Journal of Perinatology (2009) 29, S25–S45 r 2009 Nature Publishing Group All rights reserved. 0743-8346/09 $32 www.nature.com/jp REVIEW Clinical report from the Pilot USA Kernicterus Registry (1992 to 2004)

L Johnson1, VK Bhutani2, K Karp1, EM Sivieri3 and SM Shapiro4 1Pennsylvania Center for Kernicterus, Philadelphia, PA, USA; 2Stanford University School of Medicine and Lucile Packard Children’s Hospital, Stanford, CA, USA; 3Pennsylvania Hospital University of Pennsylvania Health System, Philadelphia, PA, USA and 4Virginia Commonwealth University School of Medicine and Medical College of Virginia Hospital, Richmond, VA, USA

‘crash-cart’ initiation of immediate intensive phototherapy and urgent To identify antecedent clinical and health services events in infants exchange transfusion were accomplished in 11 of 43 infants, which were (X35 weeks gestational age (GA)) who were discharged as healthy from compared with 12 of 43 infants in whom a timely exchange sometimes their place of birth and subsequently sustained kernicterus. We conducted a could not be accomplished. No overt sequelae were found in 8 of 11 infants root-cause analysis of a convenience sample of 125 infants X35 weeks GA (73%) treated with a ‘crash-cart’ approach compared with none without cared for in US healthcare facilities (including off-shore US military bases). sequelae when exchange was delayed by pre-admission delays, technical These cases were voluntarily reported to the Pilot USA Kernicterus Registry factors or need to transfer to a tertiary facility. None of the remaining 20 of (1992 to 2004) and met the eligibility criteria of acute bilirubin 43 infants treated only with phototherapy escaped sequelae. Regardless of encephalopathy (ABE) and/or post-icteric sequelae. Multiple providers at age at readmission and intervention, infants with peak measured TSB multiple sites managed this cohort of infants for their newborn jaundice >35 mg per 100 ml had post-icteric sequelae (n 73). There was a narrow and progressive hyperbilirubinemia. Clinical signs of ABE, verbalized by ¼ margin of safety between birthing hospital discharge or home birth and parents, were often inadequately elicited or recorded and often not readmission to a tertiary neonatal/pediatric facility. Progression of recognized as an emergency. Clinical signs of ABE were reported in 7 of 125 hyperbilirubinemia to hazardous levels and onset of neurological signs were infants with a subsequent diagnosis of kernicterus who were not often not identified as infant’s care and medical supervision transitioned re-evaluated or treated for hyperbilirubinemia, although jaundice was noted during the first week after birth. The major underlying root cause for at outpatient visits. The remaining infants (n ¼ 118) had total serum 1 kernicterus was systems failure of services by multiple providers at multiple bilirubin (TSB) levels >20 mg per 100 ml (342 mmol lÀ ; range: 20.7 to sites and inability to identify the at-risk infant and manage severe 59.9 mg per 100 ml). No specific TSB threshold coincided with onset of ABE. hyperbilirubinemia in a timely manner. Of infants <37 weeks GA with kernicterus, 34.9% were LGA (large for Journal of Perinatology (2009) 29, S25–S45; doi:10.1038/jp.2008.211 gestational age) as compared with 24.7% of term infants (>37 weeks GA). Although >90% mothers initiated breast-feeding, assessment of milk Keywords: newborn jaundice; kernicterus; bilirubin transfer and lactation support was suboptimal in most. Mortality was 4% hyperbilirubinemia; well babies; bilirubin-induced neurological (5 of 125) in infants readmitted at age p1 week. Along with a rapid rise of dysfunction TSB (>0.2 mg per 100 ml per hour), contributing factors, alone or in combination, included undiagnosed hemolytic disease, excessive bilirubin production related to extra-vascular hemolysis and delayed bilirubin Introduction elimination (including increased enterohepatic circulation, diagnosed and Classic signs of acute bilirubin encephalopathy (ABE) in the undiagnosed genetic disorders) in the context of known late prematurity severely hyperbilirubinemic term infant have been described by van (<37 weeks), glucose 6-phosphate-dehydrogenase deficiency, infection and Praagh,1 Jones,2 Volpe,3 and Perlstein.4 These include tone dehydration. Readmission was at age p5 days in 81 of 118 (69%) infants abnormalities such as hypotonia alternating with progressive and <10 days in 101 of 118 (86%) infants. TSB levels were p35 mg per hypertonia of extensor muscles, with retrocollis and opisthotonos, 1 100 ml (598 mmol lÀ ) in 46 (39%) infants, of whom one died before in association with varying degrees of drowsiness, lethargy- exchange transfusion, one was untreated and one was lost to follow-up. decreased feeding and irritability. When described in terms of the Timely and efficacious bilirubin reduction interventions defined by infant’s mental status, muscle tone and cry, as shown in Table 1,5 progression of ABE can be documented and provides a schema for Correspondence: Dr VK Bhutani, Department of Pediatrics, Division of Neonatal and grading its severity.5–8 Increasing scores would be indicative of Developmental Medicine, Stanford University School of Medicine, Lucile Packard Children’s Hospital, 750 Welch Ave #315, Stanford, CA 94304, USA. worsening signs of acute neurotoxicity. The earliest signs of ABE E-mail: [email protected] are non-specific and subtle and may be missed unless elicited by Root causes of kernicterus L Johnson et al S26

Table 1 Clinical BIND score of onset, severity and progression of ABE in infants with hyperbilirubinemia (TSB >95th percentile for age in hours) as elicited by history and physical examination

Clinical signs BIND score ABE Date__ /__ Date__ /__ Date__ /__ Date__ /__ Time_:_ Time_:__ Time_:__ Time_:_

Mental status Normal 0 None Sleepy but arousable; decreased feeding 1 Subtle Lethargy, poor suck and/or irritable/jittery with strong suck 2 Moderate Semi-coma, apnea, unable to feed, seizures, coma 3 Advanced

Muscle tone Normal 0 None Persistent mild to moderate hypotonia 1 Subtle Mild to moderate hypertonia alternating with hypotonia, 2 Moderate beginning arching of neck and trunk on stimulation Persistent retrocollis and opisthotonosFbicycling or 3 Advanced twitching of hands and feet

Cry pattern Normal 0 None High pitched when aroused 1 Subtle Shrill, difficult to console 2 Moderate Inconsolable crying or cry weak or absent 3 Advanced Total BIND score Nurse/MD signature

Abbreviations: BIND, bilirubin-induced neurological dysfunction; ABE, acute bilirubin encephalopathy; TSB, total serum bilirubin. Score of 7–9 represent advanced ABE: urgent, prompt and individualized intervention are recommended to prevent further brain damage, minimize severity of sequelae and possibly reverse acute damage. Score of 4–6: represent moderate ABE and are likely to be reversible with urgent and prompt bilirubin reduction strategies. Score of 1–3: are consistent with subtle signs of ABE in infants with hyperbilirubinemia. An abnormal ABR or ‘referred’ automated ABR is indicative of likely bilirubin neurotoxicity and would be suggestive of moderate ABE. In infants with these non-specific signs (score 1–3), a failed ABR hearing screen supports a diagnosis of moderate ABE. Serial ABR may be used as an objective measure of progression, stabilization or reversal of acute auditory damage and could interpret effectiveness of bilirubin reduction strategies.

direct questioning of parents and close clinical observation. to the onset and progression of ABE.6,9–12 Death in an infant with Moderate ABE (score of 4 to 6) has been considered as definitive ABE is likely to be due to respiratory failure, progressive coma or signs of kernicterus and include beginning arching of neck and intractable seizures. Currently, the transition from increasing trunk on stimulation, alternating with increasing lethargy, severity of hyperbilirubinemia to ABE is unpredictable. decreased feeding, unexplained irritability and usually Preventive management of progressive hyperbilirubinemia as accompanied by a shrill cry. During the early phases, prompt and the predecessor of potential ABE is the most effective of clinical effective interventions could prevent chronic kernicteric sequelae. strategies to prevent kernicterus.13–18 Implementation needs to be Advanced signs are progressive and marked by cessation of feeding, a system-based approach that allows for individualized care to bicycling movements, inconsolable crying with irritability, inability accommodate the clinician’s concerns, informed participation of to feed, fever, seizures and coma. These late findings are ominous the family and monitoring of the progression of hyperbilirubinemia of predictors of the probability of severe kernicteric sequelae, even at-risk newborns.5 Practice parameters developed by the American with intensive treatment. The extent of brain damage is likely to be Academy of Pediatrics (AAP) provide useful guidelines for the reduced by rapid reduction of the bilirubin load (by a combination management of term healthy newborns when these are followed of intensive phototherapy and exchange transfusion). Rate of diligently.13–17 These include a ‘crash-cart’ approach to prevent or bilirubin rise, duration of hyperbilirubinemia, adequacy of minimize sequelae of ABE.16,18 albumin-binding reserves, level of unbound bilirubin, host Randomized controlled trials to prevent kernicterus are not susceptibility and presence of co-morbidities, individually or in ethically feasible because of easy access to effective treatment combination, have been implicated but not confirmed as important options for severe hyperbilirubinemia. Thus, the only available

Journal of Perinatology Root causes of kernicterus L Johnson et al S27 evidence that would best delineate strategies to improve access to qualitative data and to use a quantitative scaling or indicators that effective and efficient treatment is through a detailed root-cause were collated to the closest age-in-hours. The database directs the analysis of infants who developed kernicterus with current operator to record specific information, including missing healthcare systems. We conducted a root-cause analysis of a information, and to seek the closest time of the day to indicate the convenience sample of all cases that were reported to the Pilot USA occurrence of the specific event. The unique nature of the design Kernicterus Registry from 1992 to 2004, prior to the updated AAP was to minimize bias, but allow for a recording of comments for guidelines.17 Our hypothesis was that we would identify additional any unclear documentation from the chart. Principal investigators clinical observations and common recurring lapses that could be adjudicated these comments. Unresolved qualitative data that were useful to delineate more effective systems strategies to inform a prone to a biased interpretation were reviewed and discussed after safer management of newborn jaundice. Preliminary data from the deliberation and reflection. During the first half of data entry, Registry5 were provided to the AAP Subcommittee on modifications and labeling of the software and fields for data entry Hyperbilirubinemia12 and presented at the 2004 National Institute was done simultaneously to ensure user-friendly computer of Child Health and Development Workshop.7,19–24 interface. Consensus-based definitions of diagnosis, interventions, sequelae and lapses in care were configured to the software Patients and methods concurrent to entry of raw data from the latter half of the cases. Kernicterus registry database Upon complete data entry and its review for accuracy as well as 176 cases voluntarily reported to the Registry from 1992 were resolution of queries, software-driven analysis was generated by the reviewed, scrutinized and entered into a specifically designed program. These unbiased analyses were studied and reviewed. computer database (ACCESS) and constituted the Kernicterus Complexities of data collected were made available for statistical Registry Database. Subsequent to raw data entry, each case report analysis, root-cause analysis and descriptive reports. From a was individually assessed by two separate reviews by the research statistical perspective, this sample was small and vulnerable to nurse (KK), the co-principal investigator (LJ) and principal over-analysis. To better understand the common root causes of investigator (VKB), and, when needed, a pediatric neurologist these adverse clinical outcomes and identify gaps in the (SMS). All patient identifications were removed and replaced by contemporaneous healthcare system, we reviewed the root causes unique identification numbers. that would be amenable to structural correction or modifications. We were hesitant to extend the data analysis to a specific statistical Patient confidentiality design and over-analysis. The Pennsylvania Hospital Review Board (University of Pennsylvania) and the Stanford University Research Review Board Clinical analysis independently approved the project. Enrollment ended on 13 April Clinical analysis included: (a) standardization of definitions for 2004. To meet a follow-up requirement for at least 18 months, the hyperbilirubinemia and kernicterus, (b) demographic analysis, last calendar year of birth was 2002. Follow-up data are current (c) clinical profile and presentation of infants who were readmitted through April 2004. A large number of parents who were familiar for acute kernicterus and those in whom acute kernicterus was not with the Registry participated in detailed interviews and volunteered recognized but developed post-icteric sequelae, (d) assessment of their participation. Others have thus far chosen to remain lapses in care provided prior to specific medical intervention. anonymous. We conformed to the Health Insurance Portability and Accountability Act Regulations on a case-by-case basis. The Standardization of definitions for hyperbilirubinemia and database was maintained with unique identifiers for confidentiality kernicterus of children with kernicterus. As these children grow and mature, Eligibility to the Kernicterus Registry. With the goal of this database is likely to be a valuable resource for the children to establishing a national reporting system for kernicterus and to link their detailed birthing period data to a potential relationship define eligibility criteria for admission to the Pilot USA Kernicterus with onset of problems and disorders in childhood and later life. Registry, it was imperative that a consensus was developed for the clinical diagnosis of both acute stage kernicterus (ABE) and the Software program chronic post-icteric sequelae. Magnetic resonance images (MRIs), The specific and unique nature of the custom-built program was when available, confirm acute or chronic neuroanatomic adapted to accommodate the multiple clinical datasets gleaned abnormalities in the globus pallidus and subthalamic nucleus. In from the medical records, medico-legal depositions, physician the absence of a confirmatory diagnosis of magnetic resonance office records and parental feedback. Software was configured to imaging, a consensus-based definition of pathognomic clinical and accommodate data entry and allow for visualization of temporal auditory abnormalities was needed to define ABE and post-icteric relationship and progression of hyperbilirubinemia, intervention, sequelae. We convened a workshop with Dr Michael Painter as well as follow-up. The configuration was designed to minimize (University of Pittsburgh) to develop definitions for

