Kernicterus on the Spectrum.

Kernicterus is the potential toxic sequela of extreme neonatal hyperbilirubinemia resulting from the passage of excess free, unconjugated bilirubin across the blood-brain barrier, irreversibly and selectively damaging vulnerable target brain cells including the basal ganglia, the cerebellum, and the auditory system. Kernicterus continues to plague the modern world. Not only does it continue to be uncontrolled in developing countries with underdeveloped medical systems, and health organizations rendered ineffective by the ravages of war, but it also remains prevalent in industrialized countries. In this review, we attempt to clarify the different and overlapping nomenclature used in the past to describe this entity and aim to offer a uniform approach to defining kernicterus spectrum disorder. We also discuss the different spectrum subtypes including motor-predominant kernicterus, auditory neural sensory dysfunction, subtle kernicterus, and kernicterus plus. In addition to reviewing several genetic factors that increase the risk of developing kernicterus, we also present some exciting potential therapeutic approaches.

Trends and Resource Use for Kernicterus Hospitalizations in the United States.

OBJECTIVE: To evaluate the trends in hospitalization for kernicterus in the United States from 2006 through 2016. METHOD: Repeated, cross-sectional analysis of the 2006 to 2016 editions of the Kids' Inpatient Database. All neonatal hospitalizations with an International Classification of Diseases, Ninth or Tenth Revision, Clinical Modification code for kernicterus and admitted at age ≤28 days were included. RESULTS: Among 16 094 653 neonatal hospitalizations from 2006 to 2016, 20.5% were diagnosed with jaundice with overall incidence of kernicterus 0.5 per 100 000. The rate of kernicterus (per 100 000) was higher among males (0.59), Asian or Pacific Islanders (1.04), and urban teaching hospitals (0.72). Between 2006 and 2016, the incidence of kernicterus decreased from 0.7 to 0.2 per 100 000 (P-trend = .03). The overall median length of stay for kernicterus was 5 days (interquartile range [IQR], 3-8 days). The overall median inflation-adjusted cost of hospitalization was $5470 (IQR, $1609-$19 989). CONCLUSIONS: Although the incidence of kernicterus decreased between 2006 and 2016, its continued occurrence at a higher rate among Asian or Pacific Islander and Black race or ethnicity in the United States require further probing. Multipronged approach including designating kernicterus as a reportable event, strengthening newborn hyperbilirubinemia care practices and bilirubin surveillance, parental empowerment, and removing barriers to care can potentially decrease the rate of kernicterus further.

Intensive phototherapy vs. exchange transfusion for the treatment of neonatal hyperbilirubinemia: a multicenter retrospective cohort study.

BACKGROUND: Intensive phototherapy (IPT) and exchange transfusion (ET) are the main treatments for extreme hyperbilirubinemia. However, there is no reliable evidence on determining the thresholds for these treatments. This multicenter study compared the effectiveness and complications of IPT and ET in the treatment of extreme hyperbilirubinemia. METHODS: This retrospective cohort study was conducted in seven centers from January 2015 to January 2018. Patients with extreme hyperbilirubinemia that met the criteria of ET were included. Patients were divided into three subgroups (low-, medium-, and high- risk) according to gestational week and risk factors. Propensity score matching (PSM) was performed to balance the data before treatment. Study outcomes included the development of bilirubin encephalopathy, duration of hospitalization, expenses, and complications. Mortality, auditory complications, seizures, enamel dysplasia, ocular motility disorders, athetosis, motor, and language development were evaluated during follow-up at age of 3 years. RESULTS: A total of 1164 patients were included in this study. After PSM, 296 patients in the IPT only group and 296 patients in the IPT plus ET group were further divided into the low-, medium-, and high-risk subgroups with 188, 364, and 40 matched patients, respectively. No significant differences were found between the IPT only and IPT plus ET groups in terms of morbidity, complications, and sequelae. Hospitalization duration and expenses were lower in the low- and medium-risk subgroups in the IPT only group. CONCLUSIONS: In this study, our results suggest that IPT is a safe and effective treatment for extreme hyperbilirubinemia. The indication of ET for patients with hyperbilirubinemia could be stricter. However, it is necessary to have a contingency plan for emergency ET as soon as IPT is commenced especially for infants with risk factors. If IPT can be guaranteed and proved to be therapeutic, ET should be avoided as much as possible.

