Special Feature - Nature

Special Feature Kernicterus: Epidemiological Strategies for Its Prevention through Systems-Based Approaches Vinod K. Bhutani, MD, FAAP Lois H. Johnson, MD, FAAP M. Jeffrey Maisels, MB, BCh, FAAP Thomas B. Newman, MD, MPH Ciaran Phibbs, PhD Ann R. Stark, MD, FAAP Marshalyn Yeargin-Allsopp, MD, APP

Kernicterus, thought to be due to severe hyperbilirubinemia, is an uncommon disorder with tragic consequences, especially when it affects healthy term and near-term infants. Early identification, prevention and treatment of severe hyperbilirubinemia should make kernicterus a preventable disease. However, national epidemiologic data are needed to monitor any preventive strategies. Recommendations are provided to obtain prospective data on the prevalence and incidence of severe hyperbilirubinemia and associate mortality and neurologic injury using standardized definitions, explore the clinical characteristics and root causes of kernicterus in children identified in the Kernicterus Pilot Registry, identify and test an indicator for population surveillance, validating systems-based approaches to the management of newborn jaundice, and explore the feasibility of using biologic or genetic markers to identify infants at risk for hyperbilirubinemia. Increased knowledge about the incidence and consequences of severe hyperbilirubinemia is essential to the planning, implementation and assessment of interventions to ensure that infants discharged as healthy from their birth hospitals have a safer transition to home, avoiding morbidity due to hyperbilirubinemia and other disorders.

Department of Pediatrics(V.K.B.), University of Pennsylvania, Philadelphia, PA, USA; Pennsylvania Hospital (L.H.J), University of Pennsylvania, Philadelphia, PA, USA; William 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 Resource Center (C.P), Veterans Affairs Palo Alto Health Care System, Department of Health 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 Women’s Hospital, Harvard Medical School, Boston, MA, USA; and National Center on Birth Defects and Developmental Disabilities (M. Y.-A.), Centers for Disease Control and Prevention, Atlanta, GA, USA. Presented in part at the NICHD Conference, Research on Prevention of Bilirubin-Induced Brain Injury and Kernicterus-From Bench to Bedside, at Bethesda, Md, USA, June 2003. 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 Pennsylvania, Philadelphia, PA 19140, USA.

At a recent NIHCD-sponsored conference, key questions were raised about kernicterus and the need for additional strategies for its prevention. These questions and an approach to their answers form the basis of this report. Journal of Perinatology (2004) 24, 650–662. doi:10.1038/sj.jp.7211152 Published online 15 July 2004

A. IS KERNICTERUS A MATTER OF PUBLIC HEALTH CONCERN? Available Evidence Kernicterus has long been recognized as the pathologic sequela of severe hyperbilirubinemia. Although the condition is uncommon, the consequences are tragic, especially when it affects otherwise healthy term and near-term infants.1–5 Kernicterus has become uncommon because of effective screening for and prevention of Rh incompatibility, a historically important cause, and the accessibility of phototherapy to treat hyperbilirubinemia due to increased production and/or decreased elimination of bilirubin. Furthermore, adherence by clinicians to the guidelines from the American Academy of Pediatrics (AAP) concerning management of neonatal jaundice was expected to eliminate severe hyperbilirubinemia and prevent kernicterus.6,7 Little contemporary information is available on the incidence or prevalence of kernicterus or its consequences. In the reports from the Pilot Kernicterus Registry and the Northern California Kaiser Permanente Medical Care Program (KPMCP) database, neonatal deaths due to kernicterus were ascertained from diagnostic codes on death certificates. Limitations of such observations include the 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 (Healthcare Cost and Utilization Project Agency for Healthcare Research and Quality, Rockville, MD; http://www.ahrq.gov/data/ hcup/hcupnet.htm) because the accuracy for annual reports is ±70 cases. That kernicterus occurs is evident from 125 cases of infants who had been discharged as healthy from their birthing hospitals that were voluntarily reported from 1992 to 2002 to the Pilot Kernicterus Registry.1–5,8,9 In contrast, no cases of kernicterus in infants with cerebral palsy were found in the retrospective database of KPMCP during a similar time period (1991 to 1998).10 In addition, among these 111,009 infants in the KPMCP database, 11 (0.01%) developed total serum bilirubin (TSB) levels Z30 mg/dl, and none of them apparently developed kernicterus.10 However, it is unclear Journal of Perinatology 2004; 24:650–662 r 2004 Nature Publishing Group All rights reserved. 0743-8346/04 $30

