Special Feature : Epidemiological Strategies for Its Prevention through Systems-Based Approaches

Vinod K. Bhutani, MD, FAAP At a recent NIHCD-sponsored conference, key questions were raised about Lois H. Johnson, MD, FAAP kernicterus and the need for additional strategies for its prevention. These M. Jeffrey Maisels, MB, BCh, FAAP questions and an approach to their answers form the basis of this report. Thomas B. Newman, MD, MPH Journal of Perinatology (2004) 24, 650–662. doi:10.1038/sj.jp.7211152 Ciaran Phibbs, PhD Published online 15 July 2004 Ann R. Stark, MD, FAAP Marshalyn Yeargin-Allsopp, MD, APP

A. IS KERNICTERUS A MATTER OF PUBLIC HEALTH CONCERN? Available Evidence Kernicterus, thought to be due to severe hyperbilirubinemia, is an Kernicterus has long been recognized as the pathologic sequela of uncommon disorder with tragic consequences, especially when it affects severe hyperbilirubinemia. Although the condition is uncommon, the healthy term and near-term infants. Early identification, prevention and consequences are tragic, especially when it affects otherwise healthy treatment of severe hyperbilirubinemia should make kernicterus a term and near-term infants.1–5 Kernicterus has become uncommon preventable disease. However, national epidemiologic data are needed to because of effective screening for and prevention of Rh monitor any preventive strategies. Recommendations are provided to obtain incompatibility, a historically important cause, and the accessibility of prospective data on the prevalence and incidence of severe phototherapy to treat hyperbilirubinemia due to increased production hyperbilirubinemia and associate mortality and neurologic injury using and/or decreased elimination of bilirubin. Furthermore, adherence by standardized definitions, explore the clinical characteristics and root causes clinicians to the guidelines from the American Academy of of kernicterus in children identified in the Kernicterus Pilot Registry, (AAP) concerning management of was expected to identify and test an indicator for population surveillance, validating eliminate severe hyperbilirubinemia and prevent kernicterus.6,7 systems-based approaches to the management of newborn jaundice, and Little contemporary information is available on the incidence or explore the feasibility of using biologic or genetic markers to identify infants prevalence of kernicterus or its consequences. In the reports from the at risk for hyperbilirubinemia. Increased knowledge about the incidence Pilot Kernicterus Registry and the Northern California Kaiser and consequences of severe hyperbilirubinemia is essential to the planning, Permanente Medical Care Program (KPMCP) database, neonatal implementation and assessment of interventions to ensure that infants deaths due to kernicterus were ascertained from diagnostic codes on discharged as healthy from their birth hospitals have a safer transition to death certificates. Limitations of such observations include the home, avoiding morbidity due to hyperbilirubinemia and other disorders. retrospective design and possible under-reporting, delayed diagnosis, or errors in coding. For example, it is not feasible to estimate accurately a national incidence of kernicterus using the ICD-9 codes 773.4 and 747.7 for this diagnosis to query the HCUP database Department of Pediatrics(V.K.B.), University of Pennsylvania, Philadelphia, PA, USA; (Healthcare Cost and Utilization Project Agency for Healthcare Pennsylvania Hospital (L.H.J), University of Pennsylvania, Philadelphia, PA, USA; William Research and Quality, Rockville, MD; http://www.ahrq.gov/data/ Beaumont Hospital (M.J.M.), Royal Oak, MI, USA; Departments of Epidemiology and Biostatistics and Pediatrics (T.B.N.), University of California, San Francisco, CA, USA; Health Economics hcup/hcupnet.htm) because the accuracy for annual reports is ±70 Resource Center (C.P), Veterans Affairs Palo Alto Health Care System, Department of Health cases. That kernicterus occurs is evident from 125 cases of infants Research and Policy, and Center for Primary Care and Outcomes Research, Stanford University School of Medicine, Stanford, USA; Department of Newborn Medicine (A.R.S.), Brigham and who had been discharged as healthy from their birthing hospitals Women’s Hospital, Harvard Medical School, Boston, MA, USA; and National Center on Birth that were voluntarily reported from 1992 to 2002 to the Pilot Defects and Developmental Disabilities (M. Y.-A.), Centers for Disease Control and Prevention, Kernicterus Registry.1–5,8,9 In contrast, no cases of kernicterus in Atlanta, GA, USA. infants with cerebral palsy were found in the retrospective database of Presented in part at the NICHD Conference, Research on Prevention of Bilirubin-Induced Brain 10 Injury and Kernicterus-From Bench to Bedside, at Bethesda, Md, USA, June 2003. KPMCP during a similar time period (1991 to 1998). In addition, among these 111,009 infants in the KPMCP database, 11 (0.01%) Address correspondence and reprint requests to Vinod K. Bhutani, MD, FAAP, Center for Research on Reproduction and Women’s Health, 1315, BRB II/III, 421 Curie Blvd, University of developed total serum bilirubin (TSB) levels Z30 mg/dl, and none 10 Pennsylvania, Philadelphia, PA 19140, USA. of them apparently developed kernicterus. However, it is unclear

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whether all cases were identified, since TSB was not routinely hospitalization (predominantly for jaundice from 14 studies listed measured in all infants nor were these infants followed prospectively. in Table 2) range from 1.7 to 30.2 per 1000 live-births and The actual incidences of kernicterus or severe represent a total of 42,470 readmissions for 1,532,924 live-births hyperbilirubinemia are not available because neither is a (27.7 per 1000) reported from 1988 to 1998.16 A disparity exists reportable condition. The incidence of severe hyperbilirubinemia between term and near-term infants in the rates for readmission has been estimated (Table 1) from a prospective study conducted in for jaundice. In a report of all California births from 1991 to 1999, the 1960s,11 a retrospective observational study of a population C. Phibbs (personal communication) reported that near-term cared for in the 1990s,12 and additional prospective data from infants were consistently 6.4 to 6.6% of all well baby births (not recent reports.13–15 Rates of readmission after the birth admitted for neonatal intensive care), but their rate of readmission for treatment of jaundice was two- to three-fold higher than term infants (Figure 1). Table 1 Proposed Definitions for Severity of Hyperbilirubinemia and Its Estimated Occurrence Research Recommendation TSB level (mg/dl)* Percentile at Proposed Estimated Obtain data on prevalence, incidence, and mortality of severe >72 hours agew definitions occurrencez hyperbilirubinemia and associated neurologic injury, including kernicterus. Z17.0 (291 mmol/L) >95th Significant B1:10 Z20.0 (342 mmol/L) >99th Severe B1:70 Z25.0 (427 mmol/L) >99.9th Extreme B1:700 th B Z30.0 (513 mmol/L) >99.99 Hazardous 1:10,000 B. WHAT IS THE RELATIONSHIP BETWEEN SEVERE *TSB ¼ total serum bilirubin. HYPERBILIRUBINEMIA AND KERNICTERUS? w Percentiles are approximate. Available Evidence zOccurrence is estimated in screened and treated infants based on data reported in Bhutani et al.,13 Stevenson et al.,14 Martinez et al.15 and Khurana et al.16 precise data A spectrum of neuronal injury associated with hyperbilirubinemia cannot be compiled because of differences in methodologies, patient selection, and is known as bilirubin-induced neurologic dysfunction (BIND). The thresholds for intervention). spectrum ranges from subtle or suspicious extrapyramidal or other