Outcome Analysis of Severe Hyperbilirubinemia in Neonates Undergoing Exchange Transfusion.

OBJECTIVE: Severe neonatal hyperbilirubinemia can cause neurological disability or mortality if not effectively managed. Exchange transfusion (ET) is an efficient treatment to prevent bilirubin neurotoxicity. The purpose of this study was to evaluate outcomes in severe neonatal hyperbilirubinemia with ET and to identify the potential risk factors for poor outcomes. METHODS: Newborns of ≥28 weeks of gestational age with severe hyperbilirubinemia who underwent ET from January 2015 to August 2019 were included. Demographic data were recorded and analyzed according to follow-up outcomes at 12 months of corrected age. Poor outcomes were defined as death due to bilirubin encephalopathy or survival with at least one of the following complications: cerebral palsy, psychomotor retardation (psychomotor developmental index < 70), mental retardation (mental developmental index < 70), or hearing impairment. RESULTS: A total of 524 infants were eligible for recruitment to the study, and 62 infants were lost to follow-up. The outcome data from 462 infants were used for grouping analysis, of which 398 cases (86.1%) had normal outcomes and 64 cases (13.9%) suffered poor outcomes. Bivariate logistic regression analysis showed that peak total serum bilirubin (TSB) (odds ratio [OR] = 1.011, 95% confidence interval [CI] = 1.008-1.015, p = 0.000) and sepsis (OR = 4.352, 95% CI = 2.013-9.409, p < 0.001) were associated with poor outcomes of hyperbilirubinemia. Receiver operator characteristic curve analysis showed that peak TSB ≥452.9 µmol/L could predict poor outcomes of severe hyperbilirubinemia. CONCLUSION: Peak TSB and sepsis were associated with poor outcomes in infants with severe hyperbilirubinemia, and peak TSB ≥452.9 µmol/L could predict poor outcomes.

POCT management of neonatal bilirubinemia ­ guidelines for an optimization of kernicterus monitoring / Intérêt de la bilirubinémie en néonatalogie : recommandations pour une utilisation coordonnée par le LBM de la biologie délocalisée et des tests rapides d'orientation diagnostique

In pediatrics, accurate measurement of total serum bilirubin (TSB) is of major importance for reliable diagnosis and appropriate management of neonatal jaundice. However, several studies evidenced poor comparability of results obtained with the different available methods either in central lab or in POCT, on serum, capillary blood or transcutaneous. This situation is partly due to the lack of Reference Materials, especially for high bilirubin concentrations but also on poor communication between central lab and neonatology unit. To progress on these issues, we have compiled some data from CNRHP to propose guidelines for choice, use and management of POCT devices and to help clinical laboratories to achieve a better answer to clinical needs with specific local constraints. The results from several CNRHP studies are presented: traceability to International System of Units, inter-laboratories comparability, POCT vs central labs comparisons with POCT CO-oximeter or photometer, integration of transcutaneous bilirubinometer. We propose, based on an analysis of devices advantages and issues, guidelines to help labs either to improve neonates monitoring in their local context; we distinguished the choices inside laboratory for a better harmonization of results compared to published thresholds and outside lab contexts, to organize a coordinated chain with POCT devices, with capillary and/or transcutaneous approaches.

En néonatalogie, la mesure précise de la bilirubinémie est essentielle pour le diagnostic et le suivi de l'ictère, en regard de seuils consensuels internationaux. Toutefois, une faible comparabilité des résultats est observée entre les laboratoires de biologie médicale (LBM) et avec les dispositifs délocalisés ou transcutanés. Cette situation est en partie due à des défauts de standardisation des méthodes, mais aussi à une coordination insuffisante entre les laboratoires et les unités de soins. L'objectif de ce travail est de progresser dans l'optimisation de la prise en charge des nouveau-nés en proposant des critères de choix et d'articulation des différentes réponses biologiques, EBM, EBMD et TROD, en fonction des besoins cliniques locaux et des moyens disponibles. Les résultats de plusieurs études ciblées sur la bilirubinémie néonatale sont présentés : raccordement au système international, harmonisation interlaboratoires, comparabilité EBMD-CNRHP d'un CO-oxymètre délocalisé en maternité, comparabilité EBMD-CNRHP d'un photomètre délocalisé en maternité, intégration d'un bilirubinomètre transcutané. Nous proposons ensuite, sur la base d'une analyse critique des différents types de dispositifs, des recommandations pour aider les LBM à améliorer la prise en charge des nouveau-nés dans leur contexte local, d'une part sur la mesure de la bilirubinémie néonatale au sein du LBM et d'autre part sur l'organisation d'une chaîne coordonnée EBM ­ EBMD ­ TROD en concertation avec les unités de soins.