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Epidemiologic and Systems-Based Perspectives on Kernicterus

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whether all cases were identified, since TSB was not routinely measured in all infants nor were these infants followed prospectively. The actual incidences of kernicterus or severe hyperbilirubinemia are not available because neither is a reportable condition. The incidence of severe hyperbilirubinemia has been estimated (Table 1) from a prospective study conducted in the 1960s,11 a retrospective observational study of a population cared for in the 1990s,12 and additional prospective data from recent reports.13–15 Rates of readmission after the birth Table 1 Proposed Definitions for Severity of Hyperbilirubinemia and Its Estimated Occurrence TSB level (mg/dl)*

Z17.0 Z20.0 Z25.0 Z30.0

(291 mmol/L) (342 mmol/L) (427 mmol/L) (513 mmol/L)

Percentile at >72 hours agew

Proposed definitions

Estimated occurrencez

>95th >99th >99.9th >99.99th

Significant Severe Extreme Hazardous

B1:10 B1:70 B1:700 B1:10,000

*TSB ¼ total serum bilirubin. w Percentiles are approximate. z Occurrence 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 cannot be compiled because of differences in methodologies, patient selection, and thresholds for intervention).

hospitalization (predominantly for jaundice from 14 studies listed in Table 2) range from 1.7 to 30.2 per 1000 live-births and represent a total of 42,470 readmissions for 1,532,924 live-births (27.7 per 1000) reported from 1988 to 1998.16 A disparity exists between term and near-term infants in the rates for readmission for jaundice. In a report of all California births from 1991 to 1999, C. Phibbs (personal communication) reported that near-term infants were consistently 6.4 to 6.6% of all well baby births (not 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). Research Recommendation Obtain data on prevalence, incidence, and mortality of severe hyperbilirubinemia and associated neurologic injury, including kernicterus.

B. WHAT IS THE RELATIONSHIP BETWEEN SEVERE HYPERBILIRUBINEMIA AND KERNICTERUS? Available Evidence A spectrum of neuronal injury associated with hyperbilirubinemia is known as bilirubin-induced neurologic dysfunction (BIND). The 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

Edmonson et al. JAMA 1997;278:299. Danielsen et al.

WI CA

1991 to 94 1992

Pediatrics 2000;106:31.

CA CA CA

1994 1995 1992 to 1994

VA MI

1994 to 1995 1992

OH OH WA

1991 1995 1991 to 1995

WA

1991 to 1994

Radmacher et al. J Ky Med Assoc 2001;99:147 Maisels et al. Pediatrics 1997;100:72

KY MI

1994 to 1998 1988 to 1994

Brown et al. J Perinat Med 1999;27:263.

NY

1995

Geiger et al. Paediatr Perinat Epidemiol 2001;15:352. Behram et al. South Med J 1998;91:541 Soskolne et al. Arch Pediatr Adolesc Med;150:373. Kotagal et al. JAMA 1999;282:1150. Grupp-Phelan et al. Arch Pediatr Adolesc Med 1999;153:1283 Liu et al. JAMA 1997;278:293

Composite data for all reports

Journal of Perinatology 2004; 24:650–662

Observation years

1988 to 1998

Study population

Statewide, nested Statewide, linked to birth records Statewide Statewide Case control for Jaundice

Total livebirths

Total readmitted

Incidence per 1000 live-births

120,290 313,748

210 8656

1.7 27.6

301,721 287,371 68,793

7745 8677 156

25.7 30.2 2.0

Community-based Private urban, community Medicaid patients

2,563 4,496

74 117

29 26

102,678

1951

Statewide

348,495

7388

21 17 21

Statewide, linked to birth records Hospital-based Private, suburban community Metropolitan city