Table 2 Reported Rates of Readmission for Babies Discharged as Healthy 1988 to 1998

Study (reference) State Observation Study population Total live- Total Incidence per years births readmitted 1000 live-births

Edmonson et al. JAMA 1997;278:299. WI 1991 to 94 Statewide, nested 120,290 210 1.7 Danielsen et al. CA 1992 Statewide, linked to birth 313,748 8656 27.6 records Pediatrics 2000;106:31. CA 1994 Statewide 301,721 7745 25.7 CA 1995 Statewide 287,371 8677 30.2 Geiger et al. Paediatr Perinat Epidemiol CA 1992 to 1994 Case control for Jaundice 68,793 156 2.0 2001;15:352. Behram et al. South Med J 1998;91:541 VA 1994 to 1995 Community-based 2,563 74 29 Soskolne et al. Arch Pediatr Adolesc MI 1992 Private urban, 4,496 117 26 Med;150:373. community Kotagal et al. JAMA 1999;282:1150. OH 1991 Medicaid patients 102,678 1951 21 OH 1995 17 Grupp-Phelan et al. Arch Pediatr Adolesc WA 1991 to 1995 Statewide 348,495 7388 21 Med 1999;153:1283 Liu et al. JAMA 1997;278:293 WA 1991 to 1994 Statewide, linked to birth 310,578 6444 20 records Radmacher et al. J Ky Med Assoc 2001;99:147 KY 1994 to 1998 Hospital-based 21,628 414 19 Maisels et al. Pediatrics 1997;100:72 MI 1988 to 1994 Private, suburban 29,934 247 8 community Brown et al. J Perinat Med 1999;27:263. NY 1995 Metropolitan city 30, 884 391 12.7

Composite data for all reports 1988 to 1998 1,532,924 42,470 27.7

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35

30

25

20

15

10

5

Rates of readmission per 1000 Babies 0 1991 1992 1993 1994 1995 1996 1997 1998 1999 Calendar Year Figure 1. Rate of readmission for well babies for jaundice treatment in California (1991 to 1998) (California birth certificates were linked to the discharge abstracts for the birth hospitalization and readmission to identify the term and near-term well baby deliveries, and to separate readmissions for treatment of jaundice from those due to other causes.); data are presented for all well babies (E) and separated as term (K) and near-term infants (m). manifestations to acute encephalopathy and chronic posticteric Research Recommendations sequelae, although some of the signs are controversial. 1. Standardize definitions of severe hyperbilirubinemia, BIND, Acute brain injury induced by bilirubin is associated with one or acute bilirubin encephalopathy, kernicterus. Uniform terminol- more posticteric sequelae in survivors. These are: (1) a movement ogy is needed to compare databases and examine outcomes. disorder consisting of athetosis, , choreoathetosis, but also 2. Determine the prevalence and incidence of severe hyperbilir- including spasticity and , (2) auditory dysfunction ubinemia and kernicterus to estimate the risk of kernicterus at consisting of deafness or hearing loss and auditory neuropathy specific levels of TSB for term and near-term infants. or dys-synchrony, (3) oculomotor impairments, especially of 3. Determine whether making a specific TSB level a reportable upward gaze, and (4) dental enamel hypoplasia of the condition will accomplish this purpose. deciduous teeth.4,17 4. Develop a case–control study of adequate size to delineate the Even though TSB is an important risk factor, bilirubin-induced role of bilirubin and other factors in the development of brain injury and kernicterus cannot be defined on the basis of TSB kernicterus. alone. Factors including the albumin binding of bilirubin, 5. Define population-based standards to help predict severe hemolysis, gestational age, and genetic vulnerability modify the hyperbilirubinemia or, as important, the absence of risk based risk of kernicterus in an individual infant.5,18 However, there is a on predefined peak TSB levels. paucity of studies that evaluate the impact of these risk factors on the incidence of BIND or the occurrence of subtle sequelae or transient neurologic abnormalities. C. WHAT ARE THE CHARACTERISTICS AND THE ROOT Contemporary prospective population-based studies that describe CAUSES OF RECENT CASES OF KERNICTERUS? the natural history of hyperbilirubinemia are unavailable; data are Preliminary Data limited to studies before the advent of phototherapy. In addition, no Preliminary data were presented on 125 of the 142 cases in the prospective studies relate the incidence of kernicterus associated United States (including uniformed services) from the Pilot with specific TSB values.19 Thus, characterizing the risk of brain Kernicterus Registry (1992 to October 1, 2002). These infants were injury at specific levels of TSB is problematic. Furthermore, the safe discharged as healthy and were included for analysis if they level of TSB, below which BIND does not occur in otherwise exhibited clinical signs of acute bilirubin encephalopathy and/or healthy jaundiced infants, is not known. A standard definition of posticteric sequelae, regardless of TSB level and comorbidities kernicterus in term and near-term infants is needed for purposes of (Appendix). Most cases (about 50%) were voluntarily reported by research. This could include a threshold value for TSB, for parents or anonymously by physicians or nurses. One limitation of example, Z20 mg/dl, plus abnormalities of muscle tone on the registry is that these cases of kernicterus likely represent only a neurological examination, auditory neurophysiological testing, and portion of affected children. Another limitation is that the magnetic resonance imaging. population of newborns at risk because of severe

