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Background: Severe neonatal hyperbilirubinemia can cause hearing impairment. Bilirubin can be deposited in nerve cells, and the brainstem and the 8th nerve are especially sensitive to bilirubin toxicity. Abnormal changes in brainstem auditory evoked potential (BAEP) can be observed, and the BAEP test measures a nerve potential induced by short, high-frequency sound stimulation; thus, it is able to detect damage to the auditory conduction pathway in children. We aimed to identify relationships between clinical features and BAEP abnormalities in children with hyperbilirubinemia and to assess the predictive power of these risk factors for bilirubin-induced neurological damage., Methods: Children with hyperbilirubinemia were evaluated with BAEP and retrospectively enrolled in the study between January 2012 and December 2018. Multivariate logistic regression was performed to identify independent predictors of BAEP abnormalities., Results: Of the 561 children with hyperbilirubinemia enrolled, the BAEP anomaly group accounted for 198 (35.3%) cases. Except for body weight, there were no significant differences in the general data between the two groups with hyperbilirubinemia ( p > 0.05). Univariate analysis showed that prematurity, abnormal umbilical cord, and gestational diabetes during pregnancy were significantly correlated with abnormal BAEP. Multivariate logistic regression analysis identified prematurity ( p = 0.001), gestational diabetes ( p = 0.03), Premature rupture of membranes ( p = 0.013), total serum bilirubin (TSB), bilirubin/albumin (B/A) as independent risk factors for BAEP abnormalities. The prediction accuracy of TSB (Area Under Curve (AUC) = 0.557) and B/A (AUC = 0.566) was low, indicating that abnormal BAEP should be detected by multiple factors., Conclusions: Multivariate detection is beneficial for predicting the occurrence of auditory nerve injury in patients with hyperbilirubinemia.

Aims: To explore the relationship between preconception severe hypoglycemia (PSH) and pregnancy outcomes in pregnancies complicated with type 1 diabetes mellitus (T1DM)., Materials and Methods: In this multicenter prospective cohort study, women with pregestational T1DM were stratified by episodes of severe hypoglycemia within 1 year before conception: No PSH, sporadic PSH (1-6 times/year), and recurrent PSH (>6 times/year). We analysed the predictive ability of PSH for maternal and neonatal outcomes using log-binomial regression models and receiver operating characteristic (ROC) curve., Results: Of the 124 women studied, 37.1% experienced at least one episode of severe hypoglycemia preconception. In the multiple adjusted regression models, recurrent PSH was significantly associated with increased incidence of preeclampsia (RR 17.59, 95% CI: 2.89-150.62, p for trend = 0.007), preterm birth (RR 6.34, 95% CI: 1.22-40.63, p for trend = 0.027), neonatal hypoglycemia (RR 4.52, 95% CI: 1.14-17.16, p for trend = 0.017), neonatal hyperbilirubinemia (RR 4.12, 95% CI: 1.11-15.56, p for trend = 0.004), and composite neonatal outcome (RR 3.85, 95% CI: 1.01-19.61, p for trend = 0.003). In the ROC analysis, PSH predicted preeclampsia, preterm birth, neonatal hypoglycemia, neonatal hyperbilirubinemia, and composite neonatal outcome with areas under the ROC curve all ≥0.6., Conclusions: Recurrent preconception severe hypoglycemia is associated with increased risks of adverse outcomes in pregnant women with T1DM., (© 2023 John Wiley & Sons Ltd.)

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., (© 2023. The Author(s).)

Objectives: Hypernatremia may facilitate the diffusion of bilirubin through the blood-brain barrier and increase the risk of bilirubin encephalopathy. This study was conducted to compare the prognosis of jaundice infants with those with jaundice and hypernatremia., Methods: A total of 615 term infants with idiopathic jaundice with or without hypernatremia were enrolled in this cohort study with 24-months follow-up at Ghaem Hospital, Mashhad, Iran, between 2010 and 2022. An in-house questionnaire including the laboratory evaluation and neonatal characteristics was used as the data collection tool. The follow-up of neonatal development status was performed using the Denver test II at 6, 12, 18, and 24 months after discharging from hospital., Results: Normal outcomes were seen in 555 (90.2%) out of 615 studied infants, while 60 cases (9.8%) showed abnormal outcomes. Serum levels of sodium (P = 0.017), bilirubin (P = 0.001), urea (P = 0.024), and creatinine (P = 0.011) as well as hyperthermia (P = 0.046) and unconsciousness (P = 0.005) showed significant differences between the two groups. Approximately 16% of the newborns with both jaundice and hypernatremia, and 9% of those with only jaundice had unfavorable prognoses. Also, bilirubin level had the most predictive power (91.3%)., Conclusions: Our results suggest that hypernatremia or jaundice alone, may affect the prognosis of infants aged 2 years; but jaundice and hypernatremia together, will intensify the developmental problems in jaundice infants. However, the role of hyperbilirubinemia in the incidence of complications is more than hypernatremia.

