin level, 105–107 phenolic detergents, 105 polycythemia, 105 predischarge bilirubin level, 104 Neonatal intensive care unit (NICU), 201, 232 Neonatal jaundice acute bilirubin encephalopathy/ kernicterus, need for accurate diagnosis of, 266–268 and associated disabilities, global scope of, 263 breast milk feeding, 18 and common etiologies, need for diagnosis of degree, 264–266 disabilities associated with, 265 in families, 97 infants and children with elevated TSB levels/ABE/kernicterus, follow-up, 269 in low and middle-income countries, 263–270 morbidity and mortality, 264t moving forward in imics, 270 need for early detection, 264 need for population-based ABE case ascertainment, 263–264 Norwegian guidelines for management, 207f risk for, 79t subsequent pregnancies, follow-up and treatment in, 269–270 treatment, 268–269 Neonatal jaundice, genetics of, biliverdin reductase polymorphisms, 12 compound/synergistic heterozygosity, 17–18 gene–diet and gene–environment interactions, 18–19 genes, controlling neonatal bilirubin concentration, genetic heritage, 2–5 glutathione S-transferase polymorphisms, 13 heme oxygenase-1 (HO-1) promoter variants, 11–12 heritable hemolytic disorders, 5–6 G6PD mutations, 6–9 hemoglobinopathies, 11 pyruvate kinase (PK) deficiency, 9–10 RBC membrane defects, 10–11 RBC metabolism, international migrants, numbers, 7t male sex, newborn, immune-mediated hemolytic disease, 11 positive family history, 1–2 SLCO1B1 polymorphisms, 12–13 twin studies, UGT1A1 polymorphisms, 13–17 Neonatal Research Network (NRN) study, 201 Neonatal serum, 50 Neonatal unconjugated hyperbilirubinemia physiology of, 29 Neural cell death, 134, 135f Neurodevelopmental impairment (NDI), 34, 209 Neuroimaging in kernicterus, 230 Neurological dysfunction, 34 Neuron-to-astrocyte interactions, 132 Newborn jaundice management, breakdowns in health systems, 256t jaundice progression to severe hyperbilirubinemia and suggested clinical action, 245t postnatal management of, 152 NICU See Neonatal intensive care unit (NICU) Nitric oxide (NO), 121 Nitric oxide synthase (NOS) system, 30 N-ω−Nitro-L-arginine methyl ester hydrochloride (L-NAME), 121 NMDA receptor See N-Methyl-D-aspartate (NMDA) receptor NNT See Number needed to treat (NNT) NO See Nitric oxide (NO) Nomogram, 179f utility of, 182 Nonimmune hemolytic disease, 82 glucose-6-phosphate dehydrogenase deficiency, 157–161 hereditary elliptocytosis, 163 hereditary ovalocytosis, 163 hereditary pyropoikilocytosis, 163 hereditary spherocytosis, 162–163 hereditary stomatocytosis, 163 pyruvate kinase deficiency, 161–162 unstable hemoglobinopathies, 163 Index NOS See NO synthase (NOS) NO synthase (NOS), 121 NPV See Negative predictive value (NPV) Number needed to treat (NNT), 206f Nutramigen, 101 O OABP See Organic anion-binding protein (OABP) OAEs See Otoacoustic emissions (OAEs) OATP See Organic anion-transporting polypeptide (OATP) OATP-2 See Organic anion transporter protein (OATP-2) OATP1B1 See OATP family, human SLC01B1 (OATP1B1) Oculomotor abnormalities, 233 OLGs See Oligodendrocytes (OLGs) Oligodendrocyte precursor cells (OPCs), 131 impair differentiation, 131 Oligodendrocytes (OLGs), 123 OPCs See Oligodendrocyte precursor cells (OPCs) Organic anion–binding protein (OABP), 55 Organic anion transporter protein (OATP-2), 98 gene polymorphism, 98 Organic anion–transporting polypeptide (OATP), 55, 56 family, human SLC01B1 (OATP1B1), 55 Otoacoustic emissions (OAEs), 231 Oxidative stress, 121 Oxygen–glucose deprivation, 129 P Pancuronium, use of hyperbilirubinemia, 105 Parents of Infants and Children with Kernicterus (PICK), 255 Partial exchange transfusion