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hyperbilirubinemia is unknown, so that estimates of incidence and Research Recommendations prevalence are unreliable. On the other hand, consistent 1. Conduct a comprehensive analysis of Registry cases to identify observations from the registry provide the basis of common characteristics, delineate the lapses in care that may recommendations for safe practices in order to prevent severe have contributed to the occurrence of kernicterus, and hyperbilirubinemia and kernicterus. determine the sentinel events that may have predicted the Characteristics of the population reported to the Pilot occurrence of kernicterus. Kernicterus Registry (and individually listed in Appendix) included 2. Test the hypothesis that severe hyperbilirubinemia or 84 male and 38 female cases, a racial distribution of White kernicterus that affects babies discharged as healthy can be (58.4%), Black (26.4%), Hispanic (8.8%), Asian (6.4%) and the predicted before discharge. mean birth weight of 3281 g (range: 2015 to 4730). The mean 3. Assess the feasibility of a national reporting system and database gestational age was 38 weeks (range: 35 to 42.5). The etiology of for cases of pre-defined severe hyperbilirubinemia and hyperbilirubinemia in these infants, as evaluated upon readmission kernicterus. that was usually before 10 days of age, is listed in Table 3. All 4. Assess the feasibility of developing a systematic centralized showed an excessive estimated rate of TSB rise (>0.20 mg/dl/hour) review process, including root cause analysis, for prospective from birth to readmission. Analysis of these cases suggests the reported cases of severe hyperbilirubinemia that can be following root causes:4,5 (a) loss or lack of concern by clinicians subsequently used to develop targeted education and systems regarding the neurotoxic potential of bilirubin, (b) limitations on improvements. visual recognition of jaundice as an index to initiate further 5. Develop measurement tools to assess whether a centralized evaluation or estimate severity, (c) failure to recognize the severity review process and interventions improve outcome. of hyperbilirubinemia at a specific age in hours; (d) failure to ensure appropriate follow-up 1 to 2 days after early discharge (24 to 72 hours of age); (e) delay in intensive or timely interventions before discharge or at readmission. More extensive analysis is D. WHAT SHOULD THE TARGET INDICATOR BE FOR needed of cases of kernicterus and predefined levels of severe PUBLIC HEALTH SURVEILLANCE OF KERNICTERUS AND/ hyperbilirubinemia (‘‘close calls’’) in order to better assess the OR HYPERBILIRUBINEMIA? performance of health-care providers and help address Institute of At present, severe hyperbilirubinemia remains the most plausible Medicine concerns, including patient (and family) centered care, surrogate indicator for kernicterus even though the risk of quality of care, and patient safety. kernicterus at specific TSB ranges is estimated by clinical consensus rather than evidence-based criteria (Table 4). Surveillance for severe hyperbilirubinemia has distinct advantages. It describes an at-risk population, similar to identifying Table 3 Contributory Causes for Severe Hyperbilirubinemia and a population with hypertension regardless of its cause or its clinical Kernicterus Determined at Subsequent Readmission (Preliminary outcome. TSB results are immediately available and objective, and Data Voluntarily Reported to the Pilot Kernicterus Registry) can be reported rapidly. The inclusion of all cases, rather than just those with sequelae, would allow study of the risk of kernicterus in Major contributory Postnatal age at readmission (n ¼ 116) cause of a population with hyperbilirubinemia, as well as study of the Hyperbilirubinemia frequency and effects of any intervention. The TSB level at which r3 days 4 to 7 days >7 days cases might become reportable can be adjusted up or down based N ¼ 8 N ¼ 85 N ¼ 23 on risk and benefits. The immediacy and greater frequency of this outcome also make it potentially more useful for quality Hemolysis 0% 20% 20.7% improvement efforts. Any initiative to begin surveillance for severe G6PD deficiency 25% 24.7% 12.5% hyperbilirubinemia should be accompanied by efforts to improve Idiopathic 50% 31.8% 50.0% standardization and minimize inter-laboratory variability.20 Birth trauma 0% 17.6% 12.5% In general, there are at least four possible targets for public Other 25% 5.9% 8.3% health surveillance related to kernicterus (Table 5). The first Hemolysis was due to ABO or minor blood group incompatibility, extensive bruising, consideration is kernicterus itself. This disorder is the focus of cephalhematoma, hereditary spherocytosis, etc. Other causes include birth trauma, sepsis, galactosemia, Crigler-Najjar syndrome. Idiopathic group represents those infants current concern. However, the diagnosis may be delayed or under- in whom no contributory cause could be ascertained following comprehensive clinical reported. In addition, occurrences of kernicterus may be too evaluation and follow-up. Several infants had additional or multiple factors such as infrequent (and too late) to provide feedback to health-care systems dehydration and/or excessive weight loss that would have contributed to the excessive bilirubin load. and providers that might reduce the risk of future cases. Surveillance for kernicterus would not capture other adverse effects

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Recommendations Table 4 Readmission TSB Levels in 118 of the 125 Cases of Infants with Kernicterus Discharged as Healthy from Newborn Nurseries 1. Identify an appropriate target indicator(s) for surveillance based (Preliminary Report from the Pilot Kernicterus Registry) These are upon advantages and disadvantages (Table 5). listed along with current opinions regarding the potential risk of kernicterus in untreated infants with severe hyperbilirubinemia E. HAVE SYSTEMS-BASED APPROACHES FOR THE MAN- TSB levels (mg/dl) Number of cases Opinions of risk in untreated reported with infants AGEMENT OF NEWBORN JAUNDICE BEEN VALIDATED? kernicterus* Available Evidence 2–4 5 (n ¼ 116) Because of the concern for the reemergence of kernicterus, AAP and JCAHO8 recommend a universal systematic approach to the < 20.0 0 Risk unlikely and unproven. management of newborn jaundice, with the aim of reducing the Possible risk of subtle effects. incidence of severe hyperbilirubinemia8,9,21–23 and kernicterus. Relationship of actual TSB level This involves using clinical risk factors analysis and/or with onset of injury is often unclear measurement of predischarge TSB levels plotted an hour-specific 20.0 to 24.9 11 Risk unlikely but unproven (infants nomogram to target appropriate follow-up and intervention. No with other factors may be vulnerable). Cases have been prospective studies have compared or confirmed the effectiveness of reported of kernicterus associated such approaches. Whether a public health campaign to increase with these levels parental and provider awareness of jaundice and its potential 25.0 to 29.9 15 High level of concern although consequences would reduce adverse outcomes is also unknown. actual risk is unknown. Some infants may not manifest acute Research Recommendations neurological injury 1. Evaluate the recommendations for systems-based approaches Z30.0 90 Risk is increasingly likely although for the prevention and management of severe hyperbilirubine- actual risk is unknown. Some mia. Approaches based on risk factors for severe hyperbilir- infants may be protected from ubinemia or predischarge hour-specific TSB measurements neurologic injury with expeditious should be prospectively validated for safety, costeffectiveness, and efficient interventions and applicability to ethnically and racially diverse populations. *Based on peak measured TSB values (these measured values may not reflect the peak 2. Assess whether systematic prediction of severe neonatal hyperbilirubinemia levels experienced by infants because of lack of serial hyperbilirubinemia prevents kernicterus in a cost-effective, measurements or potential lowering of TSB levels concurrent to onset of acute bilirubin injury). practical and safe manner. 3. Evaluate the epidemiologic impact of a public health campaign to reduce adverse outcomes of severe neonatal hyperbilirubi- nemia. of hyperbilirubinemia, including less typical sequelae and complications of exchange transfusion. Like kernicterus, cerebral palsy is a highly relevant and F. ARE THERE BIOLOGICAL OR GENETIC MARKERS THAT clinically significant indicator. The diagnosis of cerebral palsy is CAN BE USED TO BETTER DEFINE INFANTS AT RISK FOR already a matter of public health concern. Surveillance for cerebral SEVERE HYPERBILIRUBINEMIA? palsy would allow studies of risk in children with different TSB Insufficient Evidence levels, including those in whom TSB was never measured. However, The genetic contribution to neonatal hyperbilirubinemia due to the proportion of cerebral palsy due to kernicterus is not known, disorders of hepatic bilirubin conjugation and to the pathogenesis surveillance for cerebral palsy may be insensitive to changes in of neuronal cell injury caused by hyperbilirubinemia needs further kernicterus incidence, and feedback to providers would be investigation.24,25 For example, early jaundice is greater in nonspecific and delayed. newborns homozygous for the polymorphism associated with Yet another surveillance strategy could be to monitor rates of Gilbert syndrome compared to those with the normal sequence or readmission for treatment of hyperbilirubinemia or use of home heterozygous for the mutation.26 The incidence of phototherapy. Concomitant with incidence of severe hyperbilirubinemia is also increased in infants who have the hyperbilirubinemia, these offer useful indices of occurrence and Gilbert polymorphism and glucose-6-phosphatase dehydrogenase outcome. On the other hand, interpretation is limited because (G6PD) deficiency.24 An investigation of microarray gene intervention thresholds for severe hyperbilirubinemia have not been expression of hereditary disorders of unconjugated yet standardized. hyperbilirubinemia such as Gilbert, Arias, and Crigler-Najjar