310,578

6444

20

21,628 29,934

414 247

19 8

30, 884

391

12.7

1,532,924

42,470

27.7

651


Rates of readmission per 1000 Babies

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35 30 25 20 15 10 5 0 1991

1992

1993

1994 1995 1996 Calendar Year

1997

1998

1999

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 sequelae, although some of the signs are controversial. Acute brain injury induced by bilirubin is associated with one or more posticteric sequelae in survivors. These are: (1) a movement disorder consisting of athetosis, dystonia, choreoathetosis, but also including spasticity and hypotonia, (2) auditory dysfunction consisting of deafness or hearing loss and auditory neuropathy or dys-synchrony, (3) oculomotor impairments, especially of upward gaze, and (4) dental enamel hypoplasia of the deciduous teeth.4,17 Even though TSB is an important risk factor, bilirubin-induced brain injury and kernicterus cannot be defined on the basis of TSB alone. Factors including the albumin binding of bilirubin, hemolysis, gestational age, and genetic vulnerability modify the risk of kernicterus in an individual infant.5,18 However, there is a 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. Contemporary prospective population-based studies that describe the natural history of hyperbilirubinemia are unavailable; data are limited to studies before the advent of phototherapy. In addition, no prospective studies relate the incidence of kernicterus associated with specific TSB values.19 Thus, characterizing the risk of brain injury at specific levels of TSB is problematic. Furthermore, the safe level of TSB, below which BIND does not occur in otherwise healthy jaundiced infants, is not known. A standard definition of kernicterus in term and near-term infants is needed for purposes of research. This could include a threshold value for TSB, for example, Z20 mg/dl, plus abnormalities of muscle tone on neurological examination, auditory neurophysiological testing, and magnetic resonance imaging. 652

Research Recommendations 1. Standardize definitions of severe hyperbilirubinemia, BIND, acute bilirubin encephalopathy, kernicterus. Uniform terminology is needed to compare databases and examine outcomes. 2. Determine the prevalence and incidence of severe hyperbilirubinemia and kernicterus to estimate the risk of kernicterus at specific levels of TSB for term and near-term infants. 3. Determine whether making a specific TSB level a reportable condition will accomplish this purpose. 4. Develop a case–control study of adequate size to delineate the role of bilirubin and other factors in the development of kernicterus. 5. Define population-based standards to help predict severe hyperbilirubinemia or, as important, the absence of risk based on predefined peak TSB levels.

C. WHAT ARE THE CHARACTERISTICS AND THE ROOT CAUSES OF RECENT CASES OF KERNICTERUS? Preliminary Data Preliminary data were presented on 125 of the 142 cases in the United States (including uniformed services) from the Pilot Kernicterus Registry (1992 to October 1, 2002). These infants were discharged as healthy and were included for analysis if they exhibited clinical signs of acute bilirubin encephalopathy and/or posticteric sequelae, regardless of TSB level and comorbidities (Appendix). Most cases (about 50%) were voluntarily reported by parents or anonymously by physicians or nurses. One limitation of the registry is that these cases of kernicterus likely represent only a portion of affected children. Another limitation is that the population of newborns at risk because of severe Journal of Perinatology 2004; 24:650–662


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hyperbilirubinemia is unknown, so that estimates of incidence and prevalence are unreliable. On the other hand, consistent observations from the registry provide the basis of recommendations for safe practices in order to prevent severe hyperbilirubinemia and kernicterus. Characteristics of the population reported to the Pilot Kernicterus Registry (and individually listed in Appendix) included 84 male and 38 female cases, a racial distribution of White (58.4%), Black (26.4%), Hispanic (8.8%), Asian (6.4%) and the mean birth weight of 3281 g (range: 2015 to 4730). The mean gestational age was 38 weeks (range: 35 to 42.5). The etiology of hyperbilirubinemia in these infants, as evaluated upon readmission that was usually before 10 days of age, is listed in Table 3. All showed an excessive estimated rate of TSB rise (>0.20 mg/dl/hour) from birth to readmission. Analysis of these cases suggests the following root causes:4,5 (a) loss or lack of concern by clinicians regarding the neurotoxic potential of bilirubin, (b) limitations on visual recognition of jaundice as an index to initiate further evaluation or estimate severity, (c) failure to recognize the severity 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 needed of cases of kernicterus and predefined levels of severe hyperbilirubinemia (‘‘close calls’’) in order to better assess the performance of health-care providers and help address Institute of Medicine concerns, including patient (and family) centered care, quality of care, and patient safety.