technique, 152 Patent ductus arteriosus (PDA), 212 PBREM See Phenobarbital-responsive enhancer module (PBREM) PDA See Patent ductus arteriosus (PDA) Pearson correlation coefficients, 181 Peroxidase method measurement of bilirubin, 47 PGP See Phosphoglycoprotein (PGP) Pharmacological therapy, 218–220 drugs that decrease bilirubin production, 218–220 Phenobarbital-responsive enhancer module (PBREM), 59 Phonological coding system, 239 Phosphoglycoprotein (PGP), 75, 77 Photoisomerization, 196 products, 198 Photoisomers, bilirubin, 48 Photooxidation, 195, 198 Phototherapy, 195–215, 268 barriers to, 250t benefit of, 198 biological effects and complications, 211–213 bronze baby syndrome, 211–212 complications, 213 does intensive phototherapy cause hemolysis, 213 eye damage, 212 insensible water loss and thermal regulation, 212 intravenous alimentation, 212 mortality in very low birth weight infants, 212 patent ductus arteriosus, 212–213 skin, 211 checklist for technical specifications for effective devices, 251t clinical use, 200–205 hydration and feeding, 205 infants treatment with, 206–209 intermittent vs continuous phototherapy, 205 irradiance, 204 light sources, 201–204 measuring the dose, 204–205 surface area, 204 turning the infant, 205 using phototherapy effectively, 204–205 dermatologic effects, 211 devices, 250 dose of, 202t effective alternative to, 200 effect of light source and distance, 201f efficacy of, 200–205, 202t factors in, 199f hydration and feeding, 205 infants treatment with, 206–209 intermittent vs continuous phototherapy, 205 irradiance, 204 light sources, 201–204 measuring the dose, 204–205 radiometric quantities used, 200t surface area, 204 turning the infant, 205 using phototherapy effectively, 204–205 estimated number needed to treat with inpatient phototherapy, 209t exchange transfusion in preterm infants, 208t guidelines for, 206f initiate effective, 249t use, 205–210 283 home phototherapy, 214 maximum spectral irradiance, 203t mechanism of action, 195–198, 197f configurational (Z →E) isomerization, 196–198, 198f photooxidation, 198 structural isomerization, 198, 198f normal bilirubin metabolism, 196f in older children and adolescents, 214–215 principles apply to, 212 products of, 49f rate of decline in serum bilirubin, 213 rebound, 214 relationship b/w average spectral irradiance and total serum bilirubin concentration, 200f suboptimal community-based use, 250 sunlight exposure, 214 systems, 200, 204 terminology, 198–200 effect on irradiance of light spectrum and distance between light and subject, 200 irradiance, 199–200 light spectrum, 198–199 spectral power, 200 use, 247 in use with cradle, 269f when to be stopped, 213–214 Phototoxicity, 36, 218, 219 Pilot Kernicterus Registry, 256 Pilot US Kernicterus Registry, 253 observations, 253 PK deficiency See Pyruvate kinase (PK) deficiency diagnosis of, 10 Placenta hyperbilirubinemia, heme oxygenase activity, 66–67 Plexiglas color chart, 46 Porphyrin type based on chelated metal and ring substituent, 219t Pregnancy-related immunization, 153 Pregnane X receptor (PXR), 17, 59 Presynaptic proteins synaptophysin, 125 Professional organizations, 255 Proinflammatory cytokines interleukin (IL)-1β and -6, 122 tumor necrosis factor-α (TNF-α), 122 Prophylactic phototherapy, 210 Purkinje cells, 135, 230 PXR See Pregnane X receptor (PXR) Pyknocytosis, 10 Pyruvate kinase (PK) deficiency, 5, 82, 161–162 284 Index Q Queenan curve, 150 R Randomized controlled trials (RCT), 152 RBC lysis, 81 RBCs See Red blood cells (RBCs) RCT See Randomized controlled trials (RCT) Reactive nitrogen species (RNS), 121 Reactive oxygen species (ROS), 118 