SPECIAL ARTICLE |
Research on Prevention of Bilirubin-Induced Brain Injury and Kernicterus: National Institute of Child Health and Human Development Conference Executive Summary
* University of Maryland School of Medicine, Baltimore, Maryland, USA
Case Western Reserve University School of Medicine and Rainbow Babies and Children’s Hospital, Cleveland, Ohio, USA
National Institute of Child Health and Human Development, Bethesda, Maryland, USA
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ABSTRACT |
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 TOP ABSTRACT NEUROBIOLOGY AND NEUROIMAGINGCLINICAL AND EPIDEMIOLOGIC...ASSESSMENT OF JAUNDICE AND...THERAPIES FOR NEONATAL...PUBLIC HEALTH SURVEILLANCE AND...CONCLUSIONSREFERENCES |
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In July 2003, the National Institute of Child Health and Human Development convened a conference, "Research on Prevention of Bilirubin-Induced Brain Injury and Kernicterus: Bench-to-Bedside." This article will provide a summary of presentations and discussions from this conference. The summary will focus on the identified knowledge gaps in 5 areas related to bilirubin-induced brain injury and kernicterus: 1) neurobiology and neuroimaging; 2) epidemiology and issues of clinical management; 3) methodologies for assessing clinical jaundice and direct and noninvasive measurement of serum bilirubin and hemolysis; 4) therapies for management of neonatal hyperbilirubinemia; and 5) public health surveillance and systems-based approaches to prevention.
Key Words: bilirubin • kernicterus • jaundice • brain injury • infant • cerebral palsy • chorioathetosis
Abbreviations: MRI, magnetic resonance imaging
The reemergence of neonatal encephalopathy (termed bilirubin-induced brain injury or, historically, kernicterus), with resultant devastating neurologic consequences among the survivors, has occurred in the past 15 years.1–5 A disorder previously associated with severe Rh isoimmunization and presumed to have been eradicated with the widespread use of perinatal passive immunization of Rh-negative women began to be encountered unexpectedly among apparently healthy term and near-term infants, in the absence of Rh isoimmunization. Although the total number of affected infants has been small, relative to the total number of live births during the period, the magnitude of the devastation among infants who were not thought to be at risk has prompted a reassessment of the clinical problem of neonatal hyperbilirubinemia.
In July 2003, the National Institute of Child Health and Human Development convened a group of experts from relevant disciplines to review the existing knowledge base regarding neonatal hyperbilirubinemia, in their respective fields of expertise. The mandate given to the conferees included the identification of knowledge gaps in the basic biologic, clinical management, epidemiologic, laboratory assessment, and public health aspects of bilirubin-induced brain injury and kernicterus and the proposal of research questions to address the identified knowledge gaps. Invited conference presentations were organized into 5 areas: 1) neurobiology and neuroimaging, 2) clinical and epidemiologic issues, 3) methods for assessment of clinical jaundice and direct and noninvasive measurement of serum bilirubin levels and hemolysis, 4) therapies for neonatal hyperbilirubinemia, and 5) public health surveillance and systems-based approaches to prevention.
During the proceedings, gaps in both in-hospital and postdischarge management were identified as major contributors to the reported occurrences of bilirubin-induced brain injury and kernicterus. It became evident that prevention would require not only new research endeavors but also readjustment of clinical approaches to neonatal hyperbilirubinemia and reorientation of postdischarge care of newborns and their mothers.
This summary focuses on the identified knowledge and service gaps in each of the 5 areas and the proposed research questions. Strategies to effect changes in clinical management, to improve diagnostic and monitoring technologies, and to enhance coordination of postdischarge monitoring and care of jaundiced newborns are also included. Subsequent publications will provide more details from the various presentations.
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NEUROBIOLOGY AND NEUROIMAGING |
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TOPABSTRACTNEUROBIOLOGY AND NEUROIMAGINGCLINICAL AND EPIDEMIOLOGIC...ASSESSMENT OF JAUNDICE AND...THERAPIES FOR NEONATAL...PUBLIC HEALTH SURVEILLANCE AND...CONCLUSIONSREFERENCES |
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Knowledge Gaps
Although the neuropathologic features of bilirubin-induced brain injury have been well known for decades, understanding of the mechanisms of neuronal injury and cell death remains limited. The roles of regional susceptibility, infant maturation and gender, blood-brain barrier function, and clinicopathologic correlates of specific patterns of neuronal injury require additional exploration. The chronologic evolution of the encephalopathic manifestations of injury and their predictive value with respect to long-term disability are poorly defined. Although recognition of a unique pattern of magnetic resonance imaging (MRI) abnormalities is developing, the precise role of neuroimaging in confirming the diagnosis and determining the prognosis has not yet been defined.