Table 3 Contributory Causes for Severe Hyperbilirubinemia and Kernicterus Determined at Subsequent Readmission (Preliminary Data Voluntarily Reported to the Pilot Kernicterus Registry) Major contributory cause of Hyperbilirubinemia

Hemolysis G6PD deficiency Idiopathic Birth trauma Other

Postnatal age at readmission (n ¼ 116)

r3 days N¼8

4 to 7 days N ¼ 85

0% 25% 50% 0% 25%

20% 24.7% 31.8% 17.6% 5.9%

>7 days N ¼ 23 20.7% 12.5% 50.0% 12.5% 8.3%

Hemolysis was due to ABO or minor blood group incompatibility, extensive bruising, cephalhematoma, hereditary spherocytosis, etc. Other causes include birth trauma, sepsis, galactosemia, Crigler-Najjar syndrome. Idiopathic group represents those infants in whom no contributory cause could be ascertained following comprehensive clinical evaluation and follow-up. Several infants had additional or multiple factors such as dehydration and/or excessive weight loss that would have contributed to the excessive bilirubin load.


Research Recommendations 1. Conduct a comprehensive analysis of Registry cases to identify common characteristics, delineate the lapses in care that may have contributed to the occurrence of kernicterus, and determine the sentinel events that may have predicted the occurrence of kernicterus. 2. Test the hypothesis that severe hyperbilirubinemia or kernicterus that affects babies discharged as healthy can be predicted before discharge. 3. Assess the feasibility of a national reporting system and database for cases of pre-defined severe hyperbilirubinemia and kernicterus. 4. Assess the feasibility of developing a systematic centralized review process, including root cause analysis, for prospective reported cases of severe hyperbilirubinemia that can be subsequently used to develop targeted education and systems improvements. 5. Develop measurement tools to assess whether a centralized review process and interventions improve outcome.

D. WHAT SHOULD THE TARGET INDICATOR BE FOR PUBLIC HEALTH SURVEILLANCE OF KERNICTERUS AND/ OR HYPERBILIRUBINEMIA? At present, severe hyperbilirubinemia remains the most plausible surrogate indicator for kernicterus even though the risk of 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 a population with hypertension regardless of its cause or its clinical outcome. TSB results are immediately available and objective, and can be reported rapidly. The inclusion of all cases, rather than just those with sequelae, would allow study of the risk of kernicterus in a population with hyperbilirubinemia, as well as study of the frequency and effects of any intervention. The TSB level at which cases might become reportable can be adjusted up or down based on risk and benefits. The immediacy and greater frequency of this outcome also make it potentially more useful for quality improvement efforts. Any initiative to begin surveillance for severe hyperbilirubinemia should be accompanied by efforts to improve standardization and minimize inter-laboratory variability.20 In general, there are at least four possible targets for public health surveillance related to kernicterus (Table 5). The first consideration is kernicterus itself. This disorder is the focus of current concern. However, the diagnosis may be delayed or underreported. In addition, occurrences of kernicterus may be too infrequent (and too late) to provide feedback to health-care systems and providers that might reduce the risk of future cases. Surveillance for kernicterus would not capture other adverse effects 653

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Table 4 Readmission TSB Levels in 118 of the 125 Cases of Infants with Kernicterus Discharged as Healthy from Newborn Nurseries (Preliminary Report from the Pilot Kernicterus Registry) These are listed along with current opinions regarding the potential risk of kernicterus in untreated infants with severe hyperbilirubinemia TSB levels (mg/dl)