Trends in hospitalizations of newborns with hyperbilirubinemia and kernicterus in United States: an epidemiological study.

BACKGROUND: Hyperbilirubinemia is one of the most common diagnosis in newborn nurseries in United States. Universal pre-discharge bilirubin screening decreased the incidence of extreme hyperbilirubinemia and risk of kernicterus. OBJECTIVES: We sought to assess temporal population trends of hyperbilirubinemia, kernicterus and usage of phototherapy, intravenous immunoglobulin (IVIG), and exchange transfusion. DESIGN/METHODS: Data from Healthcare Cost and Utilization Project (HCUP)-the Kids' Inpatient Database (KID) obtained for years 1997-2012. All neonatal discharges with ICD-9 codes for neonatal jaundice (774.2, 774.6), kernicterus (773.4, 774.7) and procedure codes for phototherapy (99.83), IVIG infusion (99.14), exchange transfusion (99.01) were extracted. We compared the trends of diagnosis of hyperbilirubinemia, kernicterus, use of phototherapy, IVIG, and exchange transfusion. RESULTS: During the study period, the proportion of infants diagnosed with hyperbilirubinemia increased by 65% (9.4% vs. 15.5%; p<.001) in term infants and 34.5% (33.5% vs. 45%; p<.001) in preterm infants, respectively. Rate of kernicterus discharges significantly reduced from 7 to 1.9 per 100,000 newborns. Overall, the number of exchange transfusions has decreased by 67% during study period while phototherapy and IVIG use increased by 83% and 170%, respectively. CONCLUSIONS: In last two decades, there was a significant decrease in neonatal discharges with a history of exchange transfusion or with a diagnosis of kernicterus. However, there was a significant increase in number of neonates discharged home with a history of phototherapy during birth hospitalization and decreased number of exchange transfusions were observed during the study period. Incremental implementation of universal predischarge bilirubin screening and treatments based on 2004 AAP recommended risk-based strategies might have contributed to timely interventions in infants with significant hyperbilirubinemia.

Intensive phototherapy vs. exchange transfusion for the treatment of neonatal hyperbilirubinemia: a multicenter retrospective cohort study / 中华医学杂志(英文版)

BACKGROUND@#Intensive phototherapy (IPT) and exchange transfusion (ET) are the main treatments for extreme hyperbilirubinemia. However, there is no reliable evidence on determining the thresholds for these treatments. This multicenter study compared the effectiveness and complications of IPT and ET in the treatment of extreme hyperbilirubinemia.@*METHODS@#This retrospective cohort study was conducted in seven centers from January 2015 to January 2018. Patients with extreme hyperbilirubinemia that met the criteria of ET were included. Patients were divided into three subgroups (low-, medium-, and high- risk) according to gestational week and risk factors. Propensity score matching (PSM) was performed to balance the data before treatment. Study outcomes included the development of bilirubin encephalopathy, duration of hospitalization, expenses, and complications. Mortality, auditory complications, seizures, enamel dysplasia, ocular motility disorders, athetosis, motor, and language development were evaluated during follow-up at age of 3 years.@*RESULTS@#A total of 1164 patients were included in this study. After PSM, 296 patients in the IPT only group and 296 patients in the IPT plus ET group were further divided into the low-, medium-, and high-risk subgroups with 188, 364, and 40 matched patients, respectively. No significant differences were found between the IPT only and IPT plus ET groups in terms of morbidity, complications, and sequelae. Hospitalization duration and expenses were lower in the low- and medium-risk subgroups in the IPT only group.@*CONCLUSIONS@#In this study, our results suggest that IPT is a safe and effective treatment for extreme hyperbilirubinemia. The indication of ET for patients with hyperbilirubinemia could be stricter. However, it is necessary to have a contingency plan for emergency ET as soon as IPT is commenced especially for infants with risk factors. If IPT can be guaranteed and proved to be therapeutic, ET should be avoided as much as possible.

