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Breakdown in systems for safe newborn health-care delivery accounts for the majority of kernicterus cases encountered in the United States. Traditional epidemiologic investigations do not track the national incidence of severe hyperbilirubinemia and kernicterus or recognize its recent surge. Innovative investigative strategies are needed to seek more sensitive surrogates for kernicterus (often diagnosed late in infancy) and to overcome the limitations of retrospective continuity of adverse neonatal experiences because of severe hyperbilirubinemia. Root cause analysis of a cohort of infants who manifested kernicterus in the past two decades attests to some of the clinical and health-service barriers encountered by families as they negotiate health care from multiple providers at multiple sites during the first week after birth. Clinicians, health-care organizations, parents, and payors and purchasers of health care were often unaware of the ongoing patterns of care that may have obstructed preventive care. Now, partly based on these analyses, key recommendations have led to clinical usable guidelines for practitioners and have contributed to systems-oriented national guidelines for evidence-based safer management of newborn jaundice.(1) Clinician- and family-oriented tool kits have been made available, based on the report presented in this study, to facilitate effective implementation and thus optimize and institutionalize these guidelines (http://www.cdc.gov/jaundice). An informed partnership of parents and clinicians seems to be the most effective strategy to prevent severe neonatal hyperbilirubinemia and 'near-miss' cases of kernicterus in the United States.

To address systems failures and promote a safer management of newborn jaundice, we propose an 'aviation safety standard' for newborn health-care services during the first week after birth. Systems failure in newborn jaundice management has been characterized by lapses in concern, loss of continuity, and delays in care by multiple providers at multiple sites. Components for a six-step national strategy to prevent severe neonatal hyperbilirubinemia and possibly kernicterus are being implemented as delineated in the 2004 AAP guidelines. The clinical guidelines for safer and evidence-based practice have been characterized by both healthcare and societal communities. Professional and community organizations are optimizing outreach resources and facilitating institutionalization of these practices. Nationwide implementation at individual birthing hospitals concurrent with surveillance feedback needs to be initiated. Implementation of a 'six-sigma' approach, as proposed to the current Center for Disease Control and Prevention-initiated partnership (health-care providers, public health and community advocates) may be achieved through collaboration with state and national agencies.

To identify antecedent clinical and health services events in infants (/=35 weeks gestational age (GA)) who were discharged as healthy from their place of birth and subsequently sustained kernicterus. We conducted a root-cause analysis of a convenience sample of 125 infants/=35 weeks GA cared for in US healthcare facilities (including off-shore US military bases). These cases were voluntarily reported to the Pilot USA Kernicterus Registry (1992 to 2004) and met the eligibility criteria of acute bilirubin encephalopathy (ABE) and/or post-icteric sequelae. Multiple providers at multiple sites managed this cohort of infants for their newborn jaundice and progressive hyperbilirubinemia. Clinical signs of ABE, verbalized by parents, were often inadequately elicited or recorded and often not recognized as an emergency. Clinical signs of ABE were reported in 7 of 125 infants with a subsequent diagnosis of kernicterus who were not re-evaluated or treated for hyperbilirubinemia, although jaundice was noted at outpatient visits. The remaining infants (n=118) had total serum bilirubin (TSB) levels20 mg per 100 ml (342 micromol l(-1); range: 20.7 to 59.9 mg per 100 ml). No specific TSB threshold coincided with onset of ABE. Of infants37 weeks GA with kernicterus, 34.9% were LGA (large for gestational age) as compared with 24.7% of term infants (37 weeks GA). Although90% mothers initiated breast-feeding, assessment of milk transfer and lactation support was suboptimal in most. Mortality was 4% (5 of 125) in infants readmitted at age/=1 week. Along with a rapid rise of 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 elimination (including increased enterohepatic circulation, diagnosed and undiagnosed genetic disorders) in the context of known late prematurity (37 weeks), glucose 6-phosphate-dehydrogenase deficiency, infection and dehydration. Readmission was at age/=5 days in 81 of 118 (69%) infants and10 days in 101 of 118 (86%) infants. TSB levels were/=35 mg per 100 ml (598 micromol l(-1)) in 46 (39%) infants, of whom one died before exchange transfusion, one was untreated and one was lost to follow-up. Timely and efficacious bilirubin reduction interventions defined by 'crash-cart' initiation of immediate intensive phototherapy and urgent exchange transfusion were accomplished in 11 of 43 infants, which were compared with 12 of 43 infants in whom a timely exchange sometimes could not be accomplished. No overt sequelae were found in 8 of 11 infants (73%) treated with a 'crash-cart' approach compared with none without sequelae when exchange was delayed by pre-admission delays, technical factors or need to transfer to a tertiary facility. None of the remaining 20 of 43 infants treated only with phototherapy escaped sequelae. Regardless of age at readmission and intervention, infants with peak measured TSB35 mg per 100 ml had post-icteric sequelae (n=73). There was a narrow margin of safety between birthing hospital discharge or home birth and readmission to a tertiary neonatal/pediatric facility. Progression of hyperbilirubinemia to hazardous levels and onset of neurological signs were often not identified as infant's care and medical supervision transitioned during the first week after birth. The major underlying root cause for kernicterus was systems failure of services by multiple providers at multiple sites and inability to identify the at-risk infant and manage severe hyperbilirubinemia in a timely manner.