< 20.0

Number of cases reported with kernicterus* (n ¼ 116) 0

20.0 to 24.9

11

25.0 to 29.9

15

Z30.0

90

Opinions of risk in untreated infants

Risk unlikely and unproven. Possible risk of subtle effects. Relationship of actual TSB level with onset of injury is often unclear Risk unlikely but unproven (infants with other factors may be vulnerable). Cases have been reported of kernicterus associated with these levels High level of concern although actual risk is unknown. Some infants may not manifest acute neurological injury Risk is increasingly likely although actual risk is unknown. Some infants may be protected from neurologic injury with expeditious and efficient interventions

*Based on peak measured TSB values (these measured values may not reflect the peak hyperbilirubinemia levels experienced by infants because of lack of serial measurements or potential lowering of TSB levels concurrent to onset of acute bilirubin injury).

of hyperbilirubinemia, including less typical sequelae and complications of exchange transfusion. Like kernicterus, cerebral palsy is a highly relevant and clinically significant indicator. The diagnosis of cerebral palsy is already a matter of public health concern. Surveillance for cerebral palsy would allow studies of risk in children with different TSB levels, including those in whom TSB was never measured. However, the proportion of cerebral palsy due to kernicterus is not known, surveillance for cerebral palsy may be insensitive to changes in kernicterus incidence, and feedback to providers would be nonspecific and delayed. Yet another surveillance strategy could be to monitor rates of readmission for treatment of hyperbilirubinemia or use of home phototherapy. Concomitant with incidence of severe hyperbilirubinemia, these offer useful indices of occurrence and outcome. On the other hand, interpretation is limited because intervention thresholds for severe hyperbilirubinemia have not been yet standardized. 654

Recommendations 1. Identify an appropriate target indicator(s) for surveillance based upon advantages and disadvantages (Table 5).

E. HAVE SYSTEMS-BASED APPROACHES FOR THE MANAGEMENT OF NEWBORN JAUNDICE BEEN VALIDATED? Available Evidence Because of the concern for the reemergence of kernicterus,2–4 AAP5 and JCAHO8 recommend a universal systematic approach to the management of newborn jaundice, with the aim of reducing the incidence of severe hyperbilirubinemia8,9,21–23 and kernicterus. This involves using clinical risk factors analysis and/or measurement of predischarge TSB levels plotted an hour-specific nomogram to target appropriate follow-up and intervention. No prospective studies have compared or confirmed the effectiveness of such approaches. Whether a public health campaign to increase parental and provider awareness of jaundice and its potential consequences would reduce adverse outcomes is also unknown. Research Recommendations 1. Evaluate the recommendations for systems-based approaches for the prevention and management of severe hyperbilirubinemia. Approaches based on risk factors for severe hyperbilirubinemia or predischarge hour-specific TSB measurements should be prospectively validated for safety, costeffectiveness, and applicability to ethnically and racially diverse populations. 2. Assess whether systematic prediction of severe neonatal hyperbilirubinemia prevents kernicterus in a cost-effective, practical and safe manner. 3. Evaluate the epidemiologic impact of a public health campaign to reduce adverse outcomes of severe neonatal hyperbilirubinemia.

F. ARE THERE BIOLOGICAL OR GENETIC MARKERS THAT CAN BE USED TO BETTER DEFINE INFANTS AT RISK FOR SEVERE HYPERBILIRUBINEMIA? Insufficient Evidence The genetic contribution to neonatal hyperbilirubinemia due to disorders of hepatic bilirubin conjugation and to the pathogenesis of neuronal cell injury caused by hyperbilirubinemia needs further investigation.24,25 For example, early jaundice is greater in newborns homozygous for the polymorphism associated with Gilbert syndrome compared to those with the normal sequence or heterozygous for the mutation.26 The incidence of hyperbilirubinemia is also increased in infants who have the Gilbert polymorphism and glucose-6-phosphatase dehydrogenase (G6PD) deficiency.24 An investigation of microarray gene expression of hereditary disorders of unconjugated hyperbilirubinemia such as Gilbert, Arias, and Crigler-Najjar Journal of Perinatology 2004; 24:650–662


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Table 5 Potential Targets for Surveillance of BIND Indicator or surrogate

Clinical relevance

Age at identification

Potential limitations when used as a surveillance target

Kernicterus

Index disease

Usually during infancy and childhood

Clinical criteria not yet standardized 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 (existing national public health issue)