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Table 5 Potential Targets for Surveillance of BIND

Indicator or Clinical relevance Age at identification Potential limitations when used as a surveillance target surrogate

Kernicterus Index disease Usually during infancy and Clinical criteria not yet standardized childhood Often under-reported Often undiagnosed Other manifestations of BIND missed Long interval between change in neonatal practices to outcome Medicolegal concerns may delay or inhibit identification

Cerebral palsy Includes cases of Usually during infancy Dependent on identification of athetoid/dystonic features (existing national Kernicterus public health issue) Other manifestations of BIND not identified Causality hindered if there are no neonatal measures of hyperbilirubinemia Concerns of long interval between change in neonatal practices to outcome

Readmission for At-risk population During neonatal age Requires standardized guidelines for severe hyperbilirubinemia jaundice treatment (existing public health issue) Requires standardized guidelines and implementation for interventions Requires linkage to birth records Requires compliance by clinicians and families

Severe At-risk population During neonatal age Requires bilirubin measurement and follow-up for all infants hyperbilirubinemia Requires accurate, standardized and centralized reporting by laboratories Allows for objective and non biased reporting from laboratories Requires follow-up of high-risk infants for signs of BIND

syndromes may elucidate possible coinheritance with G6PD encephalopathy, and chronic posticteric sequelae is a matter of deficiency, beta-thalassemia, and hereditary spherocytosis and public health and societal concern. Accurate data on the incidence identify infants at increased risk of severe hyperbilirubinemia.27–29 of severe neonatal hyperbilirubinemia and associated adverse At this stage, it is too early to know whether genetic epidemiology outcomes are fundamental to the planning, implementation, and of hyperbilirubinemia would contribute to the prevention of BIND. assessment of interventions, including public policy and educational programs, to prevent adverse outcomes. Research Recommendation Explore the feasibility of using diagnostic oligonucleotide microarrays for the known mutations of target genes to identify infants at increased risk of severe hyperbilirubinemia or those who have sustained kernicterus. References 1. Johnson L. Hyperbilirubinemia in the term infant: when to worry, when to treat. NY State J Med 1991;91:483–9. CONCLUSION 2. Brown AK, Johnson L. Loss of concern about jaundice and the reemergence of kernicterus in full-term infants in the era of managed care. In: Fanaroff Infants discharged as healthy from their birth hospitals should AA, Klaus MH editors. The Year Book of Neonatal and Perinatal Medicine. have a safe transition to home, avoiding morbidity due to jaundice Philadelphia: Mosby Yearbook; 1996, p. xvii–viii. and other disorders. Prevention of readmission for severe 3. Johnson L, Brown AK. A pilot registry for acute and chronic kernicterus in hyperbilirubinemia in otherwise healthy infants, acute bilirubin term and near-term infants. Pediatrics Suppl 1999;104:736.

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4. Johnson LH, Bhutani VK, Brown AK. System-based approach to manage- 18. Poland RL. Preventing kernicterus: almost there. J Pediatr ment of neonatal jaundice and prevention of kernicterus. J Pediatr 2002;140(4):385–6. 2002;140:396–403. 19. Ip S, Glicken S, Kulig J, O’Brien R, Sege R. Management of Neonatal 5. AAP Subcommittee on Neonatal Hyperbilirubinemia Neonatal jaundice and Hyperbilirubinemia. Summary, Evidence Report/Technology Assessment. kernicterus Pediatrics 2001;108:763–5. Number 65. AHRQ Publication No. 03 E005, March 2002. Agency for 6. American Academy of Pediatrics Practice Parameter: Management of Healthcare Research and Quality, Rockville, MD. hyperbilirubinemia in the healthy term newborns. Pediatrics 1994;94: 20. Vreman HJ, Verter J, Stevenson DK. Interlaboratory variability of bilirubin 558–65. measurements. Clin Chem. 1996;42:869–73. 7. From the Centers for Disease Control and Prevention. Kernicterus in full- 21. Sheridan SE. Kernicterus parents’ group. J Pediatr 2002;141:597. term infantsFUnited States, 1994–1998. JAMA 2001;286(18):299–300. 22. Bhutani VK, Johnson LH. Newborn jaundice and kernicterus – health and 8. Sentinel Event Alert: KI Threatens Healthy Babies. www.JACHO.org.Issue 18, societal perspectives. Indian J Pediatr 2003;70:407–16. April, 9-11-2000. 23. Bhutani VK, Johnson LH, Keren R. Diagnosis and management of 9. Sheridan SE. Testimony at the First National Summit on Medical Errors hyperbilirubinemia in the term neonate: for a safer first week. Pediatr Clin and Patient Safety Research on 9-11-2000. AHRQ.gov. http://ahrq.gov// North Am. (in press). news/press/pr2000/summitpr.htm. 24. Watchko JF, Daood MJ, Biniwale M. Understanding neonatal hyperbilir- 10. Newman TB, Liljestrand P, Escobar GJ. Infants with bilirubin levels of ubinemia in the era of genomics. Semin Neonatol 2002;7:143–52. 30 mg/dL or more in a large managed care organization. Pediatrics 25. Dennery PA, Seidman DS, Stevenson DK. Neonatal hyperbilirubinemia. N 2003;111:1303–11. Engl J Med 2001;344:581–90. 11. Newman TB, Klebanoff MA. Neonatal hyperbilirubinemia and long-term 26. Bancroft JD, Kreamer B, Gourley GR. Gilbert syndrome accelerates outcome: another look at the Collaborative Perinatal Project. Pediatrics development of neonatal jaundice. J Pediatr 1998;132:656–60. 1993;92:651–7. 27. Beutler E, Gelbart T, Demina A. Racial variability in the UDP- 12. Newman TB, Xiong B, Gonzales VM, Escobar GJ. Prediction and prevention glucuronosyltransferase 1 (UGT1A1) promoter: a balanced polymorphism of extreme neonatal hyperbilirubinemia in a mature health maintenance for regulation of bilirubin metabolism? Proc Natl Acad Sci USA organization Arch Pediatr Adolesc Med. 2000;154:1140–7. 1998;95:8170–4. 13. Bhutani VK, Johnson LH, Sivieri EM. Predictive ability of a predischarge 28. Bosma PJ, Chowdhury JR, Bakker C, et al. The genetic basis of the reduced hour-specific serum bilirubin for subsequent significant hyperbilirubinemia expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert’s in healthy term and near-term newborns. Pediatrics 1999;103:6–14. syndrome. N Engl J Med 1995;333:1171–5. 14. Stevenson DK, Fanaroff AA, Maisels MJ, et al. Prediction of hyperbilir- 29. Kaplan M, Renbaum P, Levy-Lahad E, Hammerman C, Lahad A, Beutler E. ubinemia in near-term and term infants Pediatrics. 2001;108:31–9. Gilbert syndrome and glucose-6-phosphate dehydrogenase deficiency: a 15. Martinez JC, Garcia HO, Otheguy LE, Drummond GS, Kappas A. Control of dose-dependent genetic interaction crucial to neonatal hyperbilirubinemia. severe hyperbilirubinemia in full term newborns with the inhibitor of Proc Natl Acad Sci USA 1997;94:12128–32. bilirubin production Sn-mesoporphyrin. Pediatrics 1999;103:1–5. 16. Khurana E, Bhutani VK, Dworanczyk R, Mancini T, Johnson LH. Readmission rates of healthy newborns for severe hyperbilirubinemia and APPENDIX A Table A1 summarizes the data from Pilot intensive phototherapy in USA. Abstract. Pediatr Res 2003;54:1756A. 17. Volpe JJ. Bilirubin and brain injury. In: Neurology of the Newborn. 1st ed, Kernicterus Registry. 1981; 2nd ed 1987; 3rd ed 1995; 4th ed 2001.

