Kernicterus in Japanese infants. II. Pathologic data in 25 cases of kernicterus and in 20 cases of systemic icterus without kernicterus.
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Asian People↗
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Lack of predictive indices in kernicterus: a comparison of clinical and pathologic factors in infants with or without kernicterus.
A review of 398 neonatal autopsies at Downstate Medical Center revealed 27 cases of kernicterus during the seven-year period from 1971 through 1977. With the current intensive care of the sick newborn, kernicterus continues to occur, mainly in premature infants with relatively low levels of serum bilirubin (mean of 11.5 mg/100 ml). To understand the factors contributing to the development of kernicterus, clinical and pathologic findings in 27 infants with kernicterus were compared to 103 "control" infants with retrospectively. Birth weight, gestational age, sex, and Apgar scores were comparable in both groups. The duration of survival was significantly shorter in infants with kernicterus than in the control infants. The clinical signs and symptoms of kernicterus were nonspecific and the premortem diagnosis of kernicterus was not suspected in most of the cases. There were no significant differences in the peak serum bilirubin values, incidence of hypothermia, hypoglycemia, convulsions, anemia, infection, use of phototherapy, transfusion and exchange transfusion in the two groups. Serum albumin values and bilirubin binding capacity measured by 2-(4-hydroxybenzeneazo)benzoic acid were significantly lower in the kernicteric group although the bilirubin-albumin molar ratio was equal in both groups. The incidences of severe acidosis and hypoxic encephalopathy were significantly higher in the kernicteric infants. In this study, acidosis, hypoxia, hypoalbuminemia, and low bilirubin binding capacity were seen more often in kernicteric infants than in control infants. However, analysis of previously suggested risk factors failed to identify any single factor or combination of factors which could be predictive to the development of kernicterus.
Bilirubin↗
National Institute of Child Health and Human Development (NICHD) conference on kernicterus: a population perspective on prevention of kernicterus.
This paper reviews barriers to the prevention of kernicterus. Reports of kernicterus cases persist. We do not know why kernicterus continues to occur or how best to prevent it. We need evidence for key recommendations that make clinical guidelines usable by practitioners caring for newborns, especially for practitioners providing ambulatory care in the first week of life. Data on prevalence and incidence, mortality and morbidity are essential for launching a kernicterus public health campaign. Modeling cost-effectiveness requires data on costs and benefits of alternative strategies for managing hyperbilirubinemia and preventing kernicterus and on parental preferences concerning follow-up in the first days of life. Understanding how existing patterns of care obstruct preventive care involves exploration of the roles of clinicians, health-care organizations, parents, and payers and purchasers of health care. Lastly, discovering how to motivate change in existing practices can provide the guidance needed to prevent kernicterus in the US.
Cost-Benefit Analysis↗
Kernicterus in rats lacking glucuronyl transferase. II. Factors which alter bilirubin concentration and frequency of kernicterus.
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Animals↗
NICHD Conference on Kernicterus: Research on Prevention of Bilirubin-Induced Brain Injury and Kernicterus: Bench-to-Bedside--Diagnostic Methods and Prevention and Treatment Strategies.
In July 2003, the National Institute of Child Health and Human Development (NICHD) organized a consensus conference, where a group of experts were invited to review and discuss the current state of knowledge regarding neonatal hyperbilirubinemia and identify areas in which where future research should be directed. This paper summarizes the presentations addressing the current methodologies for direct and noninvasive assessments of serum total bilirubin concentrations as well as prevention and treatment strategies for the management of neonatal hyperbilirubinemia.
Bilirubin↗
Studies on kernicterus; relationship with sulfonamide intoxication, report on kernicterus in rats with glucuronyl transferase deficiency and review of pathogenesis.
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Animals↗
Cost-effectiveness of strategies that are intended to prevent kernicterus in newborn infants.