A jaundiced neonate in an emergency department can be a catastrophic emergency that necessitates expeditious care. Progressive and irreversible bilirubin neurotoxicity may be minimized by rapid reduction of serum bilirubin concentrations through a “crash-cart” approach: immediate administration of intensive phototherapy and preparation for a possible exchange transfusion. Onset of acute bilirubin encephalopathy (ABE) is initially nonspecific and insidious and may progress to irritability, painful tonic spasms, apnea, seizures, obtundation, coma, respiratory failure, and death. Early recognition of hyperbilirubinemia severity can facilitate rapid transition to treatment and overcome the major barriers to timely therapy. Emergency department personnel need to develop policies that define access to intensive phototherapy either on site or immediate access to a neonatal/pediatric critical care facility. This article reviews a systems strategy for a crash-cart approach that may be initiated in the emergency department for a safer transition to alternative facilities to manage and prevent ABE.

Objective To propose and implement a family‐centered systems approach to manage newborn jaundice for safer outcomes. Design Observational study for known adverse outcomes. Setting Semiprivate urban birthing hospital. Patients/Participants 31,059 well babies discharged as healthy from a cohort of 41,961 live births (1990‐2000). Interventions Incremental implementation of a systems approach that incorporated a hospital policy to (a) authorize nurses to obtain a bilirubin (total serum/transcutaneous) measurement for clinical jaundice, (b) universal predischarge total serum bilirubin (at routine metabolic screening), and (c) targeted follow‐up, using the bilirubin nomogram (hour‐specific, percentile‐based total serum bilirubin/transcutaneous bilirubin). Main Outcome Measures Known adverse outcomes assessed for early‐ and late‐onset severe hyperbilirubinemia before, during, and after systems approach implementation. Results Adverse outcomes decreased for well babies: exchange transfusion, intensive phototherapy, and readmission. During the study period, there were no "never events" (total serum bilirubin greater than or equal to 30 mg/dl), while "close calls" (total serum bilirubin greater than or equal to 25 mg/dl) were 1 in 15,000 as compared to a reported incidence of 1 in 625. Conclusions Reduced adverse events, significant reduction in close calls, and no never events met family expectations for safer experiences with this approach.

Objective To compare the clinical profile and health care experiences related to management of newborn jaundice and hyperbilirubinemia in preterm infants ( 0/7 weeks gestation) who are cared for as term infants (≥37 0/7 weeks) and develop acute and/or chronic posticteric sequelae. Methods Retrospective study of a convenient sample of term and near term infants voluntarily reported to the Pilot Kernicterus Registry (1992-2003). Study infants were required to meet the clinical definitions for acute bilirubin encephalopathy (moderate or advanced severity) and/or the classical signs of kernicterus. Main outcome measures were the comparison of etiology, severity and duration of extreme hyperbilirubinemia (TSB levels >20 mg/dL), response to interventions of intensive phototherapy and exchange transfusion, and health care delivery experiences in preterm as compared with term infants. Results No targeted attention was accorded to preterm infants during their neonatal health care experiences as related to predischarge risk assessment, feeding, discharge follow-up instructions, or breastfeeding, regardless of the known vulnerability of preterm infants to safely transition during the first week after birth. The TSB levels, age at re-hospitalization, and birth weight distribution were similar for late preterm and term infants. Large for gestational age and late preterm infants disproportionately developed kernicterus as compared with those who were appropriate for gestational age and term. Clinical management of extreme of hyperbilirubinemia, by the attending clinical providers, was not impacted or influenced by the gestational age, clinical signs, or risk assessment. This resulted in severe posticteric sequelae which was more severe and frequent in late preterm infants. Conclusions Late prematurity (34 0/7 to 36 6/7 weeks) of healthy infants was not recognized as a risk factor for hazardous hyperbilirubinemia by clinical practitioners. Unsuccessful lactation experience was the most frequent experience; being large for gestational age as well as the other known biologic risk factors for hyperbilirubinemia and bilirubin neurotoxicity were not identified by the clinical care providers either before discharge or at immediate postdischarge follow up.