Journal of Perinatology Root causes of kernicterus L Johnson et al S28 bilirubin-induced neurological dysfunction (BIND). These Definitions used for severity of hyperbilirubinemia. Neonatal definitions were presented and published following the National hyperbilirubinemia is often referred to as a ‘high’ level of TSB. Institute of Child Health and Human Development (NICHD) However, the clinical meaning of this designation must be meeting.7,8 The medical literature provides recognized descriptions recognized as a function of the postnatal age-in-hours, the and diagnostic criteria for histopathological signs of kernicterus concentration of bilirubin in a percentile-defined track. From this and extensively details the variety of its clinical signs and perspective, hyperbilirubinemia was defined as the need for an manifestations. These have generally been based on literature from acute medical intervention. Transcutaneous (TcB) or TSB values the 1950s and 1960s when kernicterus was usually the sequelae of charted in medical records were assigned to the known or, if severe hemolytic disorders. Volpe4 and Johnson et al.5,15 have necessary, the closest and plausible postnatal age-in-hours and provided more recent updates. The epidemiological limitations are then plotted on a computerized hour-specific bilirubin that clinical signs of early and ABE are often insidious and non- nomogram.24 The severity of hyperbilirubinemia was determined specific, seemingly benign and frequently missed by clinicians. by the following indices: (a) >75th percentile TSB for age-in- Suggested risk factors have included prematurity, rate of total hours, (b) >95th percentile TSB for age-in-hours, (c) >99th serum bilirubin (TSB) rise, age at peak TSB, rate of reduction of percentile for age-in-hours, (d) TSB level of either >20 or >25 mg TSB and duration of hyperbilirubinemia, as well as the mode and per 100 ml, which have been traditional clinical thresholds for timeliness of intervention.11,12 Therefore, we charted individual intervention.24,25 TSB levels >20 mg per 100 ml before 60 h of age neurological outcomes according to standardized clinical and >25 mg per 100 ml beyond 72 h of age are consistent with the definitions and correlated these to specific risk factors and co- 99th percentile before 60 h of age and the 98th percentile beyond morbidities such as gestational age, severity of hyperbilirubinemia, 72 h of age on the hour-specific bilirubin nomogram. TSB level rate of bilirubin load reductions, and sepsis, hemolysis, X25 mg per 100 ml is a recent clinical threshold for aggressive dehydration, birth trauma, glucose 6-phosphate-dehydrogenase intervention. This value represents the 99.99th percentile before (G6PD) deficiency and idiopathic causes of hyperbilirubinemia. 60 h of age and is the 99th percentile beyond 72 h of age on the The ‘idiopathic’ group most likely includes infants with hour-specific bilirubin nomogram. (e) Use of phototherapy and/or unidentified hepatic conjugation and excretion defects as well as an exchange transfusion and their initiation in accordance with infants with undiagnosed or unidentified hemolysis and excessive recommended guidelines has also been used as indices for severity bilirubin production. The initial template was standardized of hyperbilirubinemia. (f) Rate of TSB rise (mg per 100 ml per according to the definitions listed below. hour) during the first 96 h after birth, in a healthy newborn, usually increases in approximate linear manner.24,25 When the Acute bilirubin encephalopathy. For infants X35 weeks GA pre-discharge TSB level was not measured or available, we (gestational age) with hyperbilirubinemia is described by the calculated the projected rate of TSB rise using a cord TSB of constellation of progressive signs of acute kernicterus (listed in 2 mg per 100 ml (95th percentile for healthy newborns) Table 1). These data were tabulated retrospectively, using a medical to a peak TSB measurement (usually at readmission). A non-linear chart review and parental reports. The progression of ABE was or an erratic increase in TSB levels was considered in an categorized as subtle, moderate or advanced.16 For inclusion in the infant with known or proven G6PD deficiency or sepsis that Registry, infants without kernicteric sequelae were required to have may have sustained an acute unpredictable hemolytic crisis, such documented ABE of at least moderate severity. Those with as ‘favism.’ non-specific ABE were included only if they met the following criteria for post-icteric sequelae. Demographic analysis Statewide distribution. Each case in the Registry was designated Post-icteric or kernicteric sequelae. These included by the city and state of birthing. The total number of cases extrapyramidal movement disorders (especially dystonia and voluntarily reported from each state was collated for information athetosis), auditory disturbances (especially deafness or hearing purposes only. These data most likely represent bias due to location loss secondary to auditory neuropathy/dys-synchrony), gaze of professional colleagues, sources for medico-legal referrals and abnormalities (especially impairment of upward gaze), intellectual concern of specific physicians for litigation. Data analysis will be impairment (rarely in mentally retarded range) and post-icteric limited to general impressions. Absence of cases reported from a enamel dysplasia of deciduous teeth. Impairment in either state carries no significant import. neuro-motor or auditory impairment (severe enough to necessitate ongoing specialized therapy or skilled assistance) along with an Occurrence by year of birth. Each case in the Registry was additional two of the five domains defined post-icteric sequelae and collated by the year of birth. The total number of cases reported for inclusion to the Registry. Post-icteric sequelae were categorized as each calendar year was collated for informational purposes. These mild, moderate or severe.16 data were evaluated for any correlation with critical changes in

Journal of Perinatology Root causes of kernicterus L Johnson et al S29 healthcare practices, healthcare policies or prevalent provider (d) Idiopathic disorders: The definition of idiopathic educational agendas. Coincidental trends to increase or decrease in hyperbilirubinemia required apparent absence of increased relation to the reported occurrences were studied. hemolysis, G6PD deficiency and excessive birth trauma after a detailed chart review. In some cases assigned to this category, Clinical analysis studies had excluded the possibility of Gilbert’s syndrome. A family Etiological factors. The clinical diagnosis for the major history of jaundice in the absence of known isoimmune disease contributor of the hyperbilirubinemia and reasons for the was supportive of the diagnosis of idiopathic hyperbilirubinemia diagnosis, as listed in the medical charts at the time of discharge and suggested the presence of as yet unidentified familial hepatic following the sentinel event, were collated to assess the prevailing conjugation or excretion compromise. clinical perspective. Presence of concurrent morbidities, such as (e) Sepsis: It was defined as culture-proven sepsis or presumed hemolysis, prematurity, hypoalbuminemia, asphyxia/blood–brain (culture negative) sepsis based on laboratory studies and clinical barrier disruption, infection, hypoglycemia and drugs that may risk factors and treated with a full course of antibiotics. Sepsis was trigger a ‘favism’ reaction in an infant with G6PD deficiency, were considered a highly significant co-morbidity and was designated as documented. a secondary contributing cause of hyperbilirubinemia. These instances are highlighted in the clinical vignettes (Appendix 1). For analysis purposes and tabulation of results, however, it was not Definition of late preterm. Late prematurity is defined as a considered as a primary diagnostic category. gestation of 34 0/7 to 36 6/7 weeks based on pregnancy dating (last (f) Co-morbidities: These were identified and defined as menstrual period and prenatal ultrasound, when available) and shortened gestation (35 to <37 weeks GA), being born to a diabetic was corroborated by clinical examination. For the purpose of this mother, dehydration (based on a birth-weight loss of X15% report, infants <35 weeks gestation were excluded and in this and/or a serum sodium of >150 mEq per l), hypoalbuminemia report the terminology ‘late preterm’ specifically refers to infants (<3.0 g per 100 ml) if albumin had been measured (n ¼ 16 of X 35 and <37 weeks GA. 125), polycythemia (when documented), poor feeding and hypothyroidism (abnormal metabolic screen). Standardization of definitions for major contributors of (g) Non-preventable causes: Each case was individually hyperbilirubinemia. (a) Hemolytic disorders: Hemolysis was assessed by one or more co-authors, including at least one defined by presence of anemia (hematocrit p40% within 2 weeks physician, followed by software evaluation to identify preventable of age), higher than normal reticulocyte counts for postnatal age, a steps that could have been taken with reasonable ease and without peripheral smear suggestive of Hemolysis, such as spherocytes, undue cost to avert the occurrence of kernicterus. schistocytes, RBC fragments, and corroborating signs such as (h) Severity of hyperbilirubinemia exposure: Based on positive direct antiglobulin test (DAT, Coombs’s). The clinical use (as discussed above) (i) peak bilirubin level, (ii) duration of of exhaled carbon monoxide to assess hemolysis was not available hyperbilirubinemia, (iii) TSB level >20 and >25 mg per 100 ml or for any of the Registry cases. In view of the retrospective nature of (iv) >4 weeks duration. data analysis, the documentation was limited by the extent of bedside diagnostic investigation. Using existing clinical criteria, Assessment of lapses in care. Using the patient safety matrix infants with excessive bilirubin production could not be recognized recommended by the Institute of Medicine27 and Joint Commission or categorized in the absence of hemolytic disease or extra-vascular Accrediting Hospital Organizations,28 we used both qualitative and hemolysis. Thus, these infants were considered ‘idiopathic’. To quantitative data to determine the lapses in care in the context of better understand this group of infants, we estimated their rate of patient centeredness, patient safety, effectiveness and timeliness of TSB rise during the first 96 h after birth. care. For example, we assessed the following. (i) Patient (b) G6PD deficiency: The clinical and laboratory diagnosis of centeredness: Analysis for patient-centered care was assessed for: deficiency required a quantitative kinetic G6PD assay interpreted (a) experiences of newborn services at the birthing hospital, for age and gender and carried out in a reputable laboratory, done interval home care, outpatient follow-up, emergency room on the infant’s pre-exchange transfusion blood. The diagnosis was management, hospital readmission, hospital to hospital transfer or confirmed, or sometimes first made by assay of blood collected after emergency room to another facility transfer, site for targeted the age of 3 months. DNA analysis was sometimes available but not and presumed therapeutic intervention and follow-up services; required. (b) patient–provider relationships at each of these sites were (c) Birth trauma: Excessive trauma was defined as presence of ascertained based on communications charted in medical records, extensive bruising, subgaleal hemorrhage, presence and size of a depositions (if a medico-legal case) and parent interview; and cephalohematoma or other concealed or contained hemorrhage, a (c) value of the services to the family was evaluated on the fractured clavicle or other trauma related to shoulder dystocia. continued care by the attending physician, referral for