OBJECTIVE: There is concern about an increasing incidence of kernicterus in healthy term neonates in the United States. Although the incidence of kernicterus is unknown, several potential strategies that are intended to prevent kernicterus have been proposed by experts. It is necessary to assess the costs, benefits, and risks of such strategies before widespread policy changes are made. The objective of this study was to determine the direct costs to prevent a case of kernicterus with the following 3 strategies: (1) universal follow-up in the office or at home within 1 to 2 days of early newborn discharge, (2) routine predischarge serum bilirubin with selective follow-up and laboratory testing, and (3) routine predischarge transcutaneous bilirubin with selective follow-up and laboratory testing. METHODS: We performed an incremental cost-effectiveness analysis of the 3 strategies compared with current practice. We used a decision analytic model and a spreadsheet to estimate the direct costs and outcomes, including the savings resulting from prevented kernicterus, for an annual cohort of 2,800000 healthy term newborns who are eligible for early discharge. We used a modified societal perspective and 2002 US dollars. With each strategy, the test and treatment thresholds for hyperbilirubinemia are lowered compared with current practice. RESULTS: With the base-case assumptions (current incidence of kernicterus 1:100 000 and a relative risk reduction [RRR] of 0.7 with each strategy), the cost to prevent 1 case of kernicterus was 10,321463 dollars, 5,743905 dollars, and 9,191352 dollars respectively for strategies 1, 2, and 3 listed above. The total annual incremental costs for the cohort were, respectively, 202,300671 dollars, 112,580535 dollars, and 180,150494 dollars. Sensitivity analyses showed that the cost per case is highly dependent on the population incidence of kernicterus and the RRR with each strategy, both of which are currently unknown. In our model, annual cost savings of 46,179465 dollars for the cohort would result with strategy 2, if the incidence of kernicterus is high (1:10,000 births or higher) and the RRR is high (> or =0.7). If the incidence is lower or the RRR is lower, then the cost per case prevented ranged from 4,145676 dollars to as high as 77,650240 dollars. CONCLUSIONS: Widespread implementation of these strategies is likely to increase health care costs significantly with uncertain benefits. It is premature to implement routine predischarge serum or transcutaneous bilirubin screening on a large scale. However, universal follow-up may have benefits beyond kernicterus prevention, which we did not include in our model. Research is required to determine the epidemiology, risk factors, and causes of kernicterus; to evaluate the effectiveness of strategies intended to prevent kernicterus; and to determine the cost per quality-adjusted life year with any proposed preventive strategy.
Bilirubin↗
The use of critical levels of birth weight and "free bilirubin" as an approach for prevention of kernicterus.
Free bilirubin (FB) and total bilirubin (TB) were determined in 154 samples of blood taken from 112 jaundiced newborns: 51 prematures without hemolysis (19 of these with RDS); 26 full terms presenting ABO incompatibility; 35 newborns (both prematures and full terms) presenting rhesus incompatibility. Kernicterus was observed in seven cases and only three occurred in the TB group above 20 mg/100 ml; 57 cases had FB equal to or above 0.1 mg/100 ml and all kernicterus fell into this category. In the other 55 cases in which FB was less than 0.1 mg/100 ml no kernicterus was observed. In the group of healthy full-term newborns presenting ABO incompatibility, 15 had FB above or equal to 0.1 mg/100 ml ranging between 0.1 and 0.4 mg/100 ml; however no kernicterus was observed during the neonatal period. On the contrary, in the group of prematures a little more than half of the cases had a FB ranging from 0.1 to 0.4 mg/100 ml whereas four macroscopic kernicterus cases were observed. The difference between the two groups compels us to consider other factors than those acting on the albumin-bilirubin binding especially those acting on the blood-brain barrier and on the fixation of the pigment by the neurons. A second series of 605 consecutive autopsies, on a period of 10 years, on prematures excluding light-for-dates and cases of hemolysis, evaluates the distribution of 40 kernicterus as a function of birth weight. On this second series kernicterus appears with maximal frequency for birth weight between 1,000 and 1,250 g, with a nonnegligible frequency at 1,500 to 2,000 g and was absent between 2,000 and 2,500 g. 13 kernicterus were observed for a peak TB below 12 mg/100 ml. These results seem to justify a systematic determination of FB in the premature weighing less than 2,000 g from the 24th hour of life whether he has jaundice or not.
ABO Blood-Group System↗
[Critical study of erythrocyte bilirubin and predictive factors of kernicterus in premature low birth weight infants].