656 Journal of Perinatology 2004; 24:650–662 ora fPerinatology of Journal Kernicterus on Perspectives Systems-Based and Epidemiologic Table A1 Clinical Characteristics of 125 from 142 Infants with Kernicterus Discharged as Healthy (Pilot Kernicterus Registry)

Source/ Birth BW GA Sex/race Discharge Readmit Readmit Peak Acute Ex Tx Photo Likely cause Follow- Icteric Comments code year (g) (weeks) day age TSB TSB BIND Rx up sequelae (day)

C-001 1994 3260 36 m/W 0.5 4.0 35.0 35.0 Advanced Yes Yes Idiopathic Yes Moderate ABO Coombs neg 04 24:650–662 2004; C-002 1993 3725 39 m/A 0.5 4.0 40.2 40.2 Advanced Yes Yes Hemolysis Yes Severe ABO Coombs pos L-003 1988 3785 39 unk/H 0.5 4.0 45.0 45.0 Advanced Yes Yes Idiopathic Yes Severe ExTx delayed 12 hours. (Jehovah Witness) M-004 1996 3000 36 f/B 0.5 4.5 40.9 40.9 Advanced Yes Yes Idiopathic Yes Severe Hct 45%, wt loss M-005 1997 3884 38 m/W 0.5 5.0 46.0 46.0 Advanced Yes Yes Hemolysis Yes Severe ABO Coombs neg, jaundice <24 hours age, Na 149 mEq/L M-006 1993 3856 41 f/W 1.0 2.5 22.4 22.4 Advanced No Yes Idiopathic Yes Severe Dehydration, Na 153 mEq/l L-007 1995 3544 39 f/A 1.0 3.0 27.8 27.8 Subtle Yes Yes Infection Yes None Urosepsis (E. coli), MRI (at day 5): inc. globus pallidus signal M-008 1995 2920 37 m/B 1.0 3.0 33.0 36.7 Advanced No Yes G6PD Yes Severe Hct 40%, Presumed sepsis C/M-009 1990 2015 36 f/W 1.0 3.5 41.8 41.8 Advanced Yes Yes Idiopathic Yes Severe Plethora, ABO Coombs neg M-010 1998 3629 39 f/W 1.0 3.5 52.0 52.0 Advanced Yes Yes Idiopathic Yes Severe Family history, jaundice <24 hours age L/C-011 1995 2614 39 f/B 1.0 4.0 33.0 33.0 Moderate No Yes Idiopathic Yes Moderate Hct 43% P-012 1999 4026 39 m/W 1.0 4.0 39.0 45.0 Advanced Yes Yes Birth trauma Yes Severe Precipitous labor, family history of jaundice P-013 2002 3714 40 m/W 1.0 4.0 44.8 44.8 Advanced Yes Yes Hemolysis Yes Severe Congenital spherocytosis, Hct 27%, peak TSB 49 mg/dl P-014 2000 4200 35 f/W 1.0 5.0 27.0 31.5 Subtle No Yes Birth trauma Yes Severe Plethora at birth L/C-015 1994 3489 39 m/W 1.0 5.0 30.6 30.6 Advanced Yes Yes Idiopathic Yes None Hct 38%, Albumin before ExTx L-016 1996 2637 39 m/H 1.0 5.0 34.8 34.8 Moderate Yes Yes Idiopathic Yes None Hct 48% M-017 1996 3450 39 f/H 1.0 5.0 37.0 46.0 Advanced Yes Yes Hemolysis Yes Severe ABO Coombs pos, jaundice <24 hours age L-018 1993 3147 39 m/B 1.0 5.0 42.5 42.5 Advanced Yes Yes G6PD Yes Severe Mild anemia, no evident hemolysis M-019 1992 3685 39 m/B 1.0 5.5 46.8 46.8 Advanced No Yes G6PD Died Died Moribund on readmission C-020 1995 3130 39 m/H 1.0 6.0 28.5 28.5 Advanced Yes Yes Hemolysis Yes Severe ABO, Coombs unk, Hct 42% M-021 1997 3680 37 m/W 1.0 6.0 29.3 32.5 Advanced Yes Yes Birth trauma Yes Severe 13% wt loss at day 6, Hct 44% M-022 1994 3048 35 f/W 1.0 6.0 31.0 31.0 Advanced No Yes Birth trauma Yes Severe 11% wt loss at day 6 htn tal. et Bhutani P-023 2002 2745 38 f/W 1.0 6.0 46.2 46.2 Advanced Yes Yes Hemolysis No Severe ABO Coombs pos, jaundice <24 hours age P-024 1993 3487 37 m/H 1.0 8.5 41.3 53.9 Advanced Yes Yes Birth trauma Yes Severe Hct 43% P-025 1994 3090 37 m/W 1.0 12.0 41.0 41.0 Advanced Yes Yes Idiopathic Yes Severe ABO Coombs neg 17% wt loss

