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ObjectiveThe objective of this study was to assess the prevalence and trends for neonatal hyperbilirubinemia, and the development of bilirubin neurotoxicity in the USA.Study DesignWe used a de-identified national dataset for the years 2002–2017. The study included all newborn inpatients with postnatal age ≤28 days. Cochran–Armitage trend test was used for trend analyses. Regression analyses were performed and adjusted odds ratios (aOR) were reported.ResultsThe study included 57,989,476 infants; of them 53,259,758 (91.8%) were term infants and 4,725,178 (8.2%) were preterm infants. Bilirubin neurotoxicity decreased over the years in term infants (Z = 0.36, p = 0.03) without change in preterm infants (Z = 42.5, p = 0.12). Black neonates were less likely to be diagnosed with hyperbilirubinemia than White neonates (aOR = 0.77, 95% confidence interval (CI): 0.77–0.78, p < 0.001) and more likely to develop bilirubin neurotoxicity than White neonates (aOR = 3.0.5, 95% CI: 2.13–4.36, p < 0.001). Bilirubin neurotoxicity rate in the overall population was 2.4 per 100,000 live births.ConclusionsBilirubin neurotoxicity has significantly decreased in term infants and did not change in preterm infants. Despite the less diagnosis of hyperbilirubinemia in Black newborns, they are disproportionately at increased risk of developing bilirubin neurotoxicity when compared to White newborns.ImpactIn this article, we analyzed the National Inpatient Database. This is the largest study of its kind using data on 57,989,476 neonates. The article has multiple novel findings: (1) it demonstrated that utilization of phototherapy has increased significantly over the years, (2) the rate of kernicterus for neonates decreased in term infants and did not change in preterm babies, (3) kernicterus was mostly encountered in infants without isoimmunization jaundice, and (4) there is a clear racial disparity in neonatal jaundice; although Black newborns have less neonatal jaundice, they are at increased risk of developing kernicterus.

Neonatal jaundice due to hyperbilirubinemia is common, and most cases are benign. The irreversible outcome of brain damage from kernicterus is rare (1 out of 100,000 infants) in high-income countries such as the United States, and there is increasing evidence that kernicterus occurs at much higher bilirubin levels than previously thought. However, newborns who are premature or have hemolytic diseases are at higher risk of kernicterus. It is important to evaluate all newborns for risk factors for bilirubin-related neurotoxicity, and it is reasonable to obtain screening bilirubin levels in newborns with risk factors. All newborns should be examined regularly, and bilirubin levels should be measured in those who appear jaundiced. The American Academy of Pediatrics (AAP) revised its clinical practice guideline in 2022 and reconfirmed its recommendation for universal neonatal hyperbilirubinemia screening in newborns 35 weeks’ gestational age or greater. Although universal screening is commonly performed, it increases unnecessary phototherapy use without sufficient evidence that it decreases the incidence of kernicterus. The AAP also released new nomograms for initiating phototherapy based on gestational age at birth and the presence of neurotoxicity risk factors, with higher thresholds than in previous guidelines. Phototherapy decreases the need for an exchange transfusion but has the potential for short- and long-term adverse effects, including diarrhea and increased risk of seizures. Mothers of infants who develop jaundice are also more likely to stop breastfeeding, even though discontinuation is not necessary. Phototherapy should be used only for newborns who exceed thresholds recommended by the current AAP hour-specific phototherapy nomograms.

ObjectiveTo determine the incidence and etiology of extreme neonatal hyperbilirubinemia, defined as total serum bilirubin (TSB) ≥450 µmol/L, and kernicterus spectrum disorder (KSD) in Denmark between 2000 and 2015.Study designWe identified all infants born between 01.01.2000 and 31.12.2015 with TSB ≥450 µmol/L, ratio of conjugated to TSB <0.30, gestational age ≥35 weeks, and postnatal age ≤4 weeks, using Danish hospitals’ laboratory databases.ResultWe included 408 infants. The incidence of extreme neonatal hyperbilirubinemia among infants with gestational age ≥35 weeks was 42/100,000 during the study period with a seemingly decreasing incidence between 2005 and 2015. Twelve of the 408 infants developed KSD, (incidence 1.2/100,000) Blood type ABO isohemolytic disease was the most common explanatory etiology.ConclusionsOur study stresses the importance of a systematic approach to neonatal jaundice and ongoing surveillance of extreme neonatal hyperbilirubinemia and KSD.

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. 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. 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. 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. 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. 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). 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.