Among 217 premature neonates with birth-weights less than or equal to 1,500 g who died, in whom post mortem examination was carried out during the years 1978-1984, 11 cases of kernicterus (5%) were found. A comparative study was undertaken between these 11 children and 42 children of the same population matched for birth-weight, gestational age and life duration. The following clinical and biological perinatal data were found more frequently in the kernicterus group: meningitis (3/11 vs 0/42), p less than 0.01), hyperchloronatremic dehydration (3/11 vs 1/42, p less than 0.05) and hypoglycemia either severe (less than 0.83 mumol/l) (5/11 vs 3/42, p less than 0.01) or prolonged (less than 1.66 mumol/l for at least 36 hrs) (3/11 vs 0/42, p less than 0.01). The mean value of total bilirubin highest levels was 261 +/- 76 mumol/l in cases with kernicterus and 266 +/- 58 mumol/l in the control group (NS). In a case with kernicterus the total bilirubin level was 149 mumol/l (87 mg/l). Erythrocyte bilirubin was repeatedly assayed in 16 children, 4 of which were found to have kernicterus. There was no significant difference in the mean maximum peak of erythrocyte bilirubin between the 2 groups (kernicterus group: 17.8 +/- 3.4 mumol/l in the 4 cases with kernicterus. Finally, hypoglycemia, respiratory and/or metabolic acidosis were found associated with the highest erythrocyte bilirubin level, or during the 24 preceding hours in children with kernicterus only.
Acidosis↗
Magnetic resonance imaging in three children with kernicterus.
The incidence of kernicterus has been greatly reduced by effective monitoring and treatment for hyperbilirubinemia. Findings on magnetic resonance imaging (MRI) in patients with kernicterus are characteristic. This study presents three cases of possible kernicterus without typical symptoms but with MRI features consistent with kernicterus. These cases suggest that kernicterus can develop, especially in preterm infants, in the presence of relatively low levels of bilirubin and the absence of obvious acute symptoms. Therefore assessing the risk of kernicterus may be difficult in the neonatal period. In addition, MRI findings at the posteromedial border of the globus pallidus in patients with athetotic cerebral palsy are strong evidence of brain damage caused by kernicterus.
Brain↗
A clinical pathologic reappraisal of kernicterus.
Kernicterus at autopsy, traditionally associated with hyperbilirubinemia, is now often observed in the absence of markedly elevated levels of serum bilirubin. Attempts to document clinically predictive risk factors for kernicterus have been largely unsuccessful in the current population of sick neonates. In a study of 32 pairs of newborns with and without kernicterus at autopsy and matched for gestational age, weight, length of survival, and year of birth, no differences were found when multiple clinical factors thought to potentiate risk for kernicterus were compared. Microscopic sections of brains from these matched pairs were then evaluated without knowledge of the clinical or gross findings according to prearranged criteria. Statistic analysis of the microscopic findings was done, comparing each observed change in each anatomic site, all changes in each site, and each change in all sites. Although the gross pattern of staining followed that of classic kernicterus, the expected, specific histologic changes characteristic of kernicterus were found in only three patients. Spongy change, or edema, was significantly more common in the grossly stained brains (P less than .0005), but other findings were similar in both groups. Gross bilirubin staining of the neonatal brain with neither hyperbilirubinemia nor specific microscopic changes is probably not the same clinicopathologic entity as classic kernicterus.
Birth Weight↗
Lack of identifiable risk factors for kernicterus.
In recent years kernicterus at autopsy has been observed in sick premature infants in the absence of markedly elevated levels of serum bilirubin. Potentiating factors have been suggested to explain kernicterus in such a setting. In order to establish which factors are associated with increased risk for kernicterus in these small babies, this retrospective matched control study was undertaken. Thirty-two infants with kernicterus at autopsy were matched for gestational age, birth weight, length of survival, and year of birth to 32 control infants without kernicterus. Multiple historical, clinical, and laboratory factors were compared, including therapy, sepsis, hypothermia, asphyxia as reflected by Apgar score, hematocrit, acidosis, hypercarbia, hypoxia, hypoglycemia, and hyperbilirubinemia. No statistically significant differences between the kernicteric and nonkernicteric infants were demonstrated for any of these factors, including peak total serum bilirubin levels. Multivariant analysis also failed to determine a group of factors associated with increased risk for kernicterus. It was not possible to separate those infants with and without kernicterus at autopsy on the basis of the clinical factors evaluated.
Birth Weight↗
Newborn jaundice and kernicterus--health and societal perspectives.
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 CDCs 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.
Cost of Illness↗
Kernicterus in preterm newborns: past, present, and future.