657 (day 12) 658 Table A1 (Continued)

Source/ Birth BW GA Sex/race Discharge Readmit Readmit Peak Acute Ex Tx Photo Likely cause Follow- Icteric Comments al. et Bhutani code year (g) (weeks) day age TSB TSB BIND Rx up sequelae (day) P-026 1997 3433 39 m/W 1.0 None None None Moderate No No Idiopathic Yes Moderate ABO, Coombs: unk, prolonged jaundice (>8 weeks) M-027 1993 3355 37 f/W 1.0 None Not None Advanced No No Hemolysis Yes Severe ABO Coombs: unk,16% wt. loss done d15, arching (at age 1 week), Peak TSB unk C-028 1999 3720 40.5 m/B 1.5 3.0 21.4 21.4 Moderate No Yes Idiopathic Lost UNK Lost to follow-up C-029 1991 2865 39 m/H 1.5 3.0 38.4 38.4 Advanced Yes Yes G6PD No Severe Hct 40%, abnormal RBC smear M-030 1991 3374 39 f/W 1.5 3.0 38.4 44.5 Advanced Yes Yes Idiopathic Yes Severe Hct 52%, father with Gilbert’s syndrome C-031 1998 3600 37 f/W 1.5 3.5 38.5 38.5 Subtle Yes Yes Idiopathic <1 yr Moderate ABO Coombs neg, Hct 64% C-032 2001 3994 38 m/W 1.5 4.0 22.0 27.0 Moderate Yes Yes Idiopathic Yes None 14% wt loss at day 4, Na 152 mEq/l M-033 1999 3510 39 m/B 1.5 4.0 33.6 37.2 Moderate No Yes Hemolysis Yes Severe ABO Coombs neg, Hct 41% P-034 2001 3468 38.5 m/W 1.5 4.0 38.0 41.0 Advanced Yes Yes Birth trauma Yes Severe Jaundice noted at age 24 hours L-035 2000 3203 38 f/H 1.5 3.0 46.9 46.9 Advanced Yes Yes Idiopathic Yes None Sibling treated for jaundice P-036 2001 3572 39.6 m/W 1.5 4.5 28.3 28.3 Subtle No Yes Birth trauma Yes Severe Family (sibling) history of jaundice M/L-037 1991 2665 36 f/B 1.5 4.5 37.0 39.5 Advanced Yes Yes G6PD Yes Severe Hemolysis trigger unk, Hct 28% M-038 1996 2892 36 f/W 1.5 5.0 27.0 28.7 Moderate No Yes Birth trauma Yes Severe Partially treated perinatal sepsis, Hct 50%, Na 150 mEq/l M-039 1997 3985 39 f/A 1.5 5.0 30.4 37.8 Advanced YES Yes Birth trauma Yes Moderate ABO Coombs neg,15% wt loss at

day 5, Na 152 mEq/l Kernicterus on Perspectives Systems-Based and Epidemiologic C-040 1996 2500 38 m/B 1.5 5.0 41.3 41.3 Advanced Yes Yes G6PD Died Severe Urosepsis, Hct 22%, died at 6 months M-041 1993 2925 38 m/B 1.5 5.0 45.9 45.9 Advanced Yes Yes G6PD Died Died Incomplete evaluation of ora fPerinatology of Journal hyperbilirubinemia L-042 1994 2840 37 m/A 1.5 5.0 49.2 49.2 Advanced Yes Yes G6PD Died Died 13.6% wt loss at day 5, neutropenia, no hemolysis M-043 2000 3180 39 m/W 1.5 5.0 59.9 59.9 Moderate Yes Yes Hemolysis Yes Severe ABO, Coombs pos, jaundice at age 9 hours, wt loss >20% M-044 1992 2380 36 f/A 1.5 5.5 32.0 32.0 Advanced Yes Yes Birth trauma Yes Severe 13% wt loss at day 5.5, Plethora, Hct 64% 04 24:650–662 2004; M-045 1995 2863 37 m/W 1.5 5.5 34.6 34.6 Advanced No Yes Hemolysis Yes Severe ABO Coombs: unk, otitis media C-046 1997 3650 38 m/A 1.5 6.0 25.6 25.6 Advanced Yes Yes G6PD Yes None Albumin before exchange, Hct 50%, Na 154 mEq/l M-047 2001 3310 36 m/H 1.5 6.0 33.5 33.5 Subtle Yes Yes Idiopathic Yes Severe Bruising, Hct 42% ora fPerinatology of Journal Kernicterus on Perspectives Systems-Based and Epidemiologic Table A1 (Continued)

Source/ Birth BW GA Sex/race Discharge Readmit Readmit Peak Acute Ex Tx Photo Likely cause Follow- Icteric Comments code year (g) (weeks) day age TSB TSB BIND Rx up sequelae (day)