Basic Research Questions
- Why are some brain cell types more susceptible than others to bilirubin-induced injury?
- Are some brain cells more plastic and thus better able to recover from bilirubin-induced injury?
- What are the molecular sequences and mediators of bilirubin-induced brain injury and cell death?
- Are there cell surface receptors for bilirubin? If there are, how are they distributed, controlled, and inhibited?
- What is the basis for differential regional vulnerability to bilirubin-induced cellular injury?
- Are there gestational age differences in susceptibility and regional vulnerability to bilirubin-induced brain injury among human infants, in the absence of other risk factors and diseases? If there are, how are they mediated?
- What is the mechanism or pathway for extrapyramidal neuronal injury to affect learning and memory function?
- Why is there a spectrum of vulnerability to bilirubin-induced brain injury within a given population exposed to the same serum bilirubin concentration? What are the individual protective factors? How can they be assessed and manipulated to enhance protection?
- Is there a neurobiologic basis for the apparent male preponderance in reported cases of kernicterus? What is the role of fetal steroid hormones (protective or injury-enhancing)? What is the role of animal models to study this issue?
- What are the MRI patterns and evolving neuroanatomic changes in bilirubin-induced brain injury and kernicterus? How consistent are such changes? How consistent is the recognition of such changes by neuroradiologists?
- Can MRI become the standard method for the diagnosis of bilirubin-induced brain injury, from infancy through early childhood? Is a clinical history of neonatal hyperbilirubinemia necessary to make an etiologic diagnosis?
- What is the role of newer MRI diagnostic imaging techniques (such as diffusion tensor imaging, apparent diffusion coefficient mapping, and proton spectroscopy) in diagnosis and prediction of prognosis?
Strategies for Clinical Research and Improvement of Service
- Validation of intervention protocols for the prevention of bilirubin-induced brain injury, including:
- Establishment of evidence-based thresholds for interventions.
- Establishment of evidence-based efficacy monitoring of interventions.
- Confirmation of desired target responses to interventions.
- Establishment of evidence-based thresholds for interventions.
- Development and rigorous validation of measures to detect and quantify early manifestations of bilirubin-induced brain injury and to confirm the time course of such manifestations in response to interventions, including:
- Clinical scoring schema, such as that for bilirubin-induced neurologic damage.5
- Neurophysiologic testing, including auditory evoked brainstem response monitoring.
- Diagnostic imaging.
- Possible cerebrospinal fluid marker determination.
- Clinical scoring schema, such as that for bilirubin-induced neurologic damage.5
- Documentation of the longitudinal time course of classic kernicterus in the currently surviving population of children, including but not limited to:
- Associated health problems.
- Course of neurologic impairment.
- Habilitation needs with growth and maturation.
- Related adult-onset diseases.
- Associated health problems.
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CLINICAL AND EPIDEMIOLOGIC ISSUES |
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TOPABSTRACTNEUROBIOLOGY AND NEUROIMAGINGCLINICAL AND EPIDEMIOLOGIC...ASSESSMENT OF JAUNDICE AND...THERAPIES FOR NEONATAL...PUBLIC HEALTH SURVEILLANCE AND...CONCLUSIONSREFERENCES |
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Knowledge Gaps
An urgent need to develop universal definitions for jaundice, neonatal hyperbilirubinemia, bilirubin-induced brain injury, and kernicterus was acknowledged by the conferees. With contemporary neonatal treatment practices, the longitudinal course of neonatal hyperbilirubinemia needs to be reconfirmed for preterm and term infants in different populations and ethnic groups, with varying risk factors. Furthermore, given the current clinical reports of bilirubin-induced brain injury and kernicterus, the clinical courses resulting from the various recognized causes require documentation. Without agreement on the aforementioned definitions and informed understanding of the current clinical spectrum, epidemiologic surveillance will be difficult at best and unreliable at worst.
Strategies for Improvement of Epidemiologic and Clinical Research
- Convening of an international working group of relevant experts.
- Development of a universal terminology and definitions for neonatal jaundice, neonatal hyperbilirubinemia, bilirubin-induced brain injury, and kernicterus.
- Establishment of gestational age-related criteria for clinical diagnosis, staging, and categorization of bilirubin-induced brain injury and kernicterus that are stratified according to postnatal age and severity.