Includes cases of Kernicterus

Usually during infancy

Dependent on identification of athetoid/dystonic features

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 jaundice treatment (existing public health issue)

At-risk population

During neonatal age

Requires standardized guidelines for severe hyperbilirubinemia

Requires standardized guidelines and implementation for interventions Requires linkage to birth records Requires compliance by clinicians and families Severe hyperbilirubinemia

At-risk population

During neonatal age

Requires bilirubin measurement and follow-up for all infants 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 deficiency, beta-thalassemia, and hereditary spherocytosis and identify infants at increased risk of severe hyperbilirubinemia.27–29 At this stage, it is too early to know whether genetic epidemiology of hyperbilirubinemia would contribute to the prevention of BIND. 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.

CONCLUSION Infants discharged as healthy from their birth hospitals should have a safe transition to home, avoiding morbidity due to jaundice and other disorders. Prevention of readmission for severe hyperbilirubinemia in otherwise healthy infants, acute bilirubin Journal of Perinatology 2004; 24:650–662

encephalopathy, and chronic posticteric sequelae is a matter of public health and societal concern. Accurate data on the incidence of severe neonatal hyperbilirubinemia and associated adverse outcomes are fundamental to the planning, implementation, and assessment of interventions, including public policy and educational programs, to prevent adverse outcomes.

References 1. Johnson L. Hyperbilirubinemia in the term infant: when to worry, when to treat. NY State J Med 1991;91:483–9. 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 AA, Klaus MH editors. The Year Book of Neonatal and Perinatal Medicine. Philadelphia: Mosby Yearbook; 1996, p. xvii–viii. 3. Johnson L, Brown AK. A pilot registry for acute and chronic kernicterus in term and near-term infants. Pediatrics Suppl 1999;104:736. 655

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4. Johnson LH, Bhutani VK, Brown AK. System-based approach to management of neonatal jaundice and prevention of kernicterus. J Pediatr 2002;140:396–403. 5. AAP Subcommittee on Neonatal Hyperbilirubinemia Neonatal jaundice and kernicterus Pediatrics 2001;108:763–5. 6. American Academy of Pediatrics Practice Parameter: Management of hyperbilirubinemia in the healthy term newborns. Pediatrics 1994;94: 558–65. 7. From the Centers for Disease Control and Prevention. Kernicterus in fullterm infantsFUnited States, 1994–1998. JAMA 2001;286(18):299–300. 8. Sentinel Event Alert: KI Threatens Healthy Babies. www.JACHO.org.Issue 18, April, 9-11-2000. 9. Sheridan SE. Testimony at the First National Summit on Medical Errors and Patient Safety Research on 9-11-2000. AHRQ.gov. http://ahrq.gov// news/press/pr2000/summitpr.htm. 10. Newman TB, Liljestrand P, Escobar GJ. Infants with bilirubin levels of 30 mg/dL or more in a large managed care organization. Pediatrics 2003;111:1303–11. 11. Newman TB, Klebanoff MA. Neonatal hyperbilirubinemia and long-term outcome: another look at the Collaborative Perinatal Project. Pediatrics 1993;92:651–7. 12. Newman TB, Xiong B, Gonzales VM, Escobar GJ. Prediction and prevention of extreme neonatal hyperbilirubinemia in a mature health maintenance organization Arch Pediatr Adolesc Med. 2000;154:1140–7. 13. Bhutani VK, Johnson LH, Sivieri EM. Predictive ability of a predischarge hour-specific serum bilirubin for subsequent significant hyperbilirubinemia in healthy term and near-term newborns. Pediatrics 1999;103:6–14. 14. Stevenson DK, Fanaroff AA, Maisels MJ, et al. Prediction of hyperbilirubinemia in near-term and term infants Pediatrics. 2001;108:31–9. 15. Martinez JC, Garcia HO, Otheguy LE, Drummond GS, Kappas A. Control of severe hyperbilirubinemia in full term newborns with the inhibitor of 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 intensive phototherapy in USA. Abstract. Pediatr Res 2003;54:1756A. 17. Volpe JJ. Bilirubin and brain injury. In: Neurology of the Newborn. 1st ed, 1981; 2nd ed 1987; 3rd ed 1995; 4th ed 2001.