Journal of Perinatology Root causes of kernicterus L Johnson et al S30 developmental follow-up, accuracy of medical records, hyperbilirubinemia and ranked by ascending peak TSB levels medico-legal consequences and feedback from parental interviews. (Appendix 1). These vignettes represent our most updated (ii) Family experiences: Parental experiences were ascertained by information and thus may occasionally differ from an earlier their comments to measure how they perceived the management of reported preliminary analysis. An overview of the characteristics: jaundice, the attitude, the language used, the message received, the gestational age, outcome and mode of treatments for all 125 concern, the recognition of emergency, and the healthcare provider infants, is tabulated in Table 2. The birth weight (compared for realization that the outcome was not desirable. (iii) Relationships term and late-preterm infants) and gestational age of these infants with healthcare providers: Parental perspectives as to the are shown in Figures 2 and 3. Data relating to occurrence of relationships they established with medical staff and the nursing kernicterus in the late preterm have been published earlier.29 The staff during the birthing experiences, post-discharge care, subsequent tables and figures provide a perspective of the clinical emergency care and follow-up care and continuity of these data from this convenience sample. relationships were obtained. Mortality attributed to kernicterus Of the 125 infants in the Registry, overall six infants died during Results and outcome their first year. First week mortality was 5 of 125 (4%) with hazardous hyperbilirubinemia. Mortality included two infants who 176 case reports to the Registry by August 2004, 125 infants met the died earlier to exchange transfusion and one who died before any inclusion and eligibility criteria for the term and near-term treatment could be initiated. Additional risk factors were late Registry. Infants were excluded (n ¼ 23) because of their prematurity, G6PD deficiency and sepsis. Four of the five deaths gestational age being <35 weeks or because of concurrent complex were in infants of <37 weeks GA. G6PD deficiency appeared to be a neonatal conditions that were managed in neonatal intensive care confounding risk factor for both mortality and morbidity. Of the facilities; 28 infants were additionally excluded because they did 26 infants with a confirmed enzyme deficiency, 4 (15%) infants not meet the eligibility criteria for diagnosis. Eligible infants had a died. Concurrent sepsis was noted in 8 of 26 (31%), two of follow-up for up to 18 months other than those who died (n ¼ 6) whom died. or were lost to follow-up before age 3 months (n ¼ 1). Cases reported by colleagues and by families were assessed for their Morbidities associated with outcome of kernicterus calendar year of birth (Figure 1) and location of birthing site. No Individual case vignettes (Appendix 1) detail the concurrent impact extrapolation of these reports to a state or community incidence of of sepsis: either proven or presumed in infants with negative blood kernicterus can or should be made as the reporting was done on a cultures. Genetic disorders were confirmed in three infants with voluntary basis by pediatricians (usually neonatologists) and as the Crigler–Najjar syndrome (n ¼ 2) and galactosemia (n ¼ 1). clinical diagnosis was made over several years subsequent to birth. Brief clinical vignettes are provided for each case in a de-identified tabular list categorized by the most likely cause for excessive Table 2 Infants (X35 weeks GA) in the Kernicterus Registry with acute bilirubin encephalopathy and/or kernicteric sequelae (n ¼ 125; peak TSB range 20.7–59.9 mg per 100 ml) 25 21 21 Treatment for severe Exchange Phototherapy No Total 19 hyperbilirubinemia transfusion only treatment 20 17 and 15 14 phototherapy 15 Cohort sample n ¼ 91 n ¼ 26 n ¼ 8 n ¼ 125 10 8 GAX35 to <37 weeks 22 6 1 30 6 GA ¼ 37 weeks 17 6 1 24 a Cases of kernicturus 5 2 2 GA>37 weeks 52 14 6 71 Died at age <8 days 2 2 1 5 0 Lived with sequelae 81 23 7b 111 (>6 months) 79–84 85–86 87–88 89–90 91–92 93–94 95–96 97–98 99–00 2001–02 Lived with no sequelae 8 0 0 8 Infants lost to follow-up 0101 Figure 1 Calendar year of birth is shown for eligible case reports to the Pilot (<3 months) USA Kernicterus Registry. Reported cases (n ¼ 125) listed by year of birth for 2 year periods after 1984 and the 6 year period from 1979 to 1984: White 60%, Abbreviation: GA, gestational age. African American 25.6%, Hispanic 8%, Asian 6.4%; male 67%, female 33%; mean aTerm GA assumed in one infant (Amish, home birth). BW 3281 g (range: 2015 to 4730 g), mean GA 38.0 week (range: 35 to 42 weeks). bThese seven babies, managed as outpatients, received no treatment for their jaundice.

Journal of Perinatology Root causes of kernicterus L Johnson et al S31

These three infants were excluded from further analysis because culture) and four had presumed sepsis (including two with their clinical profiles were considered as usually representing probable viral illness). non-preventable causes of icteric sequelae. Clinical diagnoses for severe hyperbilirubinemia. There were Concurrent sepsis. Presumption of sepsis was based on serial multiple co-morbidities that were associated with excessive white blood cell and differential counts and treatment with hyperbilirubinemia (Appendix 1), and the severity of clinical antibiotics. Of those tested and confirmed to have G6PD deficiency sequelae was regardless of its contributory clinical cause. (n ¼ 26), six had blood culture proven sepsis and in two infants Dehydration at readmission was defined as X15% weight below sepsis was presumed, including one with probable viral sepsis. In birthweight and/or Na X150 mEq lÀ1, such as 22% weight loss in the remainder 99 infants (in whom G6PD status was often not one infant, and hypernatremia, 166 mEq lÀ1 in another infant. investigated), six were proven to have sepsis (positive blood The data in Table 3 represent the relative frequencies of diagnostic criteria related to readmission age. Most babies were admitted to

45 GA <37 weeks (n = 30) 40 GA ≥37 weeks (n = 90) 35 25 30 25 20 20 15 10 15 Average distribution / GA week

Percent distribution (%) 5 0 10 2500 3000 3500 4000 4500 – – – – – >4500

2001 2501 3001 3501 4001 Percent distrbution (%) 5 Birth weight (g) Figure 2 Percentage distribution of birth weight is shown for infants with ABE 0 as well as those without recognized ABE but with subsequent chronic kernicterus. 35 36 37 38 39 40 41 Though the number of infants with birth weight >3.5 kg is unusual for infants Gestational age (GA, weeks) <37 weeks GA, there was no difference in percentage distribution for cohort infants between 3 and 3.5 kg birth weight. These observations were consistent with Figure 3 Distribution of gestational age (weeks) is shown for infants with ABE the finding that 34.9% of the infants with GA <37 weeks with kernicterus were as well as those without recognized ABE but with subsequent chronic kernicterus. LGA (large for gestational age) as compared with 24.7% of term infants with In infants with gestational age 39 to 41 weeks (n ¼ 50) the data was often not kernicterus who were LGA. Data are not presented for 5 infants in whom there specific to delineate data for each week; data were grouped and averaged for were no credible records of birthweight. comparison.

Table 3 Infants with ABE and/or chronic kernicterus: readmission age (days), TSB (mg per 100 ml) and diagnostic categoriesa

Readmit age (days) Day 2.5–3.5 Day 4 Day 5 Day 6 Day 7–9 Day 10–27 Not admitted (untreated)

(n ¼ 122) 13 24 24 18 21 15 7 TSB, mg per 100 ml median 38.5 39.2 39.5 35.5 40 32.6 F TSB, mg per 100 ml range 21.4–52 27–50 29–59.9 24–46 24.5–54 20.7–54 F G6PD deficiency (n ¼ 26) 23% 30% 25% 17% 29% 7% 0% Hemolysis (n ¼ 25) 7% 21% 29% 17% 5% 40% 14% Birth trauma (n ¼ 18) 0% 13% 21% 28% 14% 7% 14% Idiopathicb (n ¼ 53) 69% 38% 25% 39% 52% 57% 71%

Abbreviations: ABE, acute bilirubin encephalopathy; G6PD, glucose 6-phosphate-dehydrogenase; TSB, total serum bilirubin. The data shown in this table do not include three infants with severe kernicterus: two had Crigler–Najjar, readmitted at age 3 and 5 days, and one had galactosemia, readmitted at age 7 days. aThese diagnoses represent infants investigated with usual commercially available clinical laboratory investigations (such as, exhaled carbon monoxide testing was unavailable). bThis idiopathic group includes infants as defined in the text.

Journal of Perinatology Root causes of kernicterus L Johnson et al S32 the hospital for excessive jaundice, but were often not recognized or Table 4 Concurrent morbidities in infants with acute bilirubin encephalopathy diagnosed as having ABE (Table 4). and/or chronic kernicterus (n ¼ 122) Diagnostic category Systemic infection Dehydration Early-onset hyperbilirubinemia. Infants readmitted on days 2.5 to 3.5 (<84 h of age) are infants with acute early-onset G6PD deficiency 8/26 (30.7%) 4/26 (15.4%) hyperbilirubinemia (Table 3). The highest TSB reported in these Hemolysis 3/25 (12%) 5/25 (20%) Birth trauma 1/18 (5.5%) 4/18 (22%) 13 infants was 52 mg per 100 ml in a baby girl, with an older sibling Idiopathic 6/53 (11.3%) 8/53 (15.1%) who had jaundice treated with phototherapy, and who had no blood- group incompatibility, evidence of hemolysis, excessive birth trauma Abbreviation: G6PD, glucose 6-phosphate-dehydrogenase. These data do not include three infants with severe kernicterus: two had Crigler–Najjar or infection and was not jaundiced in later infancy or childhood. syndrome, readmitted at age 3 and 5 days, respectively, and one with galactosemia who The total number of infants in whom no specific diagnosis was was readmitted at age 7 days. established, 9 of 13 (69%), was categorized as having an idiopathic cause (Appendix 1 for clinical vignettes). These nine infants, six of whom were girls, represent an unusual group of infants who had raised by parents whose infants were in early stages of ABE were excessively rapid rates of TSB rise associated with the following: inappropriate. The ‘first-contact practitioners’ were: (a) an office (a) probable increased bilirubin production due to ABO triage nurse, (b) a nurse (random) at the birthing hospital, (c) a incompatibility with a negative direct antiglobulin test, a hematocrit home-visiting nurse, (d) a practicing physician (often not the >50% and reticulocytosis at the upper limit of normal for postnatal discharging physician), (d) an emergency room physician and age, plethora and visible bruising; (b) severe dehydration and sepsis; (e) a lactation consultant. The first contact was most likely an (c) possible unidentified genetic polymorphisms or coding errors and office visit (38%), emergency room (29%) or call to a physician’s delayed bilirubin elimination based on a strong family history of office (24%). Approximately 63% had made one contact, but 37% Gilbert’s syndrome or unexplained jaundice. made between 2 to 5 contacts. A review of medical records indicated that most nurses, pediatricians and neonatologists were unfamiliar Infants not readmitted. These infants represent those with with the clinical signs of ABE and the progressive clinical unrecognized ABE and presumed excessive hyperbilirubinemia manifestations. (7 of 125, 4.8%) who subsequently showed moderate or severe post-icteric sequelae. Four of these seven babies who were not Breast-feeding support. Only two infants were exclusively readmitted had severe sequelae: two had idiopathic jaundice, one formula fed. Lactation failure was identified in over 90% of infants had jaundice associated with birth trauma and one was associated discharged on exclusive breast-feeding. There was uniformly with hemolysis. The remaining three infants never readmitted had sub-optimal lactation support (both at the birthing hospital and at moderately severe sequelae. follow-up). There was a high incidence of excessive weight loss and dehydration, and in some supplements were recommended. These Pre-discharge risk assessment infants also had confounding influences of other co-morbidities, Most infants were discharged at <48 h of age, but about 28% such as prematurity, bruising, lethargy, possible exposure to (34 of 121) were discharged beyond 48 h of age. Frequency of maternal medications or hemolytic triggers, and first-time jaundice was identified and recorded in the medical records prior to experience for breast-feeding. discharge in 70 of 125 infants: ‘no jaundice’ in 11 infants and ‘jaundice present’ in 52 infants (in 11 of these jaundice was Inappropriate parental reassurance. Commonly used evident prior to age 30 h). There was no record of jaundice in 55 of reassurances given to the babies who developed kernicterus were: 125 infant medical records. Pre-discharge TcB or TSB levels were ‘jaundice does not cause brain damage in healthy babies’, ‘kinder measured infrequently and were done in only 22 of 125 infants. and gentler approach to jaundice’, ‘do not worry, all babies get The readmission ages of these 22 infants ranged between day 3 and jaundice’, ‘you can easily get rid of jaundice with sunshine’, day 11. Severity of hyperbilirubinemia was unrecognized in all 22 ‘bilirubin is an anti-oxidant’, ‘it is like a rash’, ‘it is like a cold’, infants because their TSB levels were not interpreted on the basis of ‘jaundice gets worse before it gets better’ and ‘put them in the postnatal age-in-hours or even age-in-days, and earlier or targeted window’. follow-up was not considered, even though there was significant hyperbilirubinemia. Bilirubin and jaundice management at first follow-up visit Most infants were not given an appointment for a follow-up visit Post-birthing hospital follow-up visit within 3 to 5 days of discharge. Office-based follow-up First contact with practitioner. Data after discharge from the appointments, within 48 h of discharge from the birthing hospital, birthing hospital were often inadequate, and responses to concerns were provided for only 29 of 125 (23%) infants. Measurements of