Strategies for Clinical Research
- Design and execution of clinical and epidemiologic studies to establish the time course of neonatal hyperbilirubinemia according to gestational age, race or ethnicity, and dominant cause or risk factors, with longitudinal methods, through the first 10 to 14 days.
- Suggested gestational age categories: <32 weeks; 32 to 34 weeks; 35 to 37 weeks; and
38 weeks.
- Suggested etiologic/risk factor categories: isoimmune hemolytic disease; nonimmune hemolytic disease; breastfeeding without other risk factors; breastfeeding with other risk factors; genetic defects; and idiopathic (no recognized etiologic or risk factors).
- Suggested gestational age categories: <32 weeks; 32 to 34 weeks; 35 to 37 weeks; and
- Design and execution of studies to elucidate the mechanism of action and interactions of nonpathologic risk factors in the incidence and pathogenesis of bilirubin-induced brain injury, including but not limited to:
- Breastfeeding.
- Maternal age.
- Race or ethnicity.
- Systems of health care delivery and financing.
- Breastfeeding.
- Design and execution of longitudinal population studies to determine the most clinically appropriate surveillance measures to establish the prevalence and incidence of severe neonatal hyperbilirubinemia and to identify the neonates most at risk for bilirubin-induced brain injury and kernicterus.
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ASSESSMENT OF JAUNDICE AND MEASUREMENT OF BILIRUBIN LEVELS AND HEMOLYSIS |
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TOPABSTRACTNEUROBIOLOGY AND NEUROIMAGINGCLINICAL AND EPIDEMIOLOGIC...ASSESSMENT OF JAUNDICE AND...THERAPIES FOR NEONATAL...PUBLIC HEALTH SURVEILLANCE AND...CONCLUSIONSREFERENCES |
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Knowledge and Service Gaps
Published reports of interlaboratory variability in the analysis of serum bilirubin species raise serious concerns regarding the intrinsic accuracy of current laboratory methods for measurement of clinically significant bilirubin species.6 Higher serum bilirubin concentrations result in greater interlaboratory variability.6 Precision, reproducibility, and accuracy in laboratory analyses are of utmost importance for research and for appropriate clinical management of neonatal hyperbilirubinemia. Current laboratory reference standards are not consistently reliable and targeted to the serum concentrations of most clinical relevance in neonatal hyperbilirubinemia. Quality control in the production of reference standards is inadequate. There is an absence of a true standard for comparison of various techniques and equipment to measure clinically significant bilirubin species. Point-of-care methods for bilirubin measurement (transcutaneous bilirubin assessment) lack validation for all at-risk clinical categories of neonates. Current methods for laboratory analyses of bilirubin-albumin binding and free bilirubin levels lack verification of clinical usefulness, in terms of laboratory analytic techniques and clinical decision-making.
Basic Research Questions
- What constitutes clinically significant direct or conjugated hyperbilirubinemia?
- Are conjugated bilirubin species neurotoxic? If so, how and why? If not, why and how should the serum concentrations of such species influence treatment decisions?
- Do photoisomers of bilirubin interfere with measurement of the various bilirubin species?
Strategies for Clinical Research and Improvement of Technology and Methods
- Validation and implementation by appropriate regulatory and accrediting organizations of standards for measurement of clinically pertinent serum bilirubin species at the concentrations present in neonatal hyperbilirubinemia, to establish interlaboratory consistency and reliability, including:
- Methods.
- Reference standards.
- Instrumentation.
- Quality control in standard production and laboratory analysis.
- Methods.
- Validation of clinically efficacious methods for laboratory analysis of bilirubin-albumin binding and free bilirubin serum concentrations and implementation by appropriate regulatory and accrediting organizations of standards of measurement in clinical laboratory settings, to establish interlaboratory consistency and reliability, including:
- Methods.
- Reference standards.
- Instrumentation.
- Quality control in standard production and laboratory analysis.
- Methods.
- Validation of efficacy of state-of-the-art, noninvasive, bilirubin measurement and hemolysis detection instrumentation, such as that for end-tidal carbon monoxide measurement, in all racial and ethnic newborn populations in the United States, stratified according to:
- Gestational age.
- Postnatal age.
- Phototherapy exposure.
- Gestational age.