production, 30 Reading disorders See Dyslexia Receiver operating characteristic (ROC) curve of hour-specific bilirubin levels, 249f Red blood cells (RBCs), 29, 65 Relative risk (RR), Relative risk reduction (RRR), 252 Retinopathy of prematurity (ROP), 80 Rhesus hemolytic disease, 11, 229 isoimmune hemolytic disease, 149–152 Rhesus immunoglobulin (RhoGAM) administration of, 151 antigen, 11 development and widespread use, 250 RhoGAM See Rhesus immunoglobulin (RhoGAM) prophylaxis, 256 Rho(D) immune globulin, 266 gene technology, 151 RNS See Reactive nitrogen species (RNS) ROP See Retinopathy of prematurity (ROP) ROS See Reactive oxygen species (ROS) Rotor syndrome, 59 RR See Relative risk (RR) RRR See Relative risk reduction (RRR) S Safety and Family Education (SAFE) program, 255 Serum bilirubin levels breastfed and formula-fed newborns, 101f supplementary feedings effect, 188f testing, 46 Severe hyperbilirubinemia, 178 risk for, 188 SH-SY5Y cells, 128 Single death-signaling pathway, 115 Sinusoidal blood, 59 SLCO1B1 See Solute carrier organic anion transporter 1B1 (SLCO1B1) SnMP See Tin mesoporphyrin (SnMP) SnPP See Tin protoporphyrin (SnPP) Solute carrier organic anion transporter 1B1 (SLCO1B1), polymorphisms, 12, 13 schematic of, 12 Spasticity, 238 Spectral irradiance, 199 Spectral power, 200 Spectrophotometric method, 45 SPTA1 gene, 10 STN See Subthalamic nucleus (STN) Stool bilirubin, 103f Subcommittee on Hyperbilirubinemia, 148 Subthalamic nucleus (STN), 229–230 Subtle kernicterus, 235 Subtle neurodevelopmental disabilities, 233 Sugar absorption test, 85 Sulfanilamide powder provoke hemolysis in neonates with G6PD deficiency, 266t Sunlight phototherapy, 269 Symptomatic hypocalcemia, 216 Synergistic heterozygosity, 18 T TACE See TNF-α−converting enzyme (TACE) TCB See Total serum conjugated bilirubin (TCB) TcB See Transcutaneous bilirubin (TcB) α-Thalassemia syndromes, 6, 11 Time-constrained environment, 252 Tin mesoporphyrin (SnMP), 35, 156, 211 Tin protoporphyrin (SnPP), 218 TNF-α See Tumor necrosis factor-α (TNF-α) TNF-α−converting enzyme (TACE), 129 Total serum bilirubin (TSB) levels, 97, 117, 175, 195, 229, 243, 249 automated laboratory methods, 44 birth weight, 100 in black and white newborns, 4t breastfeeding, 101 caloric deprivation, 101 CAP chemistry survey, 45 capillary vs venous, 44 concentrations, 81, 99, 145 Crigler–Najjar syndrome, 68 curvilinear regression analysis, 146f delta-bilirubin, 42 in early neonatal period, 70f fecal bilirubin excretion, relationship, 104 heroin-addicted mothers, 99 hispanic infants, 97 interpretation, 177 measurements, 265 measurement techniques, 41, 73f, 180–181 nonenzymatic photometric analysis, 44 during pregnancy, 98 prior sibling, 97 Rhesus immunization, 65 Taiwanese infants, 98 Total serum conjugated bilirubin (TCB), 145 Transcutaneous bilirubin (TcB), 99, 156, 244 exaggerated rate of rise (EROR), 182 gestational age, 106f measurements, 46, 72, 73 monitoring, 41, 178, 246 nomograms, 46 Triple dye provoke hemolysis in neonates with G6PD deficiency, 266t Truncal hypotonia, 233 Tufts Evidence-Based Practice Center, 183 Tumor necrosis factor-α (TNF-α), 122 inflammatory signaling pathways, 130f T1-weighted images, 232 U UCB See Unconjugated bilirubin (UCB) blood–brain barriers, 60–61 cellular functions, effects, 86 cellular uptake, 55–56 factors affecting blood–brain transfer, 61 liver cell, 57–59 UDPGA See Uridinediphosphoglucuronate (UDPGA) UDP-glucuronosyltransferase (UGT) activity, 68 UDP-glucuronosyltransferase 1A1 (UGT1A1) gene, 117, 145 UDPGT See Uridine diphosphoglucuronyltransferase (UDPGT) UGT See Uridine diphosphate glucuronosyltransferase (UGT) UGT1A1 See Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) UGT1A1*6 coding sequence East Asian populations, 17 UGT1 gene locus, 13 Ultraviolet (UV) light, 199, 269 Unbound bilirubin, 48 Unconjugated bilirubin (UCB), 55, 67, 115 from albumin, 55 blood–brain barriers, 60–61 blood–CNS interfaces, 61 into brain, 61 Caco-2 cells, 57 cellular uptake, 55–56 CNS, bilirubin transfer risk BBB immaturity, 61–62 blood pH, 61 increased plasma osmolality, 61 systemic inflammation, 61 cytoskeletal alterations, schematic drawing of, 126f Index cytotoxicity, 131 delays oligodendrocyte (OLG) differentiation, 133f direct effects of, 118 exposure of immature hippocampal neurons to, 125f faces of microglial response, 132f factors affecting blood–brain transfer, 61 flux into brain, 62 general cellular injury, 118 high concentrations, 121 impairs oligodendrocyte precursor cells (OPCs), 133f induced cytotoxic effects, 134 intracellular metabolism and excretion, 58f intracellular pathways and subcellular compartments, schematic drawing of, 119f IXα isomer, 57 liver cell, 57–59 MDCKII kidney cells, 57 microglial phagocytic ability, 134f morphological assessment of cell death by apoptosis, 120f neurons and astrocytes, cell response of, 127f oxidative damage by, 128f potential harmful effects of, 136 protective effects, 115 putative transporters, 56f ramification by, 133 stimulation pathway, 129 tissue flux, 55 toxicity mechanisms, 117 transporter(s), 55 uptake of, 55 UNICEF, 263 Unstable hemoglobinopathies, 163 Uridine diphosphate glucuronosyltransferase (UGT), 220 expression, 97 Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), 98 coding sequence, isoenzyme expression, 13 polymorphisms, 3, 13 dose-dependent genetic interaction, promoter, 18 polymorphism, 160 schematic of, 14 transcription, 59 UGT1A1/OATP2 genes, 74 Uridinediphosphoglucuronate (UDPGA), 57 Uridine diphosphoglucuronyltransferase (UDPGT), 69 US Kernicterus Registry, 153 US Preventive Services Task Force (USPSTF), 183, 245, 248 USPSTF See US Preventive Services Task Force (USPSTF) UV light See Ultraviolet (UV) light V Vascular cell adhesion molecule-1 (VCAM-1) signaling, 122 Vascular endothelial growth factor (VEGF), 30 285 VCAM-1 signaling See Vascular cell adhesion molecule-1 (VCAM-1) signaling VeCO measurements, 32 nonventilated preterm infants, 32 VEGF See Vascular endothelial growth factor (VEGF) Velocity-dependent hypertonia See Spasticity Velocity-sensitive hypertonia, 236 Very low birth weight (VLBW) infants, 99, 100, 105, 201 Vitamin K analogs (K3) provoke hemolysis in neonates with G6PD deficiency, 266t VLBW infants See Very low birth weight (VLBW) infants W Well-baby nursery, 175 World Health Organization (WHO), 263 X X chromosome, 158 Xenobiotic response element (XRE), 17 Xenobiotic substrates, 57 XRE See Xenobiotic response element (XRE) Z Zinc deuteroporphyrin IX bis glycol (ZnBG), 35 Zinc protoporphyrin (ZnPP), 35, 219 ZnBG See Zinc deuteroporphyrin IX bis glycol (ZnBG) ZnPP See Zinc protoporphyrin (ZnPP) ... the use of or inability to use the work, even if any of them has been advised of the possibility of such damages This limitation of liability shall apply to any claim or cause whatsoever whether... recommendation is of particular importance in connection with new or infrequently used drugs Care of the Jaundiced Neonate David K Stevenson, MD Harold K Faber Professor of Pediatrics Department of Pediatrics... time of publication However, in view of the possibility of human error or changes in medical sciences, neither the authors nor the publisher nor any other party who has been involved in the preparation