Journal of Perinatology Root causes of kernicterus L Johnson et al S33

TcB or TSB at the follow-up office visit were not done in almost Rate of total serum bilirubin rise half of the infants. At the office visit, eliciting history for clinical We determined the rate of TSB rise for ages 24 to 72 h from a cord signs of ABE in the context of a jaundiced or symptomatic infant level of 2 mg per 100 ml and the peak TSB measured (almost was not a practice. Response to excessive TSB levels (when always at readmission) (Table 5). This rate of TSB rise was measured) was slow or referrals were made to the emergency room. corroborated in 22 of 118 infants in whom an hour-specific Among the 29 infants who returned for an office visit, follow-up pre-discharge TSB/TcB had been measured. In 18 of 22 infants, the TSB was measured within 48 h of discharge in 15 infants, and of graphic line for the projected bilirubin rate of rise from a cord TSB these five were readmitted within 2 days of the follow-up visit, to be level of 2 mg per 100 ml to the peak TSB level approximated or, treated with ‘crash-cart’ interventions. In the remaining 14 infants, was below, the measured hour-specific pre-discharge bilirubin level response to prolonged jaundice (beyond 7 days of age) was plotted on the hour-specific bilirubin nomogram. The projection reassurance. over-predicted the pre-discharge bilirubin in 4 of 22 infants: two infants with G6PD deficiency (one with a known exposure to moth Peak TSB levels and diagnostic categories by age at balls and the other in whom pre-discharge TSB was >99th readmission for infants with ABE percentile), one infant with nosocomial sepsis acquired 4 days after The likelihood of progressive hyperbilirubinemia could have been hospital readmission on day 7 and another infant with severe birth predicted based on: (a) severity of pre-discharge hyperbilirubinemia trauma. The rate of TSB rise in infants discharged at age <24 h, or excessive levels at first follow-up visit; (b) unrecognized 24 to 47 h and <72 h was determined in a select cohort of 58 of hemolysis due to major or minor blood type incompatibility; 125 infants with kernicterus who were discharged at age <72 h (c) unrecognized G6PD deficiency, which may have been suspected and readmitted at age 5 days (10 of these infants had a either because of hyperbilirubinemia or because of racial/ethnic pre-discharge bilirubin value). We also calculated what would have background; and (d) delayed bilirubin clearance complicated by been the hour-specific TSB level at discharge for each infant. suboptimal breast milk intake with diminished urine and stool Table 5 shows TSB rates of rise stratified for X0.20 to <0.30 mg output and unrecognized genetic bilirubin elimination disorders. per 100 ml per hour and X0.30 mg per 100 ml per hour. For Data are presented for peak TSB levels following admission and infants discharged at <48 h age, 29 of 39 (72%) would have had were reviewed in the context of the clinical diagnosis shown in TSB levels that meet the 2004 AAP thresholds for intensive 17,25,26 Table 3. Among the infants who were not hospitalized phototherapy. Out of 58 infants discharged before age 72 h, 43 (n ¼ 7) but subsequently showed moderate to severe post-icteric (75%) had projected rates of TSB rise X0.30 mg per 100 ml per sequelae (Appendix 1), none was treated for prolonged (>2 weeks) hour and met the criteria for exchange transfusion at discharge. All jaundice in spite of repeated parent phone calls voicing concerns. 58 infants would have showed pre-discharge TSB levels >75th The TSB level that was measured in only one of these infants at percentile for age in hours at the time of discharge. age 4 days was 20 mg per 100 ml, and no subsequent measurements were obtained for persistent jaundice. Diagnostic Outcome of infants with peak TSB levels >35 mg per 100 ml categories in the seven infants included hemolysis in one, birth All infants with peak TSB levels >35 mg per 100 ml who were trauma in one and idiopathic in five. readmitted (n ¼ 73) had post-icteric sequelae. Of these, four died

Table 5 Infants discharged before age 72 h and readmitted before age 6 days (n ¼ 58), whose estimated TSB levels at discharge met the 2004 AAP guidelines for treatment with phototherapy or exchange transfusion

Birth hospital TSB met phototherapy TSB met exchange Projected rate of rise Projected rate of rise X0.3 discharge age criteria at discharge transfusion criteria X0.2 to <0.3 (mg per (mg per 100 ml per hour) at discharge 100 ml per hour)

<24h (n ¼ 5) None (0/5) None (0/5) None (0/5) 100% (5/5) 24–47 h (n ¼ 34) 79% (27/34) 18% (6/34) 35% (12/34) 65% (22/34) 48 to <72 h (n ¼ 19) 95% (18/19) 58% (11/19) 16% (3/19) 84% (16/19) All <72 h (n ¼ 58) 78% (45/58) 29% (17/58) 25% (15/58) 75% (43/58)

Abbreviations: AAP, American Academy of Pediatrics; G6PD, glucose 6-phosphate-dehydrogenase; TSB, total serum bilirubin. Assuming a cord TSB of 2 mg per 100 ml, the hourly rate of TSB rise was estimated on the basis of age at measured peak TSB (almost always the age at readmission). The rate of TSB rise was corroborated using measured pre-discharge TSB in 8 of 10 infants (discharged before 72 h and readmitted before age 6 days). In two infants with G6PD deficiency, one with a predischarge TSB >75th percentile and subsequent mothball exposure and the other infant with predischarge TSB >99th percentile and later progressive ABE at age 3.5 days. In 53 of 58 of this select cohort of infants, the estimated pre-discharge TSB level was >95th percentile for age in hours. Of those discharged at age <24 h (n ¼ 5), four infants had a TSB>35 mg per 100 ml at readmission and would be likely to have had a rate of TSB rise >0.4 mg per 100 ml per hour. The pre-discharge TcB or TSB for all 22 of 125 infants in whom measurements were made had values X75th percentile at discharge.

Journal of Perinatology Root causes of kernicterus L Johnson et al S34 soon after readmission; 61 (83.6%) had severe sequelae, six (8.2%) and exchange transfusion, there was overlap in length of time that had moderate sequelae and two (2.7%) had mild sequelae elapsed from parents’ call for help and admission to a treatment (including one term male infant admitted with subtle signs of ABE facility, between infants with and without sequelae. However, this and treated only with phototherapy for a peak TSB level of 41 mg overlap tended to be shorter in the eight babies who survived per 100 ml). Most infants who presented with moderate (n ¼ 8) or without sequelae (Table 6). Thus, the outcome of eight infants advanced (n ¼ 55) ABE had severe sequelae (55 of 63; 87%, (73%) who did not have excessive pre-admission delays out of a including three infants who presented with moderate ABE). Severe total of 11 infants managed by a ‘crash-cart’ approach had no sequelae were also noted in three of the four infants who were sequelae. In 12 of the 23 infants treated with exchange transfusion, readmitted with subtle signs of ABE. Phototherapy was the only ‘crash-cart’ intervention was not feasible because of unavoidable treatment for four infants with TSB levels >35 mg per 100 ml. Of circumstances such as need for transport to a tertiary care facility these, two infants (50%) died at readmission and postnatal age <8 or technical issues such as resuscitation, requirement for the days as compared with 2 of 69 (3%) infants who died after interosseous route for stabilization and parenteral correction of subsequent phototherapy and exchange transfusion. severe dehydration or surgical venous access to accomplish exchange transfusion. As shown in Table 6 reversal was more likely Outcome of infants with TSB p35 mg per 100 ml in infants readmitted by age 5 days. Two infants died: one before any treatment could be initiated and Treatment of ABE with phototherapy alone (20 of 43) was the other treated with brief phototherapy. One infant was lost to uniformly dismal. Five of the 20 babies treated with only follow-up before age 3 months. The remaining infants (n ¼ 43) phototherapy were readmitted by age 4 days, one on day 2.5 were treated with phototherapy alone (n ¼ 20) or exchange (TSB of 22.4 mg per 100 ml) and four on day 4 (TSB ranged from transfusion and phototherapy (n ¼ 23). Interventions in 8 of these 28.3 to 34.5 mg per 100 ml). These infants had acute early-onset 23 infants was characterized by: (i) a pattern of immediate hyperbilirubinemia and were exposed to rapid rates of TSB rise. institution of phototherapy with multiple lights to expose as much The readmission age of eight of the 20 babies treated with only of the body surface as feasible; (ii) performance of procedures phototherapy was after day 9 (TSB ranged from 20.7 to 29.3 mg per while the infant was under phototherapy; and (iii) urgent 100 ml including one baby with congenital spherocytosis admitted preparation for exchange transfusion, implemented as soon as on day 27). These eight infants had prolonged duration of jaundice possible or indicated by clinical signs. As shown in Table 6 and and presumed significant hyperbilirubinemia that was treated with Figures 4 and 5, we noted that the interval between admission and phototherapy of unspecified intensity. institution of an exchange transfusion was <6 h in seven of eight On the basis of this data, we believe that ‘crash-cart’ infants who survived without sequelae. On the basis of these data, management after hospital admission has the potential to prevent we defined this pattern of intervention strategy as a ‘crash-cart’ sequelae in some babies even if advanced signs of ABE are present. approach. In the 15 of 23 infants treated with both phototherapy However, emergency post-admission management cannot reverse and exchange transfusion who sustained sequelae, treatment of all acute-stage damage. Our review and analysis of the Registry three met our definition for ‘crash-cart’ treatment. In these three cases lead us to recommend that infants whose TSB levels are close infants and considering all 23 infants treated with phototherapy to exchange transfusion thresholds17 should be screened with an

Table 6 Post-icteric sequelae associated with interval between time of first urgent contact to initiation of exchange transfusion for infants with peak TSBp35 mg per 100 ml (n ¼ 43)

Assessment of timeliness of response and intervention No post-icteric sequelaePhototherapy With post-icteric sequelae and exchange (n ¼ 8) Phototherapy and Phototherapy treatment exchange (n ¼ 15) only (n ¼ 20)

Hours from first call to physician/nurse until admission Mean 22.5±21.5 17.3±26.3 59.8±67.7 Range 4–52 h 0–96 h 4–216 h Number of infants treated with an exchange X6 h after admission 1/8 10/15 No exchange Hours from admission to start of exchange: median (range) 4 (3–12 h) 12 (4–29 h) Number of infants readmitted at age >5 days 2/8 10/15 10/20 Age at readmission median (range) 5 (3–8 days) 8 (4–14 days) 8 (2.5–16 days)

This table excludes three infants: one infant treated only with Phototherapy, who was lost to follow-up, one who died before any treatment could be initiated (TSB ¼ 31.7 mg per 100 ml), and one who was not readmitted or treated (TSB of 20 mg per 100 ml at 4 days of age and no subsequent TSB levels for prolonged jaundice >6 weeks).

Journal of Perinatology Root causes of kernicterus L Johnson et al S35 automated auditory brainstem response and treated using a hyperbilirubinemia persisted for over 4 weeks in one and over ‘crash-cart’ approach. 2 weeks in the other two. (c) Sepsis. One infant, at term gestation, developed sepsis and positive blood culture for clostridium Infants with peak TSB <25 mg per 100 ml who developed perfrigens and enterococcus fecalis. He was admitted with severe kernicterus dehydration (Na 160 mEq/l) on day 11.5. This infant was treated Six of the 118 infants with peak measured TSB level <25 mg per with a ten-day course of antibiotics, 2 days of intravenous fluids 100 ml developed chronic sequelae. One infant was treated with and three days of phototherapy. These five infants highlight the both exchange transfusion and phototherapy after being readmitted confounding and deleterious contributions of sepsis, hypernatremic on day 6 following a traumatic home birth and subsequent dehydration and slow post-admission reduction of the body development of E. coli sepsis (see Appendix 1). In the other five bilirubin load with sub-optimal phototherapy. infants who were treated with phototherapy alone, we explored the probable antecedent clinical factors: (a) Early postnatal age. One Association of neonatal apnea as a clinical manifestation of ABE infant was readmitted at age 2.5 days with TSB of 22.4 mg per 100 ml. Case records that provided detailed records of apnea, bradycardia, Concurrent co-morbidity included severe dehydration in the desaturations, periodic breathing as well as notations for presence absence of hemolysis and sepsis. The cause of hyperbilirubinemia or absence of apnea by either the neonatal nurses or physicians was not identified and listed as idiopathic. For this infant, increased were available and reviewed in 108 infants. Occurrence of risk for bilirubin toxicity was most likely because of decreased symptomatic apneic events, noted on readmission for ABE and for binding affinity of albumin for bilirubin during the first 3 the ensuing 72 h, was ascertained and are listed in Table 7. These postnatal days and a rapid rate of TSB rise. (b) Prolonged exposure data suggest that apnea associated with severe hyperbilirubinemia to severe hyperbilirubinemia (>2 weeks). Three infants with TSB could be a manifestation of ABE and may be confounded by range from 20.7 to 24.9 mg per 100 ml had uncomplicated delivery gestational immaturity as well as gender. and newborn courses. Their significant jaundice and

30 40.0 Phototherapy Phototherapy Phototherapy 25 and exchange and exchange treatment only Phototherapy Phototherapy Phototherapy 35.0 and exchange and exchange treatment only 20

30.0 15

25.0 10 Age at readmission (days) 20.0 5 Peak total serum bilirubin (md/dL)

0 15.0 No sequelae Infants with post-icteric sequelae No sequelae Infants with post-icteric sequelae Figure 4 Age at readmission is shown for infants with ABE and TSB p35 mg Figure 5 Outcome in infants with ABE is shown for infants with peak TSB per 100 ml as designated by intervention and sequelae. p35 mg per 100 ml as designated by intervention and sequelae.