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THERAPIES FOR NEONATAL HYPERBILIRUBINEMIA |
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TOPABSTRACTNEUROBIOLOGY AND NEUROIMAGINGCLINICAL AND EPIDEMIOLOGIC...ASSESSMENT OF JAUNDICE AND...THERAPIES FOR NEONATAL...PUBLIC HEALTH SURVEILLANCE AND...CONCLUSIONSREFERENCES |
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Knowledge and Service Gaps
Despite decades of clinical experience with phototherapy, the most effective spectrum (blue-green light) is not the most frequently used clinically. Existing devices for delivery of phototherapy have significant deficiencies in design and application.7–10 There is no universal agreement regarding the terminology for recording the clinical application of phototherapy or the appropriate monitoring of equipment performance during clinical application. However, until new evidence is obtained to support an alternative course of treatment, the continued application of current consensus-based thresholds for preventive and therapeutic application of phototherapy is endorsed. Although much research on various metalloporphyrins has been reported, the safety, efficacy, and indications for metalloporphyrin use clinically for the prevention of severe neonatal hyperbilirubinemia remain uncertain.
Basic Research Questions
- Are there potential mechanisms to reverse the neuronal toxicity of bilirubin? If so, what are the requirements for establishing clinical usefulness?
- What is the influence of the phototherapeutic medium and the concurrent environment on bilirubin photochemical processes?
- What are the photoreactive properties of each pharmacologic agent introduced for the prevention or treatment of hyperbilirubinemia?
- What are the human neonatal clinical pharmacologic features of each of the metalloporphyrin heme oxygenase inhibitors? How is each inhibitor processed, from intake to removal?
- What are the consequences, with respect to other physiologic processes, of blocking hemoglobin degradation?
- Are other byproducts of hemolysis neurotoxic? What role do they have in bilirubin-induced brain injury?
Strategies for Clinical Research and Improvement of Service
- Design and execution of studies to identify and eliminate the barriers to clinical use of the most effective spectrum for phototherapy (blue-green light).
- Development and validation of a standardized method for reporting phototherapy application, including but not limited to:
- Mode or medium (type of device and light-emitting source for phototherapy, eg, freestanding unit versus "blanket," fluorescent versus fiber-optic device).
- Duration.
- Intensity.
- Degree or quantification of surface exposure.
- Mode or medium (type of device and light-emitting source for phototherapy, eg, freestanding unit versus "blanket," fluorescent versus fiber-optic device).
- Development and validation of a standardized protocol for monitoring phototherapy device performance during clinical application, including but not limited to:
- Output measure.
- Instrumentation.
- Frequency.
- Routine maintenance requirements and documentation.
- Output measure.
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PUBLIC HEALTH SURVEILLANCE AND SYSTEMS-BASED APPROACHES TO PREVENTION |
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TOPABSTRACTNEUROBIOLOGY AND NEUROIMAGINGCLINICAL AND EPIDEMIOLOGIC...ASSESSMENT OF JAUNDICE AND...THERAPIES FOR NEONATAL...PUBLIC HEALTH SURVEILLANCE AND...CONCLUSIONSREFERENCES |
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Knowledge and Service Gaps
There is currently no process for determining the public health implications of the reported occurrences of bilirubin-induced brain injury and kernicterus. The lack of consensus regarding terminology, definitions, surveillance methods and measures, and reporting mechanisms inhibits institution of appropriate public health interventions to prevent or limit occurrences. In 1994, the American Academy of Pediatrics published guidelines for the management of neonatal hyperbilirubinemia.10 Review of the clinical courses of infants and children voluntarily reported to a kernicterus registry indicated that, in many cases, the severity of the hyperbilirubinemia probably could have been reduced if the management guidelines had been implemented.5 Current systems of primary care for newborn infants and their mothers have been found to result in barriers to appropriate postdischarge monitoring and treatment of neonatal hyperbilirubinemia.
Basic Research Questions
- What is the best clinical marker for population-based surveillance of the incidence and prevalence of infants at risk for and developing bilirubin-induced brain injury and kernicterus? How is it best determined?
Strategies for Clinical Research and Improvement of Service
- Development and validation of standardized data collection measures for a national surveillance program for bilirubin-induced brain injury and kernicterus, including:
- Criteria for reporting (see above for universal terminology and definition determination).
- Methods for defining the frequency of occurrence, ie, prevalence and incidence.
- Criteria for reporting (see above for universal terminology and definition determination).
- Creation of a central repository for analysis and archival recording (national registry).
- Development and implementation of a coordinated physician-infant-family system of care for the treatment of newborns through the first 28 days after birth.
- Development and validation of an appropriate model for cost-benefit analysis of universal neonatal hyperbilirubinemia screening.