Neonatal Hyperbilirubinemia: An Updated Appraisal of National Guidelines.

Recent reports from several developed countries have documented a resurgence of bilirubin encephalopathy causing both healthcare and forensic issues. For these reasons, many national pediatric societies have issued recommendations on the diagnosis and the treatment of clinically significant neonatal hyperbilirubinemia. The differences among individual national documents may have an impact on neonatal healthcare. This paper shortly reviews the advantages and the shortcomings of the main international guidelines with a focus on the available evidence.

Diagnosis of Bilirubin Encephalopathy in Preterm Infants with Dyskinetic Cerebral Palsy.

INTRODUCTION: Very preterm infants are susceptible to bilirubin neurotoxicity, the signs of which are unclear during early infancy. We investigated children born preterm and later diagnosed with bilirubin encephalopathy (BE) to gain insights into accurate early diagnosis. METHODS: We identified 93 children born preterm and clinically diagnosed with BE who visited our hospital between 2006 and 2018. Perinatal history, findings of auditory brainstem response (ABR), brain magnetic resonance imaging (MRI), and functional outcomes were investigated retrospectively based on chart review. RESULTS: The mean gestational age and birth weights were 27.2 weeks and 991 g, respectively. During the neonatal period, only 3% (2/71) had exchange transfusions, and none were diagnosed with acute BE. ABR was abnormal in 64% (51/80), but the majority (34/51) required no hearing aids. Brain MRI taken between 6 and 18 months of age revealed bilateral T2 hyperintensity of the globi pallidi in 91% (60/66); subsequently, the rate decreased with age. Functional communication outcomes were markedly superior to gross motor and hand function outcomes. CONCLUSION: For early diagnosis of BE, brain MRI is recommended at a corrected age of between 6 and 18 months, especially for those with abnormal ABR during early infancy, and even with no apparent history of marked neonatal hyperbilirubinemia.

Rates of Extreme Neonatal Hyperbilirubinemia and Kernicterus in Children and Adherence to National Guidelines for Screening, Diagnosis, and Treatment in Sweden.

Importance: Neonatal hyperbilirubinemia can cause lifelong neurodevelopmental impairment (kernicterus) even in high-resource settings. A better understanding of the incidence and processes leading to kernicterus may help in the design of preventive measures. Objectives: To determine incidence rates of hazardous hyperbilirubinemia and kernicterus among near-term to term newborns and to evaluate health care professional adherence to best practices. Design, Setting, and Participants: This population-based nationwide cohort study used prospectively collected data on the highest serum bilirubin level for all infants born alive at 35 weeks' gestation or longer and admitted to neonatal care at all 46 delivery and 37 neonatal units in Sweden from 2008 to 2016. Medical records for newborns with hazardous hyperbilirubinemia were evaluated for best neonatal practices and for a diagnosis of kernicterus up to 2 years of age. Data analyses were performed between September 2017 and February 2018. Exposures: Extreme (serum bilirubin levels, 25.0-29.9 mg/dL [425-509 µmol/L]) and hazardous (serum bilirubin levels, ≥30.0 mg/dL [≥510 µmol/L]) neonatal hyperbilirubinemia. Main Outcomes and Measures: The primary outcome was kernicterus, defined as hazardous neonatal hyperbilirubinemia followed by cerebral palsy, sensorineural hearing loss, gaze paralysis, or neurodevelopmental retardation. Secondary outcomes were health care professional adherence to national guidelines using a predefined protocol with 10 key performance indicators for diagnosis and treatment as well as assessment of whether bilirubin-associated brain damage might have been avoidable. Results: Among 992 378 live-born infants (958 051 term births and 34 327 near-term births), 494 (320 boys; mean [SD] birth weight, 3505 [527] g) developed extreme hyperbilirubinemia (50 per 100 000 infants), 6.8 per 100 000 infants developed hazardous hyperbilirubinemia, and 1.3 per 100 000 infants developed kernicterus. Among 13 children developing kernicterus, brain injury was assessed as potentially avoidable for 11 children based on the presence of 1 or several of the following possible causes: untimely or lack of predischarge bilirubin screening (n = 6), misinterpretation of bilirubin values (n = 2), untimely or delayed initiation of treatment with intensive phototherapy (n = 1), untimely or no treatment with exchange transfusion (n = 6), or lack of repeated exchange transfusions despite indication (n = 1). Conclusions and Relevance: Hazardous hyperbilirubinemia in near-term or term newborns still occurs in Sweden and was associated with disabling brain damage in 13 per million births. For most of these cases, health care professional noncompliance with best practices was identified, suggesting that a substantial proportion of these cases might have been avoided.