Kernicterus in sick and preterm infants is a rarity. Universal availability of phototherapy and concerted clinical efforts to identify, effectively manage and establish clinical guidelines have been instrumental in preventing kernicterus in US intensive care nurseries. However, in sick and preterm infants the absence of precise data on prevalence of bilirubin induced neurologic injury, the lack of proven predictive indices and the absence of evidence-based studies that clearly demonstrate the actual risk of kernicterus. These leave questions regarding the basis for clinical strategies and recommendations for the management of neonatal jaundice in this select population. This article reviews 6 preterm infants selected from the Pilot Kernicterus Registry who had recovered from life-threatening neonatal illnesses, briefly discusses current indices used to ascertain risk, and offers an initial bilirubin level based identification of infants while future directions and studies are conducted to supplement our presently incomplete knowledge for safer clinical practice.

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

tem-based approach to pre and postdischarge jaundice management that would minimize the potential for lapses in care and the risk of kernicterus. Such protocols need to be developed and implemented as soon as possible, with input from pediatricians, nurses, and family practitioners.

Objective.The purpose of this study was to determine whether end-tidal carbon monoxide (CO) corrected for ambient CO (ETCOc), as a single measurement or in combination with serum total bilirubin (STB) measurements, can predict the development of hyperbilirubinemia during the first 7 days of life.Methods.From 9 multinational clinical sites, 1370 neonates completed this cohort study from February 20, 1998, through February 22, 1999. Measurements of both ETCOc and STB were performed at 30 ± 6 hours of life; STB also was measured at 96 ± 12 hours and subsequently following a flow diagram based on a table of hours of age-specific STB. An infant was defined as hyperbilirubinemic if the hours of age-specific STB was greater than or equal to the 95th percentile as defined by the table at any time during the study.Results.A total of 120 (8.8%) of the enrolled infants became hyperbilirubinemic. Mean STB in breastfed infants was 8.92 ± 4.37 mg/dL at 96 hours versus 7.63 ± 3.58 mg/dL in those fed formula only. The mean ETCOc at 30 ± 6 hours for the total population was 1.48 ± 0.49 ppm, whereas those of nonhyperbilirubinemic and hyperbilirubinemic infants were 1.45 ± 0.47 ppm and 1.81 ± 0.59 ppm, respectively. Seventy-six percent (92 of 120) of hyperbilirubinemic infants had ETCOc greater than the population mean. An ETCOc greater than the population mean at 30 ± 6 hours yielded a 13.0% positive predictive value (PPV) and a 95.8% negative predictive value (NPV) for STB ≥95th percentile. When infants with STB >95th percentile at 75th percentile. The combination of these 2 measurements at 30 ± 6 hours (either ETCOc more than the population mean or STB >75th percentile) had a 6.4% PPV with a 99.0% NPV.Conclusions. This prospective cohort study supports previous observations that measuring STB before discharge may provide some assistance in predicting an infant's risk for developing hyperbilirubinemia. The addition of an ETCOc measurement provides insight into the processes that contribute to the condition but does not materially improve the predictive ability of an hours of age-specific STB in this study population. The combination of STB and ETCOc as early as 30 ± 6 hours may identify infants with increased bilirubin production (eg, hemolysis) or decreased elimination (conjugation defects) as well as infants who require early follow-up after discharge for jaundice or other clinical problems such as late anemia. Depending on the incidence of hyperbilirubinemia within an institution, the criteria for decision making should vary according to its unique population.

In view of the limitations in the accurate visual assessment of jaundice and its potential role as a predictive vector for serious neurologic sequelae, we propose that a universal screening of bilirubin be considered concurrent to the routine pre-discharge metabolic screening. Universal bilirubin screening in the term and near-term newborns when plotted on "Hour-specific Bilirubin Nomogram" in lieu of the usual "day-specific" value will predict the high-risk and the low-risk groups and facilitate cost-effective and individualized follow-up of those babies at risk. A percentile based bilirubin nomogram for the first week of age was constructed from hour-specific pre- and post-discharge bilirubin values of 2840 healthy term and near-term babies. The accuracy of the pre-discharge bilirubin values was determined as a predictive vector. Pre-discharge (18-72 hours age), 6.1% of the study population had bilirubin values in the high-risk zone (95th percentile). Of these, 39.5% remained in that zone (likelihood ratio ¿LR¿ = 14.08). Pre-discharge, 32.1% of the study population had bilirubin values in the intermediate risk zone (40-75th percentiles). In a clinically significant minority of these babies (6.4%), the post-discharge values moved to the high-risk zone (L-R = 3.2 for the move from the upper-intermediate zone and 0.48 from the lower-intermediate zone). In the remainder 61.8% of the population who were identified to be at low risk, there was no measurable risk for significant hyperbilirubinemia (L-R = 0). The bilirubin nomogram can predict which infant is at high, intermediate, and low risk for subsequent excessive hyperbilirubinemia and allows for the individualized follow-up of these high-risk babies with particular attention to those who may need evaluation and intervention. Whereas, identification of the low risk group allows for a less intense bilirubin follow-up and in whom a visual check by an experienced care-provider may suffice.