Table 7 Impact of immaturity and gender on incidence of neonatal apnea as a sign of ABE (n ¼ 108)

Associated neonatal apnea TSB p35 mg per 100 ml (n ¼ 42) TSB >35 mg per 100 ml (n ¼ 66)

Male Female Male Female

GA X35 to <37 weeks (n ¼ 28) 14/28 (50%) 6/42 (14.3%) 1/42 (2.4%) 3/66 (4.5%) 4/66 (6.1%) GA X37 weeks (n ¼ 80) 27/80 (33.8%) 6/42 (14.3%) 1/42 (2.4%) 15/66 (22.7%) 5/66 (7.6%)

Total (n ¼ 108) 41/108 (38%) 14/42 (33.3%) 27/66 (40.9%)

Abbreviations: ABE, acute bilirubin encephalopathy; GA, gestational age. Data on presence or absence of neonatal apnea were unavailable for 17 of 125 infants.

Journal of Perinatology Root causes of kernicterus L Johnson et al S36

Table 8 Infants with non-specific signs (subtle) of ABE who sustained post-icteric sequelae (n ¼ 9)

GA (weeks)/ Readmit Peak TSB Treatment Icteric sequelae Concurrent clinical events sex/race age (mg per 100 ml)

39/M/A 3 days 27.8 Phototherapy None Urosepsis (Escherichia coli) at readmission. Stat photo, exchange exchange within 6 h, MRI age 5 days confirms kernicterus 36/M/W 5 days 30.0 Phototherapy Moderate Birth trauma, very jaundiced at day 4 follow-upFNo TSB was measured for prolonged jaundice (>6 weeks) 38/M/W 6 days 30.3 Phototherapy Mild Bruising. ABO incompatibility. DAT negative. TSB X18 mg per 100 ml for several days. Family history of Gilbert syndrome. MRI at day 17 confirms kernicterus. 35/F/W 5 days 31.5 Phototherapy Severe Birth trauma. Plethora at birth. First follow-up at day 5. Family history of jaundice 36/F/W 5.5 days 36.0 Phototherapy Severe At readmission, Hct ¼ 43 and 15% weight loss from birth exchange 37/F/W 3.5 days 38.5 Phototherapy Moderate ABO incompatibility, DAT negative, Hct: 64% retic: 8.8% at readmission. exchange 38/M/W 7 days 41.0 Phototherapy Mild Office TSB ¼ 31 mg per 100 ml. Readmission TSB had progressed to 41 mg per 100 ml, then declined to 29 mg per 100 ml with intensive phototherapy and intravenous fluids. ABO incompatibility, DAT positive and dehydration. 38/F/W None None No treatment Severe Birth trauma. Jaundiced at follow-up day 12, TSB ¼ 13 mg per 100 ml. Prolonged jaundice (>6 weeks). 35/F/W None None No treatment Severe Very jaundiced at day four follow-up. No TSB done. Prolonged jaundice (>6 weeks)

Abbreviations: A, Asian; ABE, acute bilirubin encephalopathy; F, female; GA, gestational age; M, male; MRI, magnetic resonance imaging; DAT, direct antiglobulin test; TSB, total serum bilirubin; W, white. Infant birth weight range: 2951–4200 g.

Absence of definitive signs of acute kernicterus Identified ‘breakdowns’ in the health services for newborn Using the BIND score, we identified nine infants with clinical signs jaundice management for ABE and scores <4. These infants were labeled to have subtle or All cases were assessed to have multiple and specific root causes or non-specific ABE. None had an auditory brainstem response (ABR) lapses in the care provided by multiple providers at multiple sites. testing during their acute phase of hyperbilirubinemia. Clinical Delays in interventions were often related to a pervasive lack of profile and the post-icteric sequelae are shown in Table 8. Severe awareness of the impending irreversible neurotoxicity. The most sequelae were noted in 4 of 9 infants. In contrast, among 91 of 116 common root causes for failures of health systems (Table 9), based infants with advanced ABE (BIND scores >6), nine infants on the Institute of Medicine patient safety matrix, were similar to subsequently had no (n ¼ 3), mild (n ¼ 1) and moderate those provided as preliminary data in an earlier report.16 (n ¼ 5) post-icteric sequelae. The three infants with no icteric sequelae had ‘crash-cart’ management at hospital admission. Lessons learned These observations are consistent with earlier reports1,2 of 15 to The antecedent clinical and health services events experienced by 16% of babies with Rh disease who developed kernicteric sequelae infants reported to the Pilot USA Kernicterus Registry inform gaps and were not recognized as having definite neurological signs of in the clinical and public health management of newborn jaundice acute kernicterus in the first week after birth. Retrospective use of that may not be evident by traditional epidemiological investigation the BIND score based on hospital records and reported parental or surveillance. These include the following: concerns was helpful to document and monitor the progression of ABE (as shown in Table 1). However, its usefulness, in conjunction (1) Kernicterus cases are continuing to be reported in the United States. with serial ABR measurements, as a guide for treatment, as well as (2) Over 95% of the cases were attributed to a multi-factorial its prognostic value considered in association with the timeliness failure of the post-partum and newborn healthcare delivery and efficacy of treatment, needs to be validated prospectively. system.

Journal of Perinatology Root causes of kernicterus L Johnson et al S37

Table 9 Breakdowns in health systems for newborn jaundice management identified in infants who developed kernicterus (reported in 1992–2004)

1. Failure to recognize the clinical significance of jaundice within the first 24 h after birth. 2. Failure of clinicians to recognize the limitations of visual recognition of jaundice. 3. Failure of clinicians to recognize the onset and progression of clinical jaundice and document its severity by bilirubin measurement before discharge from the hospital. 4. Failure to ensure post-discharge follow-up based on the severity of pre-discharge hyperbilirubinemia. 5. Failure to respond to parental concerns of newborn jaundice, poor feeding, lactation difficulties and change in newborns behavior and activity in a timely manner. 6. Failure to provide ongoing effective lactation support in breast-feeding babies to ensure adequacy of intake. 7. Failure to recognize the impact of skin, color race, ethnicity and family history on severity of newborn jaundice. 8. Failure to monitor the progressive hyperbilirubinemia prior to onset of ABE 9. Failure to institute interventional strategies to prevent severe hyperbilirubinemia when bilirubin is rising more rapidly than expected. 10. Failure to aggressively treat severe hyperbilirubinemia with intensive phototherapy or exchange transfusion for hazardous bilirubin levels. 11. Failure to communicate with parents and educate them about the potential irreversible risks of jaundice during the newborn period and infancy. 12. Failure to recognize the need to identify post-icteric sequelae following hazardous bilirubin exposure.

Abbreviation: ABE, acute bilirubin encephalopathy.

(3) National incidences of kernicterus have been defined in with phototherapy or exchange transfusion, total serum reports from Denmark, the United Kingdom and Canada. bilirubin levels in the range between 25 and 29.9 mg per Incidences of severe neonatal hyperbilirubinemia have also 100 ml were not associated with adverse neuro-developmental been reported from Sao Paulo and Jerusalem.31–36 The Pilot outcomes in infants born at or near term. However, this USA Kernicterus Registry cases do not provide any basis to retrospective study does not report concomitant signs of ABE define a national or state incidence of kernicterus in United or timeliness of intervention. There are no new clinical data States. These cases represent the minimum number of on which to base a new danger TSB level.40,42–44 Data from infants diagnosed with kernicterus and are likely to be a the Pilot USA Kernicterus Registry note that infants with any ‘tip-of-the-iceberg’. A review of these data and the current signs of ABE and peak TSB levels >35 mg per 100 ml sustain literature support the role of a systems approach to decrease post-icteric sequelae and underscore the need to better assess the incidence of extreme hyperbilirubinemia.37,38 clinical signs of acute bilirubin neurotoxicity. In the absence (4) Virtually all cases of kernicterus in the Registry could have of alternate strategies to predict the risk of neurological been prevented with early identification of potentially severe injury, the narrow margin of safety between severe hyperbilirubinemia (TSB levels above the 40th percentile), hyperbilirubinemia and acute onset of progressive recognition (before discharge or at early follow-up) of TSB encephalopathic changes, the clinical ability to predict and increase at >0.2 mg per 100 ml per hour and institution of manage severe hyperbilirubinemia, both medical and public timely medical care, intensive phototherapy and exchange health agenda should focus on prevention. transfusion as needed. On the basis of this data and the (8) Successful implementation of a systems approach to manage availability of current treatment interventions, we conclude newborn jaundice could serve as an index for the integrity of that kernicterus is almost always an unacceptable outcome the postpartum health delivery system. On the basis of family in healthy >35 weeks gestation infants in the United States. expectations in the United States, birthing safety standards This opinion is supported by recent reports in the peer need to be transparent and impeccable, and aspire to the reviewed literature.37–40 highest feasible standards with the least adverse encounters. (5) Kernicterus is a low-frequency disease with current (9) National guidelines for US clinicians have been in place interventions, but an unacceptable outcome in prevailing since 1994. In effective implementation of the 1994 AAP health practices.39 It may be characterized as an iatrogenic guidelines has been suggested as the basis for the continuing event when the management of severe neonatal reports of kernicterus. Effective implementation of the newly hyperbilirubinemia is not effective or timely. revised 2004 AAP guidelines is a matter of urgent concern. (6) For nearly all cases, responses to parental and family (10) National awareness and partnership with new and expectant concerns and involvement were inadequate.40 In most cases, parents remains an urgent need. parents were not aware, sometimes for months subsequent to the event, that bilirubin neurotoxicity was the cause of their Optimization of clinical practice child’s developmental delay and abnormalities.41 Preliminary reports from this Registry have informed the steps (7) Data from this Registry validate the consensus opinion that initiated by the AAP,45 the Center for Disease Control and there is no evidence of a specific bilirubin level linked to the Prevention,46 the Association of Women’s Health, Obstetrics and onset of ABE. As reported by Newman et al.,42 when treated Neonatal Nurses,47 and the Joint Commission Accrediting Hospital