Emergency release uncross-matched packed red blood cells for immediate double volume exchange transfusion in neonates with intermediate to advanced acute bilirubin encephalopathy: timely but insufficient?

Given the urgency of double volume exchange transfusion (ExT) in an infant with intermediate to advanced stages of acute bilirubin encephalopathy (ABE), it has been suggested that emergency release uncross-matched packed red blood cells (ER-PRBC) be used. The efficacy of an ExT in removing bilirubin from the brain, however, is a direct function of the mass of albumin exchanged. The very low albumin content of ER-PRBC may fail to be neuroprotective. Predicted changes in total serum bilirubin (TSB), serum albumin, the bilirubin/albumin (B/A) ratio, plasma volume (PV), and bilirubin equilibration from the extravascular space during ER-PRBC ExT are described. ExT using ER-PRBC is efficacious in lowering the TSB. However, this result is falsely reassuring as significant concurrent serum albumin loss, resultant hypoalbuminemia, contraction of PV, limited bilirubin clearance from the extravascular space, and sustained B/A ratio elevations above recommended ExT treatment thresholds suggest that bilirubin neurotoxicity will continue.

Patterns of acute bilirubin encephalopathy in Nigeria: a multicenter pre-intervention study.

BACKGROUND: Acute bilirubin encephalopathy (ABE) is an important cause of neonatal morbidity in Nigeria, accounting for 5-14% of neonatal deaths. Most newborns with severe ABE have irreversible damage before receiving treatment emphasizing the need for timely pre-admission monitoring and referral. There is limited evidence that educational interventions targeting mothers and health care providers will reduce delayed care. OBJECTIVE: To provide baseline data on the incidence of ABE and associated pre-admission risk factors in five centers of Nigeria in order to evaluate the effect of subsequent educational interventions on outcome. STUDY DESIGN: The incidence of ABE among newborns treated for hyperbilirubinemia was documented prospectively. Bivariate analysis and multivariate logistic regression were used to evaluate risk factors for acute bilirubin encephalopathy and reasons for regional differences in its occurrence. RESULTS: Of 1040 infants, 159 treated for hyperbilirubinemia (15.3%) had mild to severe bilirubin encephalopathy (including 35 deaths), but the incidence ranged from 7 to 22% between centers. Logistic regression identified four common predictors: total serum bilirubin (odds ratio 1.007 per mg/dl rise), out-of-hospital births (OR 2.6), non-alloimmune hemolytic anemia (OR 2.8), and delayed care seeking (OR 4.3). CONCLUSION: The high occurrence of bilirubin encephalopathy in Nigeria is due in large part to a delay in seeking care. A planned intervention strategy will target conditions leading to severe hyperbilirubinemia and delay.

The Turkish Neonatal Jaundice Online Registry: A national root cause analysis.

BACKGROUND: Neonatal jaundice (NNJ) is common, but few root cause analyses based on national quality registries have been performed. An online registry was established to estimate the incidence of NNJ in Turkey and to facilitate a root cause analysis of NNJ and its complications. METHODS: A multicenter prospective study was conducted on otherwise healthy newborns born at ≥35 weeks of gestation and hospitalized for only NNJ in 50 collaborator neonatal intensive care units across Turkey over a 1-year period. Patients were analyzed for their demographic and clinical characteristics, treatment options, and complications. RESULTS: Of the 5,620 patients enrolled, 361 (6.4%) had a bilirubin level ≥25 mg/dL on admission and 13 (0.23%) developed acute bilirubin encephalopathy. The leading cause of hospital admission was hemolytic jaundice, followed by dehydration related to a lack of proper feeding. Although all infants received phototherapy, 302 infants (5.4%) received intravenous immunoglobulin in addition to phototherapy and 132 (2.3%) required exchange transfusion. The infants who received exchange transfusion were more likely to experience hemolytic causes (60.6% vs. 28.1%) and a longer duration of phototherapy (58.5 ± 31.7 vs. 29.4 ± 18.8 h) compared to infants who were not transfused (p < 0.001). The incidence of short-term complications among discharged patients during follow-up was 8.5%; rehospitalization was the most frequent (58%), followed by jaundice for more than 2 weeks (39%), neurological abnormality (0.35%), and hearing loss (0.2%). CONCLUSIONS: Severe NNJ and bilirubin encephalopathy are still problems in Turkey. Means of identifying at-risk newborns before discharge during routine postnatal care, such as bilirubin monitoring, blood group analysis, and lactation consultations, would reduce the frequency of short- and long-term complications of severe NNJ.