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18. Poland RL. Preventing kernicterus: almost there. J Pediatr 2002;140(4):385–6. 19. Ip S, Glicken S, Kulig J, O’Brien R, Sege R. Management of Neonatal Hyperbilirubinemia. Summary, Evidence Report/Technology Assessment. Number 65. AHRQ Publication No. 03 E005, March 2002. Agency for Healthcare Research and Quality, Rockville, MD. 20. Vreman HJ, Verter J, Stevenson DK. Interlaboratory variability of bilirubin measurements. Clin Chem. 1996;42:869–73. 21. Sheridan SE. Kernicterus parents’ group. J Pediatr 2002;141:597. 22. Bhutani VK, Johnson LH. Newborn jaundice and kernicterus – health and societal perspectives. Indian J Pediatr 2003;70:407–16. 23. Bhutani VK, Johnson LH, Keren R. Diagnosis and management of hyperbilirubinemia in the term neonate: for a safer first week. Pediatr Clin North Am. (in press). 24. Watchko JF, Daood MJ, Biniwale M. Understanding neonatal hyperbilirubinemia in the era of genomics. Semin Neonatol 2002;7:143–52. 25. Dennery PA, Seidman DS, Stevenson DK. Neonatal hyperbilirubinemia. N Engl J Med 2001;344:581–90. 26. Bancroft JD, Kreamer B, Gourley GR. Gilbert syndrome accelerates development of neonatal jaundice. J Pediatr 1998;132:656–60. 27. Beutler E, Gelbart T, Demina A. Racial variability in the UDPglucuronosyltransferase 1 (UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism? Proc Natl Acad Sci USA 1998;95:8170–4. 28. Bosma PJ, Chowdhury JR, Bakker C, et al. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert’s syndrome. N Engl J Med 1995;333:1171–5. 29. Kaplan M, Renbaum P, Levy-Lahad E, Hammerman C, Lahad A, Beutler E. Gilbert syndrome and glucose-6-phosphate dehydrogenase deficiency: a dose-dependent genetic interaction crucial to neonatal hyperbilirubinemia. Proc Natl Acad Sci USA 1997;94:12128–32.

APPENDIX A Table A1 summarizes the data from Pilot Kernicterus Registry.


Source/ code

Birth year

BW (g)

GA (weeks)

C-001 C-002 L-003

1994 1993 1988

3260 3725 3785

36 39 39

M-004 M-005

1996 1997

3000 3884

M-006 L-007

1993 1995

M-008 C/M-009 M-010

Sex/race

Readmit age (day)