This historical overview of kernicterus in prematurity, from the 1950s to the present, provides a unique perspective on this clinical conundrum. Three separate periods of pediatric history are detailed in relationship to our understanding of kernicterus in the preterm newborn: (1) the pre-intensive care era (1950 to 1965); (2) the low bilirubin kernicterus era (1965 to 1982); and (3) the 1980s. Each period demonstrates selected insights regarding kernicterus in prematurity, and together with recent reports suggest that premature newborns are now at extremely low risk of developing kernicterus when managed using current standards of care. However, the current conservative empiric guidelines for preventing kernicterus are questioned, and it is suggested that additional study is needed to clarify this issue in the 1990s.
Bilirubin↗
Kernicterus: epidemiological strategies for its prevention through systems-based approaches.
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.
Female↗
Definition of the clinical spectrum of kernicterus and bilirubin-induced neurologic dysfunction (BIND).
Kernicterus, currently used to describe both the neuropathology of bilirubin-induced brain injury and its associated clinical findings, is a complex syndrome. The neurobiology of kernicterus, including the determinants and mechanisms of neuronal injury, is discussed along with traditional and evolving definitions ranging from classical kernicterus with athetoid cerebral palsy, impaired upward gaze and deafness, to isolated conditions, for example, auditory neuropathy or dys-synchrony (AN/AD), and subtle bilirubin-induced neurological dysfunction (BIND). The clinical expression of BIND varies with location, severity, and time of assessment, influenced by the amount, duration and developmental age of exposure to excessive free bilirubin. Although total serum bilirubin (TSB) is important, kernicterus cannot be defined based solely on TSB. For study purposes kernicterus may be defined in term and near-term infants with TSB > or = 20 mg/dl using abnormal muscle tone on examination, auditory testing diagnostic of AN/AD, and magnetic resonance imaging showing bilateral lesions of globus pallidus+/-subthalamic nucleus.
Age Factors↗
Unbound bilirubin associated with kernicterus: a historical approach.
OBJECTIVE: To determine the unbound bilirubin concentration (UBC) associated with kernicterus with the use of clinical data from clusters of kernicterus after sulfisoxazole and benzyl alcohol administration. DESIGN: Sulfisoxazole at 12 mg/dL and benzoate at 10 mmol/L are associated with kernicterus at total bilirubins near 12 and 10 mg/dL, respectively. The concurrent UBC was estimated by first measuring the drug-induced increases in UBC in plasma and artificial sera (peroxidase-diazo method). The increases were then applied to baseline UBC, determined by linear regression analysis of binding data (peroxidase method) from 86 newborns, at total bilirubins of 12 mg/dL for sulfisoxazole and 10 mg/dL for benzoate. Sensitivity and specificity were determined with existing data. RESULTS: Sulfisoxazole and benzoate increased UBC in artificial sera 2.1-fold and 4.1-fold, respectively, and in plasma (sulfisoxazole) 2.4-fold. Benzoate would increase baseline UBC from 0.29 to 1.19 microg/dL and sulfisoxazole from 0.36 to 0.86 microg/dL. The sensitivity and specificity of a UBC of 0.86 microg/dL for predicting kernicterus are 79% and 92% and for 1.19 microg/dL, 50% and 98%, respectively. CONCLUSION: Historic data predict that the unbound bilirubin above which kernicterus becomes likely lies between 0.86 and 1.19 microg/dL, in good agreement with existing information.
Benzyl Alcohol↗
The neuropathology of kernicterus in the premature neonate: diagnostic problems.
Yellow staining of central nervous system (CNS) nuclei occurs in the brains of some neonates, despite low levels of serum bilirubin. Two conditions appear to be important in the evolution of this form of kernicterus: prematurity and asphyxia. In a seven year retrospective study of a large neonatal autopsy population, 102 cases had kernicterus as indicated by selective macroscopic yellow staining and microscopic damage within specific CNS nuclei. Neuropathological study disclosed minor variations and numerous similarities in the manifestations of kernicterus in the asphyctic premature neonate with low levels of serum bilirubin, as compared to kernicterus in the full-term neonate with high levels of serum bilirubin. Acidosis, hypoxia, hyperoxia, hypothermia and sepsis have been considered significant risk factors, but recent comparative clinical studies have not defined predictive indices. Analysis of this disorder is difficult because of the concurrence of other complications of asphyxia and its pathological correlates in premature infants. Diagnostic difficulties are also compounded by variations in the definitions of kernicterus as used by different investigators.
Asphyxia Neonatorum↗