Factors believed to have contributed to the reemergence of kernicterus in the United States during the 1990's are discussed: these include decreased concern about toxicity of bilirubin in term and near-term infants, increased prevalence of breastfeeding, and increasingly shortened postnatal hospital stays. The rationale for a universal predischarge bilirubin measurement at the time of the routine predischarge metabolic screen is presented: the hour-specific level of bilirubin at discharge, plotted on an Hour-Specific Bilirubin Nomogram, improves prediction of risk of excessive jaundice postdischarge and facilitates safe, cost-effective follow-up. This minimizes repeat bilirubin measurements and maximizes recognition of confounding variables and risk of hyperbilirubinemia so that timely, minimally invasive, preventive therapy can be instituted if needed.

Kernicterus, a preventable injury to the brain due to severe neonatal jaundice, has re-emerged in the United States as a health and societal concern. In its usually recognized form, kernicterus causes devastating disabilities, including athetoid cerebral palsy and speech and hearing impairments. In response to disturbing reports of kernicterus in term and near-term infants discharged as “healthy” from their place of birth, A. K. Brown and colleagues inaugurated a Pilot Kernicterus Registry in May, 1992 at the 10th Annual Kernicterus Symposium. Drs. Lois Johnson and Audrey Brown maintained a confidential manual database of acute and chronic bilirubin encephalopathies for voluntary reporting of cases of kernicterus (considered by many to be an “underground” disease). Usually referring to the icteric (yellow) staining of the basal ganglia and lesions of the extrapyramidal nervous system, kernicterus is detected at autopsy. Now, the Pilot Kernicterus Registry has offered formal clinical definitions of bilirubin-induced neurologic dysfunction (BIND) and kernicterus. (1) Audrey K. Brown, the “grande dame of bilirubin,” helped us to understand bilirubin conjugation and to respect the dangers of excessive total serum bilirubin (TSB) load. She was a leader in the campaign to prevent kernicterus. Her historical review (see accompanying special article) chronicles the achievements of the researchers of kernicterus. Her research reminds us of the universality of neonatal bilirubinemia. Sadly, she also chronicled both the fall and rise of kernicterus. Dr. Brown and other “ancestral” researchers imparted a legacy to maintain vigilance for the perpetual and ominous specter of kernicterus that can threaten humanity now and for generations to come. The current re-emergence of kernicterus in babies discharged as healthy from United States hospitals represents a crisis of pediatrician credibility, a societal demand for patient safety, and a disease that needs to be controlled by public health policy. The actual incidence of kernicterus …

The enzymatic conversion of all trans β-carotene to retinal by an intestinal mucosal enzyme (β-carotene cleavage enzyme, BCC) from autopsy samples of human neonates was demonstrated for the first time. The enzymatic product was characterized as its O -ethyl oxime, which, on high pressure liquid chromatography (HPLC), yielded a sharp peak corresponding to an authentic retinal ( O -ethyl) oxime. The enzyme blank and boiled enzyme blank failed to show any significant HPLC peaks corresponding to retinal ( O -ethyl) oxime, retinal, or retinol. Based on the observed activities among intestinal samples from 14 premature infants, the BCC enzyme activity ranged from 3.3–1210 pmoles per mg mucosal protein per hr. Studies on the stability of the enzyme using the rat as the experimental animal revealed that as much as 80% of the original activity of the fresh intestine is lost in storage of the dead animal for 8 hr at 25° C followed by storage at 4° C for 16 hr. More importantly, 70% of the fresh enzyme activity is lost after storage of the animals at 4° C for only 8 hr. Thus, the observed activities in the human autopsy samples appear to be markedly underestimated because of the marked loss of enzyme activity from the time of death to the time of assay. Therefore, the true activity of the enzyme can be assessed only after the extent of loss of activity on storage of the human samples can be accurately measured. In spite of repeated attempts, no detectable BCC activity was found in the placentas of pre-term or term infants. Nonetheless, the demonstration of BCC enzyme activity in the intestinal mucosa of human neonates shows that β-carotene can serve as an important source of vitamin A in newborn infants.