Journal of Perinatology Root causes of kernicterus L Johnson et al S38

Organizations.29 These include standardized guidelines for early and intermediate stages of ABE may be reversible with prompt management of neonatal jaundice and hyperbilirubinemia for and effective bilirubin reduction strategies, and thereby ensure pediatricians and emergency rooms.48 Most of the patient access to effective and timely interventions. Future evidence of the education materials (brochures, videos, resource links, posters and adverse effects of either under-treatment or over-treatment of transcripts) are currently available online for public access and use hyperbilirubinemia should continue to impact clinical practice. at www.aap.org/jaundice; www.cdc.gov/jaundice, www.jcaho.org/ In progress effort by the AAP to monitor and facilitate the kernicterus and www.pickonline.org. The California Perinatal implementation of the guidelines offers a promise for effective Quality Care Collaborative has developed and implemented a clinician implementation of the guidelines.52 As practicing ‘Severe Neonatal Hyperbilirubinemia Toolkit’ (http:// clinicians at the front-line of health delivery who have to deal with www.cpqcc.org/quality_improvement.htm).49,50 State-wide or the realities of a non-existent seamless transfer of clinical regional initiatives to report severe neonatal hyperbilirubinemia information during the transition after birth, continued vigilance is (TSB levels >25 mg per 100 ml) along with outcomes for necessary. As we educate and empower expectant parents and newborn screening for other inherited disorders may be feasible clinical providers, three salient perspectives based on this research through a three-pronged partnership of providers and society to need to be considered. First, the focus of the key messages should implement a state-driven national program: (1) apply an remain evidence-based and transparent. Second, the timeline for aviation safety standard to address gaps in newborn health outreach should be coordinated and consistent with the prevailing delivery using healthcare-information-technology solutions; infrastructure of healthcare system. Third, the educational format (2) implement state-wide (regional) and national surveillance for should be that of learning and empowerment and, when necessary, severe neonatal hyperbilirubinemia; (3) provide national and advocacy. As we balance evidence-based medicine with patient global education and empowerment aids for new and safety, let us be truly prudent and protective of all newborns expectant parents. entrusted to the care of health professionals. With parents as equal partners in this endeavor, we can bridge these gaps in the safety net Need for a national initiative of US newborn health services. 10 Following the initial report by Johnson et al. delineating the need Always, there is a need for continued vigilance! for a systems approach to prevent kernicterus and the 2004 AAP guidelines,13 several international reports have provided further insight into the gaps that exist in health systems, including those Acknowledgments with institutionalized home-based post-birthing follow-up.31–34 This work was supported in part by AAMC/CDC PERT Grant MM-0448. This research Recent data from US hospitals and regional health was also supported in part by funds from the Sandy Eglin Fund and her generous systems37,38,48,50,51 have provided an insight into the impact of a support of the Pilot USA Kernicterus Registry at Pennsylvania Hospital, Philadelphia. vigilant healthcare system and its ability to change the incidence of We remember the late Audrey K Brown, MD, and value her immeasurable severe neonatal hyperbilirubinemia and frequency of exchange contributions to the initiation and maintenance of the Pilot USA Kernicterus Registry. transfusions. Effective implementation of both 1994 and 2004 AAP We thank the parents logged on the newborn jaundice list-serve as well as our guidelines remains a challenge to the AAP and the Pediatrics colleagues who contributed their experiences to the Registry. We also appreciate the administrative support of Donna Spitz (Philadelphia) and Stella Dina-Gengania community. The AAP has initiated an implementation plan.52 (Stanford). Strategies for implementation should include monitoring for its effectiveness. Currently, there is no formal reporting of kernicterus or severe hyperbilirubinemia in the United States, and the Disclosure incidence of these indices of adverse outcomes is unknown. There The authors have declared no financial interests. is an urgent need to establish a formal mechanism to identify the success or failure of any national outreach program for both References the professional and public communities. 1 Van Praagh R. Diagnosis of kernicterus in the neonatal period. Pediatrics 1961; 28: 870–874. 2 Jones MH, Sands R, Hyman CB, Sturgeon P, Koch FP. Longitudinal study of the Conclusions incidence of central nervous system damage following erythroblastosis fetalis. Regardless of the cause for jaundice, the potential risk for Pediatrics 1954; 14: 346. unrecognized, unmonitored and untreated severe 3 Perlstein M. Neurologic sequelae of erythroblastosis fetalis. Am J Dis Child 1950; 79: hyperbilirubinemia is a matter of newborn safety. As chronic 605–606. 4 Volpe JJ. Bilirubin and brain injury. In: Volpe JJ (ed). Neurology of the Newborn, 4th kernicterus is preventable but not treatable, our focus needs to be edn. 2001. rooted in a preventive approach. We need to educate clinicians and 5 Johnson L, Brown AK, Bhutani V. BINDFa clinical score for bilirubin induced society about the warning signs of bilirubin neurotoxicity because neurologic dysfunction in newborns. Pediatrics 1999; 104: 746.

Journal of Perinatology Root causes of kernicterus L Johnson et al S39

6 Bhutani VK, Johnson L, Keren R. Acute bilirubin encephalopathyy before it is too late. 28 Institute of Medicine. To err is human: building a safer health system. 1 November Contemporary Pediatr 2005; 54–74. http://www.modernmedicine.com/modernmedicine/ 1999. http://www.iom.edu/?id ¼ 12735. Features/Treating-acute-bilirubin-encephalopathy–before-it/ArticleStandard/Article/detail/ 29 Joint Commission Accrediting Hospital Organizations (JCAHO). Revised guidance to 161379. help prevent kernicterus. Sentinel Event Alert 2004; 31(31): 1–2. 7 Shapiro SM. Definition of the clinical spectrum of kernicterus and bilirubin-induced 30 Bhutani VK, Johnson L. Kernicterus in late preterm infants cared for as term healthy neurologic dysfunction (BIND). J Perinatol 2005; 25(1): 54–59. infants. Semin Perinatol 2006; 30(2): 89–97. 8 Shapiro SM, Bhutani VK, Johnson L. Hyperbilirubinemia and kernicterus. Clin 31 Ebbesen F, Nyboe J. Postnatal changes in the ability of plasma albumin to bind Perinatol 2006; 33(2): 387–410. bilirubin. Acta Paediatr Scand 1983; 72: 665–670. 9 Odell GB, Storey GNB, Rosenberg LA. Studies in kernicterus. III. The saturation of 32 Ebbesen F. Recurrence of kernicterus in term and near-term infants in Denmark. Acta serum proteins with bilirubin during neonatal life and its relationship to brain damage Paediatr 2000; 89: 1213–1217. at five years. J Pediatr 1970; 76: 12–21. 33 Ebbesen F, Andersson C, Verder H, Grytter C, Pedersen-Bjergaard L, Petersen JR et al. 10 Johnson L, Boggs Jr TR. Bilirubin-dependent brain damage: incidence and indication for Extreme hyperbilirubinaemia in term and near-term infants in Denmark. Acta treatment. In: Odell GB, Schaffer R, Simopoulous AP (eds). Phototherapy in the Newborn: Paediatr 2005; 94: 59–64. An Overview. National Academy of Sciences: Washington, DC, 1974, pp 122–149. 34 Manning DJ, Maxwell MJ, Todd PJ, Platt MJ. Prospective surveillance study of severe 11 Diamond I. Kernicterus: revised concepts of pathogenesis and management. Pediatrics hyperbilirubinaemia in the newborn in the United Kingdom and Ireland. Arch Dis 1966; 38: 539–542. Child. Fetal Neonatal Ed. Online publication. 0.1136/adc.2006.105361. http:// 12 Zuelzer WW, Mudgett RT. Kernicterus; etiologic study based on an analysis of 55 cases. fn.bmj.com/cgi/rapidpdf/adc.2006.105361v1. Pediatrics 1950; 6(1:3): 452–474. 35 Sgro M, Campbell D, Shah V. Incidence and causes of severe neonatal 13 American Academy of Pediatrics, Provisional Committee for Quality Improvement. hyperbilirubinemia in Canada. CMAJ 2006; 175: 587–590. Practice parameter: management of hyperbilirubinemia in the healthy term newborn. 36 Facchini FP, Mezzacappa MA, Rosa IR, Mezzacappa Filho F, Aranha-Netto A, Marba ST. Pediatrics 1994; 94: 558–565. Follow-up of neonatal jaundice in term and late premature newborns. J Pediatr (Rio J) 14 Palmer RH, Ezhuthachan S, Newman C, Maisels MJ, Testa MA. Management of 2007; 83(4): 313–322. hyperbilirubinemia in newborns: measuring performance using a benchmarking 37 Kaplan M, Bromiker R, Schimmel MS, Algur N, Hammerman C. Evaluation of model. Pediatrics 2004; 114(3): 902. discharge management in the prediction of hyperbilirubinemia: the Jerusalem 15 Johnson LH, Bhutani VK. Guidelines for management of the jaundiced term and near- experience. J Pediatr 2007; 150(4): 412–417. term infant. Clin Perinatol 1998; 25: 555–574. 38 Bhutani VK, Johnson LH, Schwoebel A, Gennaro S. A systems approach for neonatal 16 Johnson L, Brown AK, Bhutani VK. System-based approach to management of neonatal hyperbilirubinemia in term and near-term newborns. J Obstet Gynecol Neonatal Nurs jaundice and prevention of kernicterus. J Pediatr 2002; 93: 488–494. 2006; 35(4): 444–455. 17 American Academy of Pediatrics Clinical Practice Guideline: Management of 39 Eggert LD, Wiedmeier SE, Wilson J, Christensen RD. The effect of instituting a hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics prehospital-discharge newborn bilirubin screening program in an 18-hospital health 2004; 114: 297–316. system. Pediatrics 2006; 117: e855–e862. 18 Hansen TW. Acute management of extreme neonatal jaundiceFthe potential benefits 40 Bhutani VK, Donn SM, Johnson LH. Risk management of severe neonatal of intensified phototherapy and interruption of enterohepatic bilirubin circulation. Acta hyperbilirubinemia: to prevent kernicterus. Clin Perinatol 2005; 32(1): 125–139. Paediatr 1997; 86(8): 843–846. 41 Susan E. Sheridan, consumer, Testimony to the National Summit on Medical Errors 19 Ip S, Chung M, Kulig J, O’Brien R, Sege R, Glicken S, et al., Subcommittee on and Patient Safety Research, Washington, DC, 11 September 2000, www.quic.gov/ Hyperbilirubinemia. An evidence-based review of important issues concerning neonatal summit/wsheridan.htm (accessed 21 March 2003). hyperbilirubinemia. Pediatrics 2004; 114: e130–e153. 42 Newman TB, Liljestrand P, Escobar GJ. Infants with bilirubin levels of 30 mg/dl or more 20 Raju TN, Higgins RD, Stark AR, Leveno KJ. Optimizing care and outcome for late-preterm in a large managed care organization. Pediatrics 2003; 111(6 Pt 1): 1303–1311. (near-term) infants: a summary of the workshop sponsored by the National Institute of Child 43 Lucey JE. Kernicterus: revised concepts of pathogenesis and management. Commentary. Health and Human Development. Pediatrics 2006; 118(3): 1207–1214. Pediatrics 1966; 38: 545–546. 21 Palmer RH, Keren R, Maisels MJ, Yeargin-Allsopp M. National Institute of Child Health 44 Wennberg RP, Ahlfors CE, Bhutani VK, Johnson LH, Shapiro SM. Toward and Human Development (NICHD) conference on kernicterus: a population perspective understanding kernicterus: a challenge to improve the management of jaundiced on prevention of kernicterus. J Perinatol 2004; 24(11): 723–725. newborns. Pediatrics 2006; 117: 474–485. 22 Stevenson DK, Wong RJ, Vreman HJ, McDonagh AF, Maisels MJ, Lightner DA. NICHD 45 Lannon C, Stark AR. Closing the gap between guidelines and practice: ensuring safe Conference on Kernicterus: research on prevention of bilirubin-induced brain injury and healthy beginnings. Pediatrics 2004; 114: 494–496. and kernicterus: bench-to-bedsideFdiagnostic methods and prevention and treatment 46 Center for Disease Control and Prevention. http://www.cdc.gov/ncbddd/dd/kernichome.htm. strategies. J Perinatol 2004; 24: 521–525. 47 Association of Women’s Health, Obstetrics and Neonatal Nurses. http://www.awhon- 23 Sheridan SE. Parents of infants and children with kernicterus. J Perinatol 2005; 25(4): n.org/awhonn/product.detail.do?productCode ¼ HNPP-CD-2NDI. 227–228. 48 Smitherman H, Stark AR, Bhutani VK. Early recognition of neonatal hyperbilirubinemia 24 Bhutani VK, Johnson LH, Maisels MJ, Newman TB, Phibbs C, Stark AR et al. and its emergent management. Semin Fetal Neonatal Med 2006; 11: 214–224. Kernicterus: epidemiological strategies for its prevention through systems-based 49 California Perinatal Quality Care Collaborative. http://www.cpqcc.org/ approaches. J Perinatol 2004; 24: 650–662. quality_improvement.htm. 25 Bhutani VK, Johnson L, Sivieri EM. Predictive ability of a pre-discharge hour-specific 50 Keren R, Luan X, Friedman S, Saddlemire S, Cnaan A, Bhutani VK. A comparison serum bilirubin for subsequent significant hyperbilirubinemia in healthy term and of alternative risk-assessment strategies for predicting significant neonatal near-term newborns. Pediatrics 1999; 103(1): 6–14. hyperbilirubinemia in term and near-term infants. Pediatrics 2008; 121(1): 26 Stevenson DK, Fanaroff AA, Maisels MJ, Young BW, Wong RJ, Vreman HJ et al. e170–e179. Prediction of hyperbilirubinemia in term and near-term newborn infants. Pediatrics 51 Lazarus C, Avchen RN. Neonatal hyperbilirubinemia management: a model for change. 2001; 108: 31–39. J Perinatol 2009; 29(Suppl 1): S58–S60. 27 Bhutani VK, Johnson LH, Keren R. Diagnosis and management of hyperbilirubinemia in 52 Stark AR, Lannon CM. Systems changes to prevent severe hyperbilirubinemia and the term neonate: for a safer first week. Pediatr Clin North Am 2004; 51(4): 843–861. promote breastfeeding: pilot approaches. J Perinatol 2009; 29(Suppl 1): S53–S57.