L-048 1995 3400 41 m/B 1.5 6.0 41.0 41.0 Advanced Yes Yes G6PD Yes Severe Concurrent sepsis (E. coli) 04 24:650–662 2004; C-049 1996 4280 39 m/A 1.5 6.0 45.7 45.7 Advanced Yes Yes G6PD Yes Moderate Hemolysis trigger: mothball exposure L-050 1988 unk 39 unk/B 1.5 7.0 24.0 28.0 Advanced Yes Yes G6PD Yes Severe Direct bilirubin 9 mg/dl at day 7 P-051 2002 3057 38.5 m/W 1.5 7 31.0 41.0 Subtle No Yes Hemolysis Yes Moderate Wt loss: 15%, ABO, Coombs pos P-052 2000 3317 36 m/W 1.5 7.0 35.0 35.0 Advanced Yes Yes Hemolysis Yes None Plethora, 17% wt loss at day 7.0 C-053 1994 4455 41 m/W 1.5 7.0 42.0 42.0 Advanced Yes Yes Idiopathic Lost Severe Follow-up incomplete M-054 1990 2608 36 m/B 1.5 8.0 33.7 36.4 Advanced Yes Yes Idiopathic Yes Severe Hct 43% P-055 1989 4224 38 m/W 1.5 8.5 37.0 39.0 Moderate Yes Yes Idiopathic Yes Severe Seen by MD at day 7.5, no TSB done M-056 1995 2700 36 m/B 1.5 10.0 32.5 32.5 Advanced Yes Yes Idiopathic Yes Severe Hct 41% C-057 1996 3150 36 m/W 1.5 11.0 40.0 40.0 Advanced Yes Yes Hemolysis Yes Severe Hct 22%, abnormal RBC morphology, hemolysis cause unk. P-058 1997 3033 36.5 m/W 1.5 13.0 25.0 27.7 Advanced No Yes Hemolysis Yes Severe Hct 18%, abnormal RBC morphology M-059 2002 3199 37 m/W 1.5 19.0 44.7 44.7 Advanced Yes Yes Idiopathic Yes Severe Hct 43%, direct bilirubin 1.7 mg/dl M-060 1994 3062 37 m/W 1.5 None 31.6 31.6 Moderate No Yes Hemolysis Yes Severe ABO Coombs pos, home phototherapy day 4 for TSB 31.6 mg/dl P-061 2000 2951 38 f/W 1.5 None Not None Subtle No No Birth trauma Yes Severe First office visit at d12 done (TSB ¼ 13 mg/dl), peak TSB Unk. M-062 2001 2715 37.5 f/B 2.0 3.5 35.0 38.4 Advanced Yes Yes Hemolysis Yes Severe ABO Coombs pos, Hct 31%, retic 18%, Bacteremia g+cocci bacillus species M-063 2000 2438 36 f/W 2.0 3.5 35.4 35.4 Advanced No Yes Idiopathic Died Died Plethora, bruising M-064 1999 3626 38 m/B 2.0 3.5 39.0 44.0 Moderate Yes Yes G6PD No Severe 9% wt loss at day 3.5, Hct 50% M-065 2001 3260 36 m/B 2.0 4.0 33.0 34.0 Subtle Yes Yes Idiopathic Yes Severe ABO Coombs negative, IDM al. et Bhutani M-066 1984 2850 36.5 m/W 2.0 4.0 33.9 39.8 Advanced Yes Yes Birth trauma Yes Moderate Hct 53%, family (sibling) history of jaundice M-067 1992 2825 37.5 m/B 2.0 4.0 34.5 34.5 Advanced No Yes Idiopathic Yes Severe Hct 45% C-068 1995 3459 39 m/B 2.0 4.0 39.2 39.2 Advanced Yes Yes G6PD Yes Severe Neutropenia, presumed sepsis, 659 Hct 38% 660 Table A1 (Continued)

Source/ Birth BW GA Sex/race Discharge Readmit Readmit Peak Acute Ex Tx Photo Likely cause Follow- Icteric Comments al. et Bhutani code year (g) (weeks) day age TSB TSB BIND Rx up sequelae (day) M-069 1993 2625 40 M/B 2.0 4.0 44.2 46.0 Advanced Yes Yes G6PD Yes Severe Hct 45%, hemolytic trigger: mothball exposure L-070 1992 3400 39 m/H 2.0 4.0 50.1 50.1 Advanced Yes Yes G6PD Yes Severe Sepsis (E. coli) C/L-071 2002 2609 40 m/B 2.0 4.5 31.7 31.7 Advanced No Yes G6PD Died Died 9% wt loss at day 4.0, Hct 34% P-072 2002 3402 38 m/W 2.0 4.5 38.0 38.0 Advanced Yes Yes Idiopathic Yes Severe Jaundice noted before 24 hours age L-073 1989 3150 39 m/W 2.0 5.0 28.7 29.5 Subtle Yes Yes Hemolysis Yes None ABO Coombs pos, failed BAER at d/c (passed at 6 months) P-074 2001 2384 35 M/W 2.0 5.0 31.0 31.0 Moderate Yes Yes Idiopathic Yes Severe Mom has congenital spherocytosis M-075 1990 2790 36.5 m/W 2.0 5.0 36.8 39.8 Advanced Yes Yes G6PD Yes Severe E. coli sepsis, birth trauma, ABO Coombs neg M-076 1995 4687 39 f/H 2.0 5.0 37.0 46.5 Advanced Yes Yes Hemolysis Yes Severe ABO Coombs neg, abnormal RBC morphology, Hct 39 M-077 1991 2835 36 f/W 2.0 5.0 41.1 44.4 Advanced Yes Yes Hemolysis Yes Severe 20% wt loss at day 5 M-078 1993 3260 39 f/H 2.0 6.0 30.2 38.0 Advanced Yes Yes Hemolysis Yes Severe Plethora, hemolysis cause: unk M-079 1996 3350 36 m/W 2.0 6.0 34.7 34.7 Advanced Yes Yes Idiopathic Yes Severe Hct 56% P-080 2000 3178 37.5 m/W 2.0 6.0 35.0 42.0 Advanced Yes Yes Idiopathic Yes Severe 14% wt loss at day 6 C-081 1987 3175 37 m/W 2.0 6.0 41.8 41.8 Advanced Yes Yes Idiopathic Yes Severe 18% wt loss at day 6, Hct 57% P-082 2002 3320 37 f/W 2.0 6.5 25.3 25.3 Advanced No Yes Birth trauma Yes Moderate ABO Coombs pos, Hct 51%, jaundice <24 hours M-083 2000 3856 37.5 m/W 2.0 6.5 28.6 36.2 Advanced Yes Yes Birth trauma Yes Severe Hct 45% Kernicterus on Perspectives Systems-Based and Epidemiologic M-084 1991 3310 38 m/B 2.0 7.0 21.5 36.0 Advanced Yes Yes G6PD No Severe TSB 36 at day 10.8, nosocomial sepsis day 11 C-085 1998 unk 39 f/B 2.0 7.0 48.0 48.0 Advanced Yes Yes Infection Yes Severe Vomiting for 4 days, ora fPerinatology of Journal intraosseous fluids. Hct 28% P-086 2002 2724 37 m/B 2.0 7.0 33.0 33.0 Moderate Yes Yes G6PD Yes Moderate Family (maternal) history of jaundice P-087 1994 3572 38 m/W 2.0 7.0 39.0 39.0 Advanced Yes Yes Idiopathic Yes Mild Apneic spells on admission P-088 1998 3263 39 f/W 2.0 7.0 42.0 42.0 Advanced Yes Yes Idiopathic Yes Severe Atraumatic forceps delivery C-089 2002 2700 35.5 m/B 2.0 7.0 46.2 46.2 Advanced Yes Yes G6PD Yes Severe Urosepsis (Citrobacter) L-090 1996 3210 39 m/W 2.0 7.0 47.9 47.9 Advanced Yes Yes Galactosemia Yes Severe 15% wt loss at day 7 04 24:650–662 2004; C-091 1996 2808 39 m/B 2.0 8.0 30.0 30.0 Moderate Yes Yes G6PD Yes None M-092 1987 2700 36.5 m/B 2.0 8.0 32.0 35.0 Advanced Yes Yes Idiopathic Yes Severe ABO Coombs neg, Hct 47% L-093 1992 unk 39 unk/W 2.0 8.0 49.4 49.4 Advanced Yes Yes Idiopathic Yes Severe Persistent incr. signals in globus pallidus on multiple MRI <1 year age ora fPerinatology of Journal Kernicterus on Perspectives Systems-Based and Epidemiologic Table A1 (Continued)