The hypothesis that both perinatal events and stage of retinal development are important factors in determining the age at onset of retinopathy of prematurity (ROP) was tested by comparing gestational age at birth with postnatal and postconceptional age when ROP (using ICROP) was first seen. The study population consisted of 207 infants (111 placebo (P) treated, 96 vitamin E (E) treated) who developed ROP among a group of 914 premature infants (460 P, 454 E) enrolled in a randomised clinical trial of the effect of prophylactic use of vitamin E at pharmacological serum levels on incidence and severity of retinopathy. The mean postnatal age at onset of retinopathy was delayed in E treated infants compared with P treated infants by 1.4 weeks (t = 4.004, p < 0.0001). For both P and E treated infants postnatal age at onset of ROP (which reflects the state of retinal development at which birth insults occur) and postconceptional age at onset of ROP which defines state of maturity) were correlated with gestational age at birth. This suggests that both the event of premature birth and the extent of retinal development are important in determining when ROP will first be observed.

Acute kernicterus remains a clinical emergency and its delayed management represents an easily preventable neonatal brain injury. Yet, practitioners encounter recurrent questions regarding the risk and timing of bilirubin-related neurotoxicity. These include the following: does bilirubin damage the brain of healthy infants? Is there a re-emergence of kernicterus in the United States? Was kernicterus previously prevented in the United States? What was the public health impact of 1994 American Academy of Pediatrics Guidelines? What is the current incidence of kernicterus and severe neonatal hyperbilirubinemia? What is the estimated risk of kernicterus in infants with excessive hyperbilirubinemia? Is there a specific bilirubin threshold total serum bilirubin (TSB) value for neurotoxicity? Are there sequelae of severe or prolonged moderate hyperbilirubinemia in the absence of recognized acute bilirubin encephalopathy? Can we define a bilirubin level that is safe in newborns? We address these questions in the context of available data and evidence, and estimate the current risk of chronic kernicterus is about one in seven in infants with TSB >30 mg per 100 ml (513 micromol l(-1)).

Our approach for risk management of severe neonatal hyperbilirubinemia to prevent kernicterus--one of the most easily preventable causes of neonatal brain damage--includes management of certain high-risk clinical situations, identification of systems failure, and suggestions for implementation strategies to enhance patient safety.

New data support restructuring the approach toward diagnosis and management of hyperbilirubenia in the term neonate to make it more physician-friendly and gain wider implementation. The authors advocate clear criteria for patient safety, preventive approaches, and timely interventions. Structural changes to facilitate a system-based approach should include predischarge bilirubin management; follow-up bilirubin management; and lactational support and nutritional management. The authors advocate total serum bilirubin screening and a scoring system based on clinical risk factors as predischarge screening strategies; we should screen all babies for hyperbilirubinemia and for targeted follow-up based on an hour-specific total serum bilirubin measured for risk assessment. We should also provide focused universal education emphasizing adequate lactational nutrition, to decrease severe hyperbilirubinemia and thus prevent kernicterus.

Kernicterus, a preventable brain injury resulting from severe neonatal jaundice, has reemerged in the US (1)(2)(3). Newborn jaundice, a usually benign condition that typically resolves with supervision and appropriate nutritional intake, can progress to severe hyperbilirubinemia in ∼8–10% of healthy newborn infants. Severe hyperbilirubinemia may need treatment with phototherapy. Some newborns discharged as healthy have developed severe hyperbilirubinemia after discharge and succumbed to serious and often irreversible posticteric sequelae. Kernicterus, as described in neonates, refers to the icteric (yellow) staining of the basal ganglia, specifically the globus pallidus (4). The voluntary Pilot Kernicterus Registry now recognizes a syndrome of bilirubin-induced neurologic dysfunction (BIND), which includes kernicterus in its most severe acute and chronic forms. Using the Registry eligibility criteria, Johnson et al. (1) have documented the reemergence of kernicterus in a population of term and near-term “healthy” infants after its near eradication following prevention of Rh sensitization and widespread availability of phototherapy. The common insult in all cases of BIND results from a total serum bilirubin (TSB) concentration that exceeds the infant’s neuroprotective defenses and leads to neuronal injury, primarily in the basal ganglia, central and peripheral auditory pathways, hippocampus, diencephalon, subthalamic nuclei, midbrain, cerebellum and pontine and brain-stem nuclei for oculomotor function and for respiratory, neurohumoral, and electrolyte control. The manifestations of acute bilirubin encephalopathy and chronic kernicteric sequelae may be minimal to severe and occur as various combinations (or possibly, isolated findings) of extrapyramidal disorders, neuromotor abnormalities, sensorineural hearing loss, and visual disability. Although not yet demonstrated, some experts believe that milder and subtler neurologic manifestations of BIND exist. The current reemergence of kernicterus in babies discharged as healthy from US hospitals represents a crisis of credibility and calls into question our ability to measure TSB with accuracy and precision. There is a need …