The purpose of this research was to define the functions of MRS and ABR as predictors of bilirubin-induced neurologic dysfunction (BIND) in full-term neonates who required intervention (phototherapy and/or exchange transfusion ). This prospective cohort study was done at the NICU of Tanta University Hospitals over a 2-year duration. Fifty-six full-term neonates with pathological unconjugated hyperbilirubinemia were divided according to MRS and ABR findings into 2 groups: group (1) included 26 cases with mild acute bilirubin encephalopathy (BIND-M score 1–4). Group (2) included 30 cases with neonatal hyperbilirubinemia only. In addition, 20 healthy neonates with similar ages were employed as the controls. When compared to group 2 and the control group, group 1’s peak-area ratios of NAA/Cr and NAA/Cho were found to be significantly reduced ( P  < 0.05). As compared to group 2 and the control group, group 1’s Lac/Cr ratio was significantly greater ( P  < 0.05), but the differences were not significant for group 2 when compared to the control group. Waves III and V peak latencies, I–III, and I–V interpeak intervals were significantly prolonged in group 1 in comparison to group 2 and controls ( P  < 0.05) with no significant difference between group 2 and control group.     Conclusion : When the symptoms of ABE are mild and MRI does not show any evident abnormalities, MRS and ABR are helpful in differentiating individuals with ABE from patients with neonatal hyperbilirubinemia.     Trial registration :  ClinicalTrials.gov , Identifier: NCT06018012. What is Known: • MRS can be used as a diagnostic and prognostic tool for the differential diagnosis of patients with acute bilirubin encephalopathy, from patients with neonatal hyperbilirubinemia What is New: • ABR is a useful diagnostic and prognostic tool in the care and management of neonates with significantly raised bilirubin. It can be used as early predictor of acute bilirubin encephalopathy in the earliest stage of auditory damage caused by bilirubin.

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) levels >20 mg per 100 ml (342 μmol l −1 ; range: 20.7 to 59.9 mg per 100 ml). No specific TSB threshold coincided with onset of ABE. Of infants <37 weeks GA with kernicterus, 34.9% were LGA (large for gestational age) as compared with 24.7% of term infants (>37 weeks GA). Although >90% 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 and <10 days in 101 of 118 (86%) infants. TSB levels were ⩽35 mg per 100 ml (598 μmol 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 TSB >35 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.

Neonatal hyperbilirubinemia is one of the most common conditions managed by pediatricians. Although many infants are affected, most will experience complete resolution without complication. Acute bilirubin encephalopathy and kernicterus are rare yet debilitating sequelae of severe hyperbilirubinemia that can be avoided through careful monitoring and treatment with phototherapy. Appropriate management of neonatal hyperbilirubinemia must balance the risks of these severe conditions with the effects of overtreatment. Released in 2022, the American Academy of Pediatrics revised the clinical practice guideline for the management of hyperbilirubinemia, which aims to provide that balance through updates to the previous guideline. This article will provide the reader with (1) an evidence-based harm and benefit analysis of the guideline, (2) an overview of key changes and clarifications made in the new guideline, and (3) a practical summary of guideline updates. [Pediatr Ann. 2024;53(6):e208–e216.]

Neonatal hyperbilirubinemia (NH) is a common phenomenon. In most cases, NH is benign and transient. However, in severe NH cases, neonates can develop encephalopathy and kernicterus. With appropriate screening and treatment, these adverse sequelae can be prevented. This article aims to provide the reader with an in-depth understanding of (1) bilirubin metabolism, (2) risk factors for severe NH, (3) NH screening and treatment, (4) various etiologies of severe NH, and (5) consequences of severe, untreated NH. [Pediatr Ann. 2022;51(6):e219–e227.]

BackgroundKernicterus Spectrum Disorders (KSDs) result from hyperbilirubinemia-induced brain injury. We developed a Toolkit (KSD-TK) to predict the likelihood of KSDs. This study aims to validate the KSD-TK by comparing it to clinical diagnoses made by the Kernicterus Clinic in the Division of Neurology.MethodsThrough retrospective chart review, we completed a KSD-TK for 37 patients evaluated between 2011 and 2019 using highest bilirubin, newborn risk factors, neonatal exam, follow-up exam, auditory testing, tooth enamel, and MRI brain results. KSD-TK results were compared to the clinical diagnoses given by a kernicterus expert (SS).ResultsOf 37 patients, 29 were clinically diagnosed with kernicterus, including 14/14 with KSD-TK scored as “definite”, 14/15 “probable”, and 1/2 with “possible” kernicterus. None of 6 patients with KSD-TK “not kernicterus” were clinically diagnosed with kernicterus. Combining KSD-TK “definite” and “probable”, the KSD-TK has 96.6% sensitivity and 87.5% specificity. Each KSD-TK component had high sensitivity, but only three had specificity ≥0.75: auditory neuropathy spectrum disorder, abnormal movements and/or tone on follow-up exam, and abnormal globus pallidus and/or subthalamic nucleus on MRI.ConclusionThe KSD-TK is a promising screening tool for patients at risk for kernicterus.ImpactThis study provides validation of a Kernicterus Spectrum Disorders (KSDs) Toolkit.The toolkit provides screening criteria for predicting KSD diagnosis.Scores of definite or probable have high sensitivity and specificity for KSDs.Abnormal auditory processing, exam, and MRI were most specific for KSDs.

Despite efforts to eliminate permanent and irreversible brain damage due to bilirubin encephalopathy and kernicterus, these conditions continue to accompany us into the third millennium. This phenomenon occurs not only in developing countries with emerging medical systems, but in Westernized countries as well. Comprehensive guidelines to detect newborns with jaundice and treat those in whom hyperbilirubinemia has already developed have been formulated in several countries, but have not been successful in completely eliminating the problem. In this appraisal of the situation we review selected aspects of bilirubin encephalopathy and/or kernicterus. We highlight recent reports of severe hyperbilirubinemia and kernicterus, discuss some of the factors responsible for the continuing appearance of these conditions, and briefly review what can be done to decrease bilirubin-related morbidity and mortality to the minimum.