Source/ Birth BW GA Sex/race Discharge Readmit Readmit Peak Acute Ex Tx Photo Likely cause Follow- Icteric Comments code year (g) (weeks) day age TSB TSB BIND Rx up sequelae (day) M-094 1992 3050 38 f/W 2.0 10.0 49.4 49.4 Advanced Yes Yes Hemolysis Yes Severe ABO, Coombs neg, Hct 23%

04 24:650–662 2004; C-095 1997 3415 39 m/W 2.0 11.5 21.6 21.6 Advanced No Yes Infection Yes Severe Clostridium sepsis, >20% wt loss at day 11.5, Na 166 mEq/l, ABO Coombs neg M-096 1992 3175 35 m/H 2.0 14.0 29.4 32.7 Moderate Yes Yes Birth trauma Yes Severe Hct 51% P-097 2000 3320 35.7 f/W 2.0 None not None Subtle No No Idiopathic Yes Severe Prolonged marked jaundice done (>6weeks) P-098 2001 4075 39 m/W 2.0 None Not Unk Moderate No No Idiopathic Yes Severe Prolonged jaundiced (>8 done weeks), TSB 20 done and recorded at day 4. M-099 2001 3487 39 m/B 2.5 4.0 41.4 41.4 Advanced Yes Yes G6PD Yes Severe Hct 42%, no sepsis P/M-100 1992 3289 39 f/W 2.5 4.5 23.8 23.8 Advanced No Yes Birth trauma Yes Severe 20% wt loss at day 4.5, Hct 50% M-101 2000 3346 36.5 m/W 2.5 5.0 39.5 39.5 Advanced Yes Yes Idiopathic Yes Severe 16% wt loss at day 5 C-102 1994 3025 36 f/W 2.5 5.5 36.0 36.0 Subtle Yes Yes Idiopathic Yes Severe 15% wt loss at day 5.5 P-103 1993 3062 37 m/A 2.5 7.0 31.4 31.4 Advanced Yes Yes G6PD Yes Severe Birth trauma, 15% wt. loss at day 7, Na 161 mEq/l P-104 1989 3260 38.5 m/W 2.5 7.0 40.0 40.0 Advanced Yes Yes Birth trauma Yes Severe Jaundice <24 hours age P-105 1987 2977 40 m/W 2.5 9.0 24.5 24.5 Advanced No Yes Idiopathic Yes Severe Hct 56%, TSB at day 8.5 was 23.5 mg/dl P-106 1998 4309 38 m/W 2.5 12.5 29.3 29.3 Moderate No Yes Hemolysis Yes Severe ABO Coombs neg, Hct 43%, jaundice < 24 hours C-107 1993 3296 38 m/W 2.5 15.0 28.9 28.9 Advanced No Yes Idiopathic Yes Severe Weak suck, arching (age 1 week) P-108 1998 3757 36 m/W 3.0 5.0 30.0 30.0 Subtle No Yes Birth trauma Yes Moderate Prolonged jaundiced (>6 weeks) L-109 1985 3771 37 m/W 3.0 5.0 39.0 39.0 Advanced Yes Yes Idiopathic Yes Severe >20% wt loss at day 5, Hct 70% C-110 2002 unk 39 m/B 3.0 6.0 39.0 39.0 Moderate Yes Yes Infection Yes Moderate Probable urosepsis M-111 1993 2905 36 f/B 3.0 6.0 43.0 43.0 Advanced Yes Yes Hemolysis Yes Severe Hct 36%, abnormal RBC morphology L-112 1979 2820 37 m/W 3.0 7.0 49.7 49.7 Advanced Yes Yes Idiopathic Yes Severe 11% wt loss at day 7, Hct 50%

P-113 1999 3348 39 f/W 3.0 10.0 24.0 24.0 Moderate No Yes Idiopathic Yes Moderate Prolonged jaundiced >4 weeks al. et Bhutani L-114 1989 4280 39 m/W 3.0 10.0 40.3 40.3 Advanced Yes Yes Idiopathic Yes Severe Hct 49% P-115 1994 3632 39.5 m/W 3.0 None None None Moderate No No Idiopathic Yes Moderate Jaundice >8weeks, peak TSB unk M-116 1986 2977 37 f/W 3.5 16.0 20.7 20.7 Moderate No Yes Idiopathic Yes Moderate Plethora 661 C-117 1987 3250 39 f/W 4.0 8.0 41.0 41.0 Moderate Yes Yes Birth trauma No Moderate Hct 40% 662 Table A1 (Continued)

Source/ Birth BW GA Sex/race Discharge Readmit Readmit Peak Acute Ex Tx Photo Likely cause Follow- Icteric Comments al. et Bhutani code year (g) (weeks) day age TSB TSB BIND Rx up sequelae (day) P-118 1994 2325 38 m/W 4.0 None None None Moderate No No Idiopathic Yes Moderate 12% wt loss at day 4 C-119 2000 2977 37 m/B 6.0 13.0 54.0 54.0 Advanced Yes Yes G6PD Yes Severe 10.5% wt loss at day 13 C-120 1999 3700 38 m/W HB 3.0 41.3 41.3 Advanced Yes Yes Crigler-Najjar Lost Severe ABO Coombs neg, abnormal RBC morphology, Hct 66%, Na 149 mEq/l C-121 1998 Unk Unk m/W HB 5.0 40.0 40.0 Advanced Yes Yes Crigler-Najjar Lost Severe Follow-up incomplete. C-122 1999 4730 39 m/W HB 6.0 24.0 24.0 Advanced Yes Yes Infection Yes Severe Home birth Shoulder dystocia; sepsis (E. coli), renal abscess. L-123 1990 4026 37 f/W HB 7.0 44.7 44.7 Advanced Yes Yes Idiopathic Yes Severe 20% wt loss at day 7, Hct 54% C-124 2002 3632 42.5 f/W HB 27.0 28.1 28.1 Moderate No Yes Hemolysis No Severe Cong Spherocytosis, Hct 27% C-125 1992 2500 36.5 f/B None 8.0 42.0 46.0 Advanced Yes Yes G6PD Yes Severe Family history of jaundice, 2 sibs had ExTx

C: colleague; f: female; HB: home birth; Hct: hematocrit; L: literature; m: male; M: malpractice case; neg: negative; P: parent; pos: positive; retic: reticulocyte count; Unk: Unknown. pdmooi n ytm-ae esetvso Kernicterus on Perspectives Systems-Based and Epidemiologic ora fPerinatology of Journal 04 24:650–662 2004;