Kernicterus, a preventable injury to the brain from severe neonatal jaundice, has re-emerged in the United States as a public and societal health concern. Kernicterus, in its usually recognized form, causes devastating disabilities, including athetoid cerebral palsy and speech and hearing impairment. This condition not only ranks amongst the highest cost per new case (per CDC’s Financial Burden of Disability study, 1992), but also results in profound and uncompromising grief for the family and loss to siblings of healthy, talkative playmates. And for the child with kernicterus (usually remarkably intelligent, but trapped in an uncontrollable body), grief and frustration are enormous. In 2001 national healthcare organizations, including Centers for Disease Control (CDC), the Joint Commission for the Accreditation of Healthcare Organizations (JACHO) and the American Academy of Pediatrics (AAP) issued alerts to all accredited hospitals and public health professionals in the United States that all healthy infants are at potential risk of kernicterus if their newborn jaundice is unmonitored and inadequately treated. The re-emergence of kernicterus in the United States is the result of interacting phenomena including (a) Early hospital discharge (before extent of jaundice is known and signs of impending brain damage have appeared); (b) Lack of adequate concern for the risks of severe jaundice in healthy term and near newborns; (c) An increase in breast feeding; (d) Medical care cost constraints; (e) Paucity of educational materials to enable parents to participate in safeguarding their newborns; and (f) Limitations within in healthcare systems to monitor the outpatient progression of jaundice. A multidisciplinary approach that encompasses both healthcare and societal needs should be evaluated at a national level for practical and easy to implement strategies. An approach that is based on principles of evidence-based medicine, patient-safety and family centeredness is presented in this article. These strategies should also be based on public awareness campaign such that the healthcare providers can attempt to achieve a “Zero Tolerance of Kernicterus” and thereby decrease both childhood disabilities and infant mortality within the community.

Background.Jaundice in near-term and term newborns is a frequent diagnosis that may prompt hospital readmission in the first postnatal week. Hyperbilirubinemia, when excessive, can lead to potentially irreversible bilirubin-induced neurotoxicity. Predischarge risk assessment (at 24–72 hours of age) for subsequent excessive hyperbilirubinemia is feasible by a laboratory-based assay of total serum bilirubin (TSB).Hypothesis.Noninvasive, transcutaneous, point-of-care measurement of transcutaneous bilirubin (TcB) predischarge by multiwavelength spectral analysis, using a portable BiliCheck device (SpectRx Inc, Norcross, GA), is clinically equivalent to measurement of TSB in a diverse, multiracial term and near-term newborn population and predictive of subsequent hyperbilirubinemia.Methodology.We evaluated a hand-held device that uses multiwavelength spectral reflectance analysis to measure TcB (BiliCheck). The study population (490 term and near-term newborns) was racially diverse (59.1% white, 29.5% black, 3.46% Hispanic, 4.48% Asian, and 3.46% other) and was evaluated at 2 separate institutions using multiple (11) devices. The postnatal age ranged from 12 to 98 hours and the ranges of birth weights and gestational ages were 2000 to 5665 g and 35 to 42 weeks, respectively. All transcutaneous evaluations were performed contemporaneously and paired with a heelstick TSB measurement. All TSB assays were performed by high performance liquid chromatography, as well as by diazo dichlorophenyldiazonium tetrafluoroborate techniques.Results.TSB values ranged from .2 to 18.2 mg/dL (mean ± standard deviation: 7.65 ± 3.35 mg/dL). The overall correlation of TSB (by high performance liquid chromatography technique) to TcB (by BiliCheck devices) was linear and statistically significant (r = .91;r2 = .83; TcB = .84; TSB = +.75; standard error of regression line = 1.38; P< .001; n = 490 infants; 1788 samples). Similar regression statistics were evident in subset populations categorized by race (white: r = .91 [n = 289 infants]; black: r = .91 [n = 145 infants]) as well as by gestation (term: r = .91 [n = 1625 samples]; near-term:r = .89 [n = 163 samples]). Intradevice precision was determined to be .59 mg/dL (2–3 measurements per infant with 1 device; n = 210 infants; 510 samples in a separate subset). Interdevice evaluation of 11 devices determined the precision to be .68 mg/dL (2–4 devices used for measurements per patient).In 23 of 419 of the study population infants who were in the 24- to 72-hour age range, the predischarge TSB values designated them to be at high risk for subsequent excessive hyperbilirubinemia (above the 95th percentile track on the hour-specific bilirubin nomogram). For these infants, the paired BiliCheck TcB values were all above the 75th percentile track (negative predictive value = 100%; positive predictive value = 32.86%; sensitivity = 100%; specificity = 88.1%; likelihood ratio = 8.43).Conclusions.Our data demonstrate the accuracy and reproducibility of the predischarge BiliCheck measurements in term and near-term newborn infants of diverse races and ethnicities. Infants with predischarge BiliCheck values above the 75th percentile of hour-specific TSB values on the bilirubin nomogram may be considered to be at high risk for subsequent excessive hyperbilirubinemia. Further studies are needed to assess the efficacy of this technique in preterm infants, those undergoing phototherapy, and those with TSB values of ≥15 mg/dL (≥256 μmol/L).