Journal of Perinatology ora fPerinatology of Journal S40

Appendix 1

Code Birth year BW (g) GA (weeks) Sex Race Discharge Readmit Readmit Peak TSB ABE Exch Photo Icteric Contributing factors age (days) age (days) TSB (mg per sequelae (mg per 100 ml) 100 ml)

Birth trauma P-082 2002 3320 37 F W 2.0 6.5 25.3 25.3 ADV No Yes MOD ABO incompatibility, DAT positive; Hct 51%, jaundice <24 h, prolonged jaundice P-036 2001 3572 39.6 M W 1.5 4.5 25.0 28.3 MOD No Yes SEV Family (sibling) history of jaundice

P-108 1998 3757 36 M W 3.0 5.0 30.0 30.0 SUB No Yes MOD Prolonged jaundiced (>6 weeks) kernicterus of causes Root M-022 1994 3048 35 F W 1.0 6.0 31.0 31.0 ADV No Yes SEV 11% weight loss at day 6 at readmission P-014 2000 4200 35 F W 1.0 5.0 31.5 31.5 SUB No Yes SEV Plethora at birth M-044 1992 2380 36 F A 1.5 5.5 32.0 32.0 ADV Yes Yes SEV 13% weight loss at readmission, Plethora, Hct 64%

M-021 1997 3680 37 M W 1.0 6.0 29.3 32.5 ADV Yes Yes SEV 13% weight loss at readmission, Hct 44% at readmission Johnson L M-096 1992 3175 35 M H 2.0 14.0 32.7 32.7 MOD Yes Yes SEV Hct 51% at day 14 (at readmission) M-039 1997 3985 39 F A 1.5 5.0 30.4 37.8 ADV Yes Yes MOD ABO incompatibility, DAT negative; 15% weight loss at

day 5, Na 152 mEq/l al et M-066 1984 2850 36.5 M W 2.0 4.0 33.8 39.8 ADV Yes Yes MOD Hct 53%, Family (sibling) history of jaundice P-104 1989 3260 38.5 M W 2.5 7.0 38.0 40.0 ADV Yes Yes SEV Jaundice <24 h age C-117 1987 3250 39 F W 4.0 8.0 41.0 41.0 MOD Yes Yes MOD Mother blood type A, Baby blood type A. Hct 40% at day 4 P-012 1999 4026 39 M W 1.0 4.0 39.0 45.0 ADV Yes Yes SEV Precipitous delivery. ABO incompatibility, family history of jaundice P-024 1993 3487 37 M H 1.0 8.5 41.3 53.9 ADV Yes Yes SEV Hct 43% at day 8.5 (at readmission) P-061 2000 2951 38 F W 1.5 none none none SUB No No SEV Seen at day 4 for jaundice. Day 12 TSB ¼ 13 mg per 100 ml, TSB peak unknown. Never treated C-122 1999 4730 39 M W HB 6.0 24.0 24.0 ADV Yes Yes SEV Sepsis (E. Coli), renal abcsess. Home birth shoulder dystocia M-038 1996 2892 36 F W 1.5 5.0 27.0 28.7 MOD No Yes SEV Sepsis presumed: partially treated maternal chotrioamnionitis for 40 h before labor. Infant blood culture negative and not treated with antibiotics; Hct 50%, Na 150 mEq/l M-083 2000 3856 37.5 M W 2.0 6.5 28.6 36.2 ADV Yes Yes SEV Nosocomial sepsis, Hct ¼ 45%

Crigler–Najjar syndrome C-121 1998 x x M W HB 5.0 40.0 40.0 ADV Yes Yes SEV Visiting nurse noted severe arching at day 5 C-120 1999 3700 38 M W HB 3.0 41.3 41.3 ADV Yes Yes SEV ABO incompatibility, DAT negative, abn. RBC morphology, Hct 66%, Na 149 mEq/l

G6PD deficiency C-046 1997 3650 38 M A 1.5 6.0 25.6 25.6 ADV Yes Yes NONE Albumin infused before exchange, Hct 50%, Na 154 mEq/l Appendix 1 Continued

Code Birth year BW (g) GA (weeks) Sex Race Discharge Readmit Readmit Peak TSB ABE Exch Photo Icteric Contributing factors age (days) age (days) TSB (mg per sequelae (mg per 100 ml) 100 ml)

L-050 1988 x 39 U Bl 1.5 7.0 24.0 28.0 ADV Yes Yes SEV Sepsis presumed; Direct bilirubin 9 mg per 100 ml at day 7 C-091 1996 2808 39 M Bl 2.0 8.0 30.0 30.0 MOD Yes Yes NONE Mild cephalohematoma P-103 1993 3062 37 M A 2.5 7.0 31.4 31.4 ADV Yes Yes SEV Birth trauma, 15% weight loss at day 7, Na 161 mEq/l C/L-071 2002 2609 40 M Bl 2.0 4.5 31.7 31.7 ADV No No DIED Died soon after admission, Hct 34% P-086 2002 2724 37 M Bl 2.0 8.5 33.0 33.0 MOD Yes Yes MOD Family (maternal) history of jaundice; Hct 35.5% M-008 1995 2920 37 M Bl 1.0 3.0 33.0 36.7 ADV No Yes SEV Hct 40% C-029 1991 2865 39 M H 1.5 3.0 38.4 38.4 ADV Yes Yes SEV Hct 40%, Abnormal RBC smear C-068 1995 3459 39 M Bl 2.0 4.0 39.2 39.2 ADV Yes Yes SEV Hct 38% M-037 1991 2665 36 F Bl 1.5 4.5 37.0 39.5 ADV Yes Yes SEV Hemolysis trigger unknown, Hct 28% at day 4.5 (at readmission) M-099 2001 3487 39 M Bl 2.5 4.0 41.4 41.4 ADV Yes Yes SEV Hct 42% at day 6 (at readmission) L-018 1993 3147 39 M Bl 1.0 5.0 37.0 42.5 ADV Yes Yes SEV Mild anemia, No evidence of hemolysis M-064 1999 3626 38 M Bl 2.0 3.5 44.0 44.0 MOD Yes Yes SEV 9% weight loss at readmssion, Hct 50% at readmission C-049 1996 4280 39 M A 1.5 6.0 45.7 45.7 ADV Yes Yes MOD Hemolysis trigger: mothball exposure M-041 1993 2925 38 M Bl 1.5 5.0 45.9 45.9 ADV Yes Yes DIED Died on day 8, two days after exchange transfusion C-125 1992 2500 36.5 F Bl x (4*) 42.0 46.0 ADV Yes Yes SEV *Day 2 discharge held for maternal reasons and infant

remained as ‘rooming-in’ patient. Day 4: Jaundice noted- Johnson L kernicterus of causes Root TSB drawn. 2 siblings had exchange transfusions M-069 1993 2625 40 M Bl 2.0 4.0 44.2 46.0 ADV Yes Yes SEV Hct 45% at readmission, hemolytic trigger: mothball

exposure al et M-019 1992 3685 39 M Bl 1.0 5.5 x 46.8 ADV No Yes DIED Moribund on readmission C-119 2000 2977 37 M Bl 6.0 13.0 54.0 54.0 ADV Yes Yes SEV 10.5% weight loss at day 13 M-084 1991 3310 38 M Bl 2.0 7.0 21.5 36.0 ADV Yes Yes SEV Nosocomial sepsis on day 11. TSB 36 at day 10.8 M-075 1990 2790 36.5 M W 2.0 5.0 36.8 39.8 ADV Yes Yes SEV Urosepsis:(E. coli), birth trauma, ABO incompatibility, DAT negative L-048 1995 3400 41 M Bl 1.5 6.0 41.0 41.0 ADV Yes Yes SEV Sepsis (E. coli) C-040 1996 2500 38 M Bl 1.5 5.0 41.3 41.3 ADV Yes Yes SEV Urosepsis, Hct 22%, Died at 6 mos. C-089 2002 2700 35.5 M Bl 2.0 7.0 46.2 46.2 ADV Yes Yes SEV Urosepsis (Citrobacter) L-042 1994 2840 37 M A 1.5 5.0 49.2 49.2 ADV Yes Yes DIED Sepsis presumed. 13.6% weight loss at day 5, Neutropenia, Blood culture negative; No hemolysis L-070 1992 3400 39 M H 2.0 4.0 50.1 50.1 ADV Yes Yes SEV Sepsis (E. coli) ora fPerinatology of Journal Galactosemia L-090 1996 3210 39 M W 2.0 7.0 47.9 47.9 ADV Yes Yes SEV 15% weight loss at day 7

Hemolysis P-058 1997 3033 36.5 M W 1.5 13.0 25.0 27.7 ADV No Yes SEV Hct 18% at readmission, abnormal RBC morphology,

TSB 18.2 and 18.6 on day 5 S41 ora fPerinatology of Journal S42 Appendix 1 Continued

Code Birth year BW (g) GA (weeks) Sex Race Discharge Readmit Readmit Peak TSB ABE Exch Photo Icteric Contributing factors age (days) age (days) TSB (mg per sequelae (mg per 100 ml) 100 ml)

C-124 2002 3632 42.5 F W HB 27.0 28.0 28.1 MOD No Yes SEV Congenital spherocytosis, Hct 27% at day 28 (readmission) C-020 1995 3130 39 M H 1.0 6.0 28.5 28.5 ADV Yes Yes SEV ABO incompatibility, DAT unknown; Hct 42% at day 6 (sibling with jaundice) P-106 1998 4309 38 M W 2.5 12.5 24.0 29.3 MOD No Yes SEV ABO incompatibility, DAT negative, Hct ¼ 43% at day 12.5. Prolonged jaundice

L-073 1989 3150 39 M W 2.0 5.0 28.7 29.5 MOD Yes Yes NONE ABO incompatibility, DAT positive, failed BAER at d/c, kernicterus of causes Root passed at 6 mos. P-074 2001 2384 35 M W 2.0 4.0 29.0 31.0 MOD Yes Yes SEV Mom has congenital spherocytosis. Baby with confirmed congenital spherocytosis

M-060 1994 3062 37 M W 1.5 (*4) 31.6 31.6 MOD NO Yes SEV Home phototherapy day 4 for TSB 31.6 mg per 100 ml, Johnson L ABO incompatibility, DAT positive M-045 1995 2863 37 M W 1.5 5.5 34.6 34.6 ADV No Yes SEV ABO incompatibility, DAT unknown, otitis media

M-033 1999 3510 39 M Bl 1.5 4.0 33.6 37.2 MOD No Yes SEV ABO incompatibility, DAT negative, Hct 41% at day 4 al et (readmission) M-078 1993 3260 39 F H 2.0 6.0 30.2 38.0 ADV Yes Yes SEV Plethora. Mom and Baby blood types: A Rh positive; hemolysis cause unknown C-057 1996 3150 36 M W 1.5 11.0 38.0 40.0 ADV Yes Yes SEV Hct 22% at day 11, Abnormal RBC morphology, hemolysis cause unknown C-002 1993 3725 39 M A 0.5 4.0 40.2 40.2 ADV Yes Yes SEV ABO incompatibility, DAT positive, sibling with jaundice P-051 2002 3057 38.5 M W 1.5 7.0 37 41.0 SUB No Yes MILD Weight loss: 15% at day 7, ABO incompatibility, DAT positive M-077 1991 2835 36 F W 2.0 5.0 44.1 44.4 ADV Yes Yes SEV 20% weight loss at day 5, hyponatremia, pertinatal methylene blue exposure. Hct=71% at birth. P-013 2002 3714 40 M W 1.0 4.0 44.8 44.8 ADV Yes Yes SEV Congenital spherocytosis, Hct 27% at day 4, Peak TSB 49 mg/dl M-017 1996 3450 39 F H 1.0 5.0 37.0 46.0 ADV Yes Yes SEV ABO incompatibility, DAT positive, jaundice <24 h age.hyponatremia, hypothyroid M-005 1997 3884 38 M A 0.5 5.0 46.0 46.0 ADV Yes Yes SEV ABO incompatibility, DAT negative, jaundice <24 h age, Na 149 mEq/l at day 5 P-023 2002 2745 38 F W 1.0 6.0 44.0 46.2 ADV Yes Yes SEV ABO incompatibility, DAT positive, jaundice at age <24 h age. M-076 1995 4687 39 F H 2.0 5.0 37.2 46.5 ADV Yes Yes SEV ABO incompatibility, DAT negative, abnormal RBC morphology, Hct 39% at day 5 M-094 1992 3050 38 F W 2.0 10.0 49.4 49.4 ADV Yes Yes SEV ABO incompatibility, DAT negative, Hct 23% at day 10.5 (readmission) M-043 2000 3180 39 M W 1.5 5.0 59.9 59.9 MOD Yes Yes SEV ABO incompatibility, DAT positive, jaundice at age 9 h, weight loss >20% Appendix 1 Continued