Readmit TSB

Peak TSB

Acute BIND

Ex Tx

Photo Rx

Likely cause

Followup

Icteric sequelae

Comments

m/W m/A unk/H

0.5 0.5 0.5

4.0 4.0 4.0

35.0 40.2 45.0

35.0 40.2 45.0

Advanced Advanced Advanced

Yes Yes Yes

Yes Yes Yes

Idiopathic Hemolysis Idiopathic

Yes Yes Yes

Moderate Severe Severe

36 38

f/B m/W

0.5 0.5

4.5 5.0

40.9 46.0

40.9 46.0

Advanced Advanced

Yes Yes

Yes Yes

Idiopathic Hemolysis

Yes Yes

Severe Severe

3856 3544

41 39

f/W f/A

1.0 1.0

2.5 3.0

22.4 27.8

22.4 27.8

Advanced Subtle

No Yes

Yes Yes

Idiopathic Infection

Yes Yes

Severe None

1995 1990 1998

2920 2015 3629

37 36 39

m/B f/W f/W

1.0 1.0 1.0

3.0 3.5 3.5

33.0 41.8 52.0

36.7 41.8 52.0

Advanced Advanced Advanced

No Yes Yes

Yes Yes Yes

G6PD Idiopathic Idiopathic

Yes Yes Yes

Severe Severe Severe

L/C-011 P-012

1995 1999

2614 4026

39 39

f/B m/W

1.0 1.0

4.0 4.0

33.0 39.0

33.0 45.0

Moderate Advanced

No Yes

Yes Yes

Idiopathic Birth trauma

Yes Yes

Moderate Severe

P-013

2002

3714

40

m/W

1.0

4.0

44.8

44.8

Advanced

Yes

Yes

Hemolysis

Yes

Severe

P-014 L/C-015 L-016 M-017

2000 1994 1996 1996

4200 3489 2637 3450

35 39 39 39

f/W m/W m/H f/H

1.0 1.0 1.0 1.0

5.0 5.0 5.0 5.0

27.0 30.6 34.8 37.0

31.5 30.6 34.8 46.0

Subtle Advanced Moderate Advanced

No Yes Yes Yes

Yes Yes Yes Yes

Birth trauma Idiopathic Idiopathic Hemolysis

Yes Yes Yes Yes

Severe None None Severe

L-018

1993

3147

39

m/B

1.0

5.0

42.5

42.5

Advanced

Yes

Yes

G6PD

Yes

Severe

M-019 C-020 M-021 M-022 P-023

1992 1995 1997 1994 2002

3685 3130 3680 3048 2745

39 39 37 35 38

m/B m/H m/W f/W f/W

1.0 1.0 1.0 1.0 1.0

5.5 6.0 6.0 6.0 6.0

46.8 28.5 29.3 31.0 46.2

46.8 28.5 32.5 31.0 46.2

Advanced Advanced Advanced Advanced Advanced

No Yes Yes No Yes

Yes Yes Yes Yes Yes

G6PD Hemolysis Birth trauma Birth trauma Hemolysis

Died Yes Yes Yes No

Died Severe Severe Severe Severe

P-024 P-025

1993 1994

3487 3090

37 37

m/H m/W

1.0 1.0

8.5 12.0

41.3 41.0

53.9 41.0

Advanced Advanced

Yes Yes

Yes Yes

Birth trauma Idiopathic

Yes Yes

Severe Severe

ABO Coombs neg ABO Coombs pos ExTx delayed 12 hours. (Jehovah Witness) Hct 45%, wt loss ABO Coombs neg, jaundice 4 weeks Hct 49% Jaundice >8weeks, peak TSB unk Plethora Hct 40%

Bhutani et al.

661

Discharge day



Table A1 (Continued)

662

Table A1 (Continued) Birth year

BW (g)

GA (weeks)

P-118 C-119 C-120

1994 2000 1999

2325 2977 3700

38 37 38

C-121 C-122

1998 1999

Unk 4730

L-123 C-124 C-125

1990 2002 1992

4026 3632 2500

Sex/race

Discharge day

Readmit age (day)

Readmit TSB

Peak TSB

Acute BIND

Ex Tx

Photo Rx

Likely cause

Followup

Icteric sequelae

Comments

m/W m/B m/W

4.0 6.0 HB

None 13.0 3.0

None 54.0 41.3

None 54.0 41.3

Moderate Advanced Advanced

No Yes Yes

No Yes Yes

Idiopathic G6PD Crigler-Najjar

Yes Yes Lost

Moderate Severe Severe

Unk 39

m/W m/W

HB HB

5.0 6.0

40.0 24.0

40.0 24.0

Advanced Advanced

Yes Yes

Yes Yes

Crigler-Najjar Infection

Lost Yes

Severe Severe

37 42.5 36.5

f/W f/W f/B

HB HB None

7.0 27.0 8.0

44.7 28.1 42.0

44.7 28.1 46.0

Advanced Moderate Advanced

Yes No Yes

Yes Yes Yes

Idiopathic Hemolysis G6PD

Yes No Yes

Severe Severe Severe

12% wt loss at day 4 10.5% wt loss at day 13 ABO Coombs neg, abnormal RBC morphology, Hct 66%, Na 149 mEq/l Follow-up incomplete. Home birth Shoulder dystocia; sepsis (E. coli), renal abscess. 20% wt loss at day 7, Hct 54% Cong Spherocytosis, Hct 27% Family history of jaundice, 2 sibs had ExTx

Bhutani et al.

Source/ code

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.