Objective.To assess the predictive ability of a universal predischarge serum bilirubin measurement to screen for risk of subsequent significant hyperbilirubinemia in the direct Coombs negative healthy term and near-term newborn during the first postnatal week.Methods.Total serum bilirubin (TSB) levels were obtained at the time of the routine metabolic screen in all term and near-term newborns cared for in the Pennsylvania Hospital Well Baby Nursery (n = 13 003). Postnatal age (in hours) at the time of TSB measurement was recorded. A percentile-based bilirubin nomogram for the first week was constructed from hour-specific predischarge and postdischarge TSB values of newborns (n = 2840; median BW = 3230 g and median gestational age = 39 weeks) who met classification criteria for healthy newborns (excluding those with a positive direct Coombs test or those requiring phototherapy before age 60 hours) and who were enrolled in a hospital supervised home or outpatient follow-up program. The accuracy of the predischarge TSB as a predictor of subsequent degree of hyperbilirubinemia was determined.Results.The study patients in the nomogram were racially diverse. Nearly 60% were breastfed. Predischarge, 6.1% of the study population (172/2840) had TSB values in the high-risk zone (≥95th percentile) at 18 to 72 hours; of these, 39.5% (68/172) remained in that zone (likelihood ratio [LR] = 14.08, sensitivity = 54%; specificity = 96.2%, probability = 39.5%). Predischarge, 32.1% of the population (912/2840) had TSB values in the intermediate-risk zone. In a clinically significant minority of these newborns (58/912 or 6.4%), the postdischarge TSB moved into the high-risk zone (LR of this move: 3.2 from the upper-intermediate zone and .48 from the lower-intermediate risk zone). The predischarge TSB in 61.8% of the newborns (1756/2840) was in the low-risk zone (Conclusions.An hour-specific TSB before hospital discharge can predict which newborn is at high, intermediate or low risk for developing clinically significant hyperbilirubinemia (specifically defined as TSB levels ≥95th percentile for age in hours). Risk designation and subsequent increases or decreases of in TSB can be easily monitored on an hour-specific percentile based predictive bilirubin nomogram. A predischarge TSB measured as a universal policy would facilitate targeted intervention and follow-up in a safe, cost-effective manner. In conjunction with bilirubin practice parameter of the American Academy of Pediatrics, it could reduce the potential risk for bilirubin-induced neurologic dysfunction.

To the Editor .— We commend Engle et al for their study of a large Dallas Hispanic population with elevated bilirubin levels.1 Visual assessment of jaundice is particularly challenging in this population. Before all differences between cutaneous bilirubin and total serum bilirubin (TSB) are ascribed as errors in transcutaneous (TcB) measurement, we must acknowledge TSB measurement is also susceptible to errors of similar magnitude in a clinical laboratory.2 Quality control of their TSB measurements (using the College of American Pathologists’ guidelines) was limited to a few samples sent to an independent laboratory for high-performance liquid chromatography (HPLC) analysis (gold standard). Differences between clinical method and HPLC analysis were reported as usually 10 mg/dL certainly would be cause for concern in a 24- to 36-hour-old infant being discharged …