Code Birth year BW (g) GA (weeks) Sex Race Discharge Readmit Readmit Peak TSB ABE Exch Photo Icteric Contributing factors age (days) age (days) TSB (mg per sequelae (mg per 100 ml) 100 ml)

M-027 1993 3355 37 F W 1.0 None Not done None ADV No No SEV ABO incompatibility, DAT unknown, jaundice at age 16 h, no TSB, 16% weight loss day 15, sibling had phototherapy for jaundice M-062 2001 2715 37.5 F Bl 2.0 3.5 38.4 38.4 ADV Yes Yes SEV Sepsis: Bacteremia, gram positive organism; ABO incompatibility, DAT positive, Hct 31%, retic 18% at day 3.5 (readmission)

Idiopathic P-098 2001 4075 39 M W 2.0 none not done 20.0 MOD No No SEV Irritable day 4, TSB 20 mg per 100 ml; jaundice persisted >8 weeks. Sibling with jaundice history M-116 1986 2977 37 F W 3.5 16.0 20.7 20.7 MOD No Yes MOD ABO incompatibility, DAT negative. Plethora, jaundice at discharge, Hct 45% day 16 C-028 1999 3720 40.5 M Bl 1.5 3.0 21.4 21.4 MOD No Yes unknown O/O, Hct 48%, Retics 6%, day 3, lost to follow-up M-006 1993 3856 41 F W 1.0 2.5 22.4 22.4 ADV No Yes SEV O/O blood type, Hct 45% day 2.5Fsevere dehydrationFNa 153 mEq/l treated with interosseous fluids

P-113 1999 3348 39 F W 3.0 10.0 24.0 24.0 MOD No Yes MOD Jaundice >2 weeks that cleared after formula replaced Johnson L kernicterus of causes Root breast feedings P-105 1987 2977 40 M W 2.5 9.0 24.5 24.5 ADV No Yes SEV On formula supplement for jaundice, TSB d 8.5 was

23.5 mg per 100 ml, : Hct 56% on day 9 al et C-032 2001 3994 38 M W 1.5 4.0 22.2 27.0 SEV Yes Yes NONE A/O blood type. Some bruising, 14% wt loss day 4, Na 152 mEq/l C-107 1993 3296 38 M W 2.5 15.0 28.9 28.9 ADV No Yes SEV B/O blood type, called nurse day 7 for jaundice and arching, told jaundice is ‘OK’. First office visit day 12 C-100 2002 3419 38 M W 2.0 6.0 30.0 30.3 SUB No Yes MILD Mild bruising from preciptous birthing. ABO incompatibility, DAT unknown, Hct 58%:Retic 1%; office visit day 6 L/C-015 1994 3489 39 M W 1.0 5.0 30.6 30.6 ADV Yes Yes NONE A/O blood type, DAT negative; Hct 38%, blood smear normal M-056 1995 2700 36 M Bl 1.5 10.0 32.5 32.5 ADV Yes Yes SEV Hct 41% at day 10 admission with hypothermia and difficult intrvenous access

ora fPerinatology of Journal L/C-011 1995 2614 39 F Bl 1.0 4.0 33.0 33.0 MOD No Yes MOD B/B blood type, Hct 43% day 4, retics 1.9% day 6 M-047 2001 3310 36 M H 1.5 6.0 33.5 33.5 ADV Yes Yes SEV O/O blood type. Some bruising, jaundicd at <33 h, Hct 42% day 6 M-065 2001 3260 36 M Bl 2.0 4.0 33.0 34.0 MOD Yes Yes SEV ABO incompatibility, DAT negative M-067 1992 2825 37.5 M Bl 2.0 4.0 34.5 34.5 ADV No Yes SEV ABO incompatibility, DAT unknown, Hct 45% on day 4 M-079 1996 3350 36 M W 2.0 6.0 34.7 34.7 ADV Yes Yes SEV A/A blood type, day 6 Hct 56%

L-016 1996 2637 39 M H 1.0 5.0 34.8 34.8 MOD Yes Yes NONE Day 5 Hct 45%, retics 1.1%, albumin 2.9 g per 100 ml S43 ora fPerinatology of Journal S44 Appendix 1 Continued

Code Birth year BW (g) GA (weeks) Sex Race Discharge Readmit Readmit Peak TSB ABE Exch Photo Icteric Contributing factors age (days) age (days) TSB (mg per sequelae (mg per 100 ml) 100 ml)

M-092 1987 2700 36.5 M Bl 2.0 8.0 32.0 35.0 ADV Yes Yes SEV ABO incompatibility, DAT negative, Hct 47% on day 5 C-001 1994 3260 36 M W 0.5 4.0 35.0 35.0 ADV Yes Yes MOD ABO incompatibility, DAT negative. obvious jaundice day after discharge P-052 2000 3317 36 M W 1.5 5.0 32.0 35.0 ADV Yes Yes NONE Plethora, 17% wt. loss at day 7.0; Na=162 mEq/L M-063 2000 2438 36 F W 2.0 3.5 35.4 35.4 ADV No Yes DIED Plethora, some bruising, breast feeding ‘OK’, died soon after admission

C-102 1994 3025 36 F W 2.5 5.5 36.0 36.0 SUB Yes Yes SEV 15% weight loss at day 5.5. No ABO incompatibility, kernicterus of causes Root M-054 1990 2608 36 M Bl 1.5 8.0 33.7 36.4 ADV Yes Yes SEV Hct 43%, day 6, A/A blood type, breast feeding ‘OK’ P-072 2002 3402 38 M W 2.0 4.5 38.0 38.0 ADV Yes Yes SEV O/O blood type, Jaundice

C-031 1998 3600 37 F W 1.5 3.5 x 38.5 SUB Yes Yes MOD ABO incompatibility, DAT negative, Hct 64% retics 8.8%, Johnson L Hgb electrophoresis, pyruvate kinase and G6PD normal L-109 1985 3771 37 M W 3.0 5.0 39.0 39.0 ADV Yes Yes SEV A/A blood type, 22% weight loss day 7, Hct 70%, retic

2.4% al et P-055 1989 4224 38 M W 1.5 8.5 37.0 39.0 MOD Yes Yes SEV 15% weight loss day 7 office visit, no TSB, sib had jaundice with phototherapy P-087 1994 3572 38 M W 2.0 7.0 39.0 39.0 ADV Yes Yes MILD Jaundice at discharge. Apneic spells on readmission M-101 2000 3346 36.5 M W 2.5 5.0 39.5 39.5 ADV Yes Yes SEV B/O blood type, 16% wt loss day 5 Follow up, Na 152 mEq/l, Hct 45%, retic 5% L-114 1989 4280 39 M W 3.0 10.0 40.3 40.3 ADV Yes Yes SEV O/O blood type, day 10 Hct 48%, retic 0.6% M-004 1996 3000 36 F Bl 0.5 4.0 40.9 40.9 ADV Yes Yes SEV O/O blood type, day 4 Hct 45%, retics 3.2%, Na normal, weight loss <10%. Strong family history of jaundice. P-025 1994 3090 37 M W 1.0 12.0 41.0 41.0 ADV Yes Yes SEV ABO incompatibility, DAT negative; 17% weight loss (day 12) C-081 1987 3175 37 M W 2.0 6.0 41.8 41.8 ADV Yes Yes SEV A/A blood type. 18% wt. loss at day 6, Hct 57% C-009 1990 2015 36 F W 1.0 3.5 41.8 41.8 ADV Yes Yes SEV ABO incompatibility, DAT negative. plethora, jaundice: age 27 h: Hct 51%, retic 3.6% on day 3.5 C-053 1994 4455 41 M W 1.5 7.0 42.0 42.0 ADV Yes Yes SEV No ‘increased’ hemolysisFstudies for hepatic excretion defect ‘normal’ P-088 1998 3263 39 F W 2.0 7.0 42.0 42.0 ADV Yes Yes SEV Discharge diagnosis- breast milk jaundice: no evidence of increased hemolysis P-080 2000 3178 37.5 M W 2.0 6.0 35.0 42.0 ADV Yes Yes SEV No ABO incompatibility, 14% wt. loss at day 6 M-030 1991 3374 39 F W 1.5 3.0 36.6 44.5 ADV Yes Yes SEV O/O blood type, ruddy at birth, readmission Hct 52% at day 3, Retics ¼ 8%, Heterozygous for Gilbert’s disease (Dad has Gilberts disease) L-123 1990 4026 37 F W HB 7.0 44.7 44.7 ADV Yes Yes SEV B/B blood type, 20% weight loss day 7, Hct 54%, retic 3%, M-059 2002 3199 37 M W 1.5 19.0 44.7 44.7 ADV Yes Yes SEV Hct 43%, retic 1%: day 19, blood smear normal, possible hepatic excretion defect Appendix 1 Continued

Code Birth year BW (g) GA (weeks) Sex Race Discharge Readmit Readmit Peak TSB ABE Exch Photo Icteric Contributing factors age (days) age (days) TSB (mg per sequelae (mg per 100 ml) 100 ml)

L-003 1988 3785 39 U H 0.5 4.0 45.0 45.0 ADV Yes Yes SEV No ABO incompatibility, Exchange delayed 12 h (parental consent factors) M-035 2000 3203 38 F H 1.5 2.5 46.9 46.9 ADV Yes Yes SEV O/O Blood type, Hct ¼ 48%, Retic 5.5% at day 2.5; 2 siblings with jaundice L-093 1992 x 39 x W 2.0 8.0 49.4 49.4 ADV Yes Yes SEV Persistent increased signals in globus pallidus on multiple MRI <1 year age L-112 1979 2820 37 M W 3.0 7.0 49.7 49.7 ADV Yes Yes SEV O/O blood type, 11% weight loss day 7, Hct 50%, retic 2% M-010 1998 3629 39 F W 1.0 3.5 52.0 52.0 ADV Yes Yes SEV No ABO incompatibility, jaundice at 24 h, sibling had photoRx. G6PD sufficient P-118 1994 2325 38 M W 4.0 none none none MOD No No MOD 12% wt loss at day 4 follow up, jaundice at days 4, 7, 10 visits, no TSB done P-115 1994 3632 39.5 M W 3.0 none none none MOD No No MOD Jaundice >8 weeks, Seen at age 2 weeks, very jaundiced, no TSB done, no treatment P-026 1997 3433 39 M W 1.0 none none none MOD No No MOD ABO incompatibility, jaundice at day 2 office visit, no TSB done, jaundiced >8 weeks P-097 2000 3320 35.7 F W 2.0 none not done none SUB No No SEV No ABO incompatibility; very yellow at day 4. Prolonged

jaundice (>6 weeks): no TSB Johnson L kernicterus of causes Root C-095 1997 3415 39 M W 2.0 11.5 21.6 21.6 ADV No Yes SEV Sepsis (Clostridia), >20% weight loss at day 11.5, Na 166 mEq/l, ABO incompatibility, DAT negative

L-007 1995 3544 39 M A 1.0 3.0 27.8 27.8 SUB Yes Yes NONE Urosepsis (E. coli), MRI (at day 5) showed increased al et globus pallidus signal. Retic=5.2%, Hct=50.9% at day 3. C-110 2002 x 39 M Bl 3.0 6.0 39.0 39.0 MOD Yes Yes MOD Urosepsis: probable; Hct=58% on day 5 P-034 2001 3468 38.5 M W 1.5 4.0 38.0 41.0 ADV Yes Yes SEV Sepsis: Coagulase negative staph aureus at readmission. Jaundice noted at age 24 h M-111 1993 2905 36 F Bl 3.0 6.0 43.0 43.0 ADV Yes Yes SEV Sepsis: Day 6 Hct 36%, retic 3.2%, abnormal RBC morphology, hepatomegaly, cholestasisFprenatal or viral infection: high GGT, IGM, elevated CSF protein, C-085 1998 x 39 F Bl 2.0 7.0 48.0 48.0 ADV Yes Yes SEV Viremia: Emesis for 4 days, Hct 28% after 250 ml fluids given, intraosseous, over 3 h

Abbreviations: A, Asian; ABO, blood types; ADV, advanced; Bl, black; DAT, direct antiglobulin test; Exch, exchange; F, Female; G6PD, glucose 6-phosphate-dehydrogenase; H, Hispanic; Hct, hematocrit; M, male; MOD, moderate; Photo, phototherapy; Retic, reticulocyte count; SEV, severe; SUB, subtle; W, white. *Home care (infant not hospitalized). ora fPerinatology of Journal S45