Effectiveness of universal hyperbilirubinemia screening on newborn health: a systematic review protocol.

REVIEW QUESTION/OBJECTIVE: The objective of this review is to assess the effectiveness of the universal hyperbilirubinemia screening program on common newborn health outcomes.Specifically, the review will assess: the incidence of severe hyperbilirubinemia/kernicterus/exchange transfusion, rate of readmission due to jaundice, length of hospital stay on birth admission, rate and utilization of phototherapy during birth hospitalization, and jaundice related emergency visits.

The Neurological Sequelae of Neonatal Hyperbilirubinemia: Definitions, Diagnosis and Treatment of the Kernicterus Spectrum Disorders (KSDs).

BACKGROUND: Despite its lengthy history, the study of jaundice, hyperbilirubinemia and kernicterus suffers from a lack of clarity and consistency in the key terms used to describe both the clinical and pathophysiological nature of these conditions. For example, the term Bilirubin-induced Neurological Dysfunction (BIND) has been used to refer to all neurological sequelae caused by exposure to high levels of bilirubin, to only mild neurological sequelae, or to scoring systems that quantitate the progressive stages of Acute Bilirubin Encephalopathy (ABE). OBJECTIVE: We seek to clarify and simplify terminology by introducing, defining, and proposing new terms and diagnostic criteria for kernicterus. METHODS: We propose a systematic nomenclature based on pathophysiological and clinical criteria, presenting a logical argument for each term. Acknowledging observations that kernicterus is symptomatically broad and diverse, we propose the use of the overarching term Kernicterus Spectrum Disorders (KSDs) to encompass all the neurological sequelae of bilirubin neurotoxicity including Acute Bilirubin Neurotoxicity (ABE). We further suggest subclassification of KSDs based on the principal disabling features of kernicterus (motor, auditory). Finally, we suggest the term subtle KSD to designate a child with a history of significant bilirubin neurotoxicity with mild or subtle developmental delays. RESULTS AND CONCLUSION: We conclude with a brief description of the limited treatments currently available for KSD, thereby underscoring the importance of further research. We believe that adopting a systematic nomenclature for the spectrum of clinical consequences of hyperbilirubinemia will help unify the field and promote more effective research in both prevention and treatment of KSDs.

The use of therapeutic plasma exchange to reduce serum bilirubin in a dog with kernicterus.

OBJECTIVE: To describe the use of a manual method of therapeutic plasma exchange to reduce total serum bilirubin, manage kernicterus, and halt progression of neurological dysfunction in a dog with immune-mediated hemolytic anemia (IMHA). CASE SUMMARY: A 5-year-old male neutered Lhasa Apso diagnosed with IMHA developed acute onset neurologic signs consistent with kernicterus. Manual therapeutic plasma exchange was performed in an attempt to reduce total serum bilirubin. The initial exchange was performed at a lower plasma exchange volume due to the dog's critical status and the dog's clinical signs progressed. More aggressive plasma exchange was performed that resulted in a reduction in total serum bilirubin and no further progression of neurologic signs. The dog was euthanized due to suspicion of permanent neurologic changes and need for further blood transfusions. Histopathology postmortem confirmed a diagnosis of kernicterus. NEW OR UNIQUE INFORMATION PROVIDED: Kernicterus secondary to hyperbilirubinemia is well described in people, but has rarely been reported in dogs. Therapeutic plasma exchange has been used for decades in people to rapidly decrease serum bilirubin when hyperbilirubinemia progresses to neurologic signs, but to the authors' knowledge this has not been described in a dog.