Protective effect of alpha-tocopherol on the structure and function of brain cell membranes was investigated by measuring Na+,K(+)-ATPase activity and products of lipid peroxidation (fluorescent compounds) in brain cell membranes obtained from newborn piglets. Four groups of anesthetized, ventilated piglets were studied: five hypoxic piglets and five normoxic piglets were pretreated with free alpha-tocopherol (20 mg/kg/dose i.m.), five additional hypoxic piglets received i.m. placebo and five normoxic piglets served as control. Placebo and alpha-tocopherol were given 48 and 3 h prior to onset of hypoxia. Hypoxic hypoxia was induced and cerebral hypoxia was documented as a decrease in the ratio of phosphocreatine to inorganic phosphate (PCr/P(i)) using 31P NMR spectroscopy. PCr/P(i) decreased from baseline of 2.62 +/- 0.54 to 1.05 +/- 0.27 in alpha-tocopherol-pretreated and from 2.44 +/- 0.48 to 1.14 +/- 0.30 in the placebo-pretreated group during hypoxia. Na+,K(+)-ATPase activity was unchanged in both normoxic and hypoxic alpha-tocopherol-pretreated groups. However, in placebo-pretreated hypoxic group, Na+,K(+)-ATPase activity decreased as compared with control (44.9 +/- 9.7 vs. 61.8 +/- 5.7 mumol P(i)/mg protein/h, P < 0.005). The level of fluorescent compounds increased in placebo-pretreated but not in alpha-tocopherol-pretreated group as compared with control. During hypoxia, serum alpha-tocopherol levels were higher in alpha-tocopherol-pretreated groups as compared with placebo-pretreated hypoxic group. The present data indicates that alpha-tocopherol protects brain cell membranes in newborn piglets from lipid peroxidative damage during tissue hypoxia probably by being incorporated in cell membrane and also as circulating antioxidant.

Drs Newman and Maisels1 have provided valuable new guidelines for management of jaundice in the term newborn which take into account age at discharge from the hospital and some of the factors altering the general risk of bilirubin toxicity. They note that much of the information needed to identify the individual at risk is still unavailable and remind their readers that their "recommendations should be reevaluated periodically as new data become available." I have serious concerns, however, with the second half of their paper which almost completely downplays the toxic potential of bilirubin, its often erratic expression, and its ability to cause a spectrum of damage ranging from frank kernicterus to insults that are so minor as to be compensated for completely over time.2-4

Placental transfer of vitamin E was investigated from 19 to 35 weeks of gestation by analysis of fetal and maternal blood samples for total tocopherol, total lipids, and fetal red blood cell antioxidant reserves. Fifty-two fetal blood samples were obtained under ultrasonographic guide by percutaneous umbilical blood sampling. Thirteen were from fetuses with gestational age less than or equal to 22 weeks (x serum vitamin E = 0.4 +/- 0.14 mg/dl), 12 were from fetuses at 23-27 weeks gestation (x serum vitamin E = 0.4 +/- 0.21 mg/dl), and 27 were from fetuses with gestational age 28-38 weeks (x serum level = 0.37 +/- 0.18). Total lipid levels ranged from 140 to 216 mg/dl. Maternal plasma vitamin E concentrations correlated significantly with concurrent values in the fetus. There were no significant differences in serum vitamin E levels or vitamin E to total lipid ratio in samples from early, mid, or late gestation in either the mother or fetus. Red blood cell antioxidant reserve on samples from 18 fetuses were grossly abnormal by three different functional assays. On the basis of these data, placental transfer of vitamin E appears to be relatively constant through advancing gestation. Red blood cell antioxidant reserve is uniformly low.

This paper presents the results of a 20 year survey of ROP among less than or equal to 2000 g BW infants cared for at Pennsylvania Hospital. It relates changes in perinatal care and nutrition, survival rates, and serial serum E levels with incidence and severity of ROP. It includes our protocol for monitoring E nutrition so as to optimize its effectiveness at physiologic serum levels for prophylaxis for ROP. Also presented are the promising results of our experience with vitamin E at pharmacologic serum levels as a treatment for severe ROP (defined as in the Cryo ROP Trial). These indicate the need for a multicenter trial to assess the effect of pharmacologic Vitamin E therapy as an alternative or supplement to therapy of severe ROP with laser or cryo surgery.

Transcutaneous Measurement (TcB) of Total Serum Bilirubin (TSB) by Multi-Wavelength Spectral Reflectance (BiliCheck™): Accuracy and Precision in Newborn Babies

Neurologic Outcome in Singleton ≥ 2500g BW CORE Project Babies Not Treated for Hyperbilirubinemia

Clinical Risk Assessment of Coombs Positive ABO Isoimmunization for Excessive Neonatal Hyperbilirubinemia

Measurement of Serum Bilirubin in Newborn Infants: Common Clinical Laboratory Methods versus High Performance Liquid Chromatography (HPLC)† 1522