- Design, execution, and evaluation of effectiveness of strategies to effect changes in professional practice behavior in the management of neonatal hyperbilirubinemia.
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CONCLUSIONS |
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TOPABSTRACTNEUROBIOLOGY AND NEUROIMAGINGCLINICAL AND EPIDEMIOLOGIC...ASSESSMENT OF JAUNDICE AND...THERAPIES FOR NEONATAL...PUBLIC HEALTH SURVEILLANCE AND...CONCLUSIONSREFERENCES |
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Conferees agreed that the observed reemergence of bilirubin-induced brain injury and kernicterus constitutes a serious problem of public health significance. Factors contributing to the reemergence include changes in perception regarding the importance of active surveillance for neonatal hyperbilirubinemia by health care professionals, alteration of previous routines of postnatal care of newborns with respect to preventive interventions, hospital stays, and follow-up care, and knowledge gaps regarding the neurobiologic features of bilirubin-induced brain injury. Urgent needs for scientific investigation and for a systems-based approach to clinical management have been identified. Both governmental and health care system interventions will be required to resolve the problem. Such efforts are underway, under the auspices of the National Institute of Child Health and Human Development and the Centers for Disease Control and Prevention. The American Academy of Pediatrics is addressing the need for alteration of professional approaches through the publication of updated management guidelines.
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ACKNOWLEDGMENTS |
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The conference was sponsored by NICHD and supported in part by the NIH Office of Rare Diseases, the Centers for Disease Control and Prevention, the American Academy of Pediatrics, and the March of Dimes. The agenda and a complete list of participants is available at www.nichd.nih.gov/about/cdbpm/pp/PastMeetings/bench_to_bedside.htm.
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FOOTNOTES |
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Received for publication Jan 28, 2004; Accepted Feb 3, 2004.
Address correspondence to Tonse N. K. Raju, MD, DCH, Pregnancy and Perinatology Branch, National Institute of Child Health and Human Development/National Institutes of Health, 6100 Executive Blvd, Room 4B03, Bethesda, MD 20892-7510. E-mail: rajut{at}mail.nih.gov
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REFERENCES |
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TOPABSTRACTNEUROBIOLOGY AND NEUROIMAGINGCLINICAL AND EPIDEMIOLOGIC...ASSESSMENT OF JAUNDICE AND...THERAPIES FOR NEONATAL...PUBLIC HEALTH SURVEILLANCE AND...CONCLUSIONSREFERENCES |
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- Maisels MJ, Newman TB. Kernicterus in otherwise healthy, breast-fed term newborns.
Pediatrics. 1995;96
:730
–733
[Abstract/Free Full Text] - MacDonald MG. Hidden risks: early discharge and bilirubin toxicity due to glucose 6-phosphate dehydrogenase deficiency.
Pediatrics. 1995;96
:734
–738
[Abstract/Free Full Text] - Penn AA, Enzmann DR, Hahn JS, Stevenson DK. Kernicterus in a full term infant.
Pediatrics. 1994;93
:1003
–1006
[Abstract/Free Full Text] - Washington EC, Ector W, Abboud M, Ohning B, Holding KR. Hemo-lytic jaundice due to G6PD deficiency causing kernicterus in a newborn female. South Med J. 1995;88 :776 –779[Web of Science][Medline]
- Johnson L, Bhutani VK, Brown AK. System-based approach to management of neonatal jaundice and prevention of kernicterus. J Pediatr. 2002;140 :396 –403[CrossRef][Web of Science][Medline]
- Vreman HJ, Verter J, Oh W, et al. Interlaboratory variability of bilirubin measurements.
Clin Chem. 1996;42
:869
–873
[Abstract/Free Full Text] - McDonagh AF, Lightner DA. Phototherapy and the photobiology of bilirubin. Semin Liver Dis. 1988;8 :272 –283[Web of Science][Medline]
- Tan KL. Efficacy of fluorescent daylight, blue, and green lamps in the management of nonhemolytic hyperbilirubinemia. J Pediatr. 1989;114 :132 –137[CrossRef][Web of Science][Medline]
- Vreman HJ, Wong RJ, Murdock JR, Stevenson DK. In vitro efficacy of an LED-based phototherapy device (neoBlue) compared to traditional light sources. Pediatr Res. 2003;53 :400A[CrossRef]
- American Academy of Pediatrics, Provisional Committee for Quality Improvement. Practice parameter: management of hyperbilirubinemia in the healthy term newborn.
Pediatrics. 1994;94
:558
–565
[Abstract/Free Full Text]
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