Background: The prevalence of atopic dermatitis (AD) is high among children, with development of AD occurring during early childhood in most affected children and some having a chronic disease course. Risk factors for AD in this group remain undefined. Objectives: We analyzed the medical records of children with AD under 5 years of age. We summarized characteristics of the natural course of AD in these children and explored relevant risk factors of AD in infancy and early childhood. Methods: Using a self-developed questionnaire, we investigated 716 children under 5 years of age who were treated for AD at the Dermatology Department of the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China. We conducted the study from October 2021 to September 2022 using telephone and on-site interviews with the children's parents. In parental interviews, data were gathered on neonatal diseases, comorbidities, parental allergy history, maternal history of tobacco and alcohol use, and basic infant information at birth. Some children were tested for serum total immunoglobulin E (IgE) before this study. Results: Neonatal hyperbilirubinemia, neonatal respiratory distress syndrome (NRDS), neonatal infection, and infection during childhood had a significant impact on persistent symptoms and the onset of first symptoms in children with AD ( P  < 0.05). Allergic diseases as common comorbidities with AD, which had earlier onset of AD related to more obvious disease activity ( P  < 0.05). Parental history of allergy was also significant in AD ( P  < 0.05). Serum total iIgE levels in children with AD showed an impact on the clinical course of AD; neonatal hyperbilirubinemia and NRDS may affect IgE levels ( P  < 0.05). Persistent AD had a significant effect on the physical growth of children with height/length for age Z score ≤3 and weight for height/length Z score ≤3 ( P  < 0.05). Conclusions: Early adverse events in infants, infection before onset, and susceptibility to infection may affect the onset and clinical course of childhood AD. Serum total IgE levels affect the progression of AD. Persistent AD in childhood may have a slight impact on children's physical growth.

Objective: Jaundice (icterus) is the visible manifestation of the accumulation of bilirubin in the tissue and is indicative of potential toxicity to the brain. Since its very first description more than 2000 years ago, many efforts have been undertaken to understand the molecular determinants of bilirubin toxicity to neuronal cells to reduce the risk of neurological sequelae through the use of available chemicals and in vitro, ex vivo, in vivo, and clinical models. Although several studies have been performed, important questions remain unanswered, such as the reasons for regional sensitivity and the interplay with brain development. The number of new molecular effects identified has increased further, which has added even more complexity to the understanding of the condition. As new research challenges emerged, so does the need to establish solid models of prematurity., Methods: This review critically summarizes the key mechanisms of severe neonatal hyperbilirubinemia and the use of the available models and technologies for translational research., Impact: We critically review the conceptual dogmas and models used for studying bilirubin-induced neurotoxicity. We point out the pitfalls and translational gaps, and suggest new clinical research challenges. We hope to inform researchers on the pro and cons of the models used, and to help direct their experimental focus in a most translational research., (© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

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.

This retrospective study aimed to investigate the correlation between neonatal hyperbilirubinemia (NHB) and hypoglycemia (NH) in Chinese women with diabetes in pregnancy (DIP), and the influencing factors. All the data were collected July 1, 2017 and June 30, 2020, and 10,558 Chinese women with DIP and live births were included. Two separate multivariate binary stepwise forward logistic regression analysis calculated OR with 95% CI. The prevalence rates of NHB and NH was respectively 3.65% and 5.82% among women with DIP. The comorbidity of both diseases was 0.59%. NH were 1.81 times (OR 1.81, 1.19-2.76) more likely to have hyperbilirubinemia. NHB is positively correlated with NH (OR 1.93, 1.27-2.92). Increased gestational age has a protective effect on both NH (OR 0.76, 0.68-0.85) and NHB (OR 0.80, 0.69-0.92). Abnormal placental morphology is related to NH (OR 1.55, 1.16-2.08) and NHB (OR 1.64, 1.10-2.45). Regarding neonatal outcomes, congenital heart disease (CHD) (OR 2.16, 1.25-3.73; and OR 10.14, 6.47-15.90) was a risk factor for NH and NHB. NHB and NH were significantly correlated in women with DIP. The offspring of DIP with multiple risk factors have a significantly increased risk of neonatal hyperbilirubinemia., (© 2022. The Author(s).)

Background: ABO blood group incompatibility, neonatal sepsis, G-6-PD deficiency, thyroid dysfunction, and hereditary spherocytosis are all probable causes of neonatal hyperbilirubinemia. However, the etiology of some hyperbilirubinemia is extremely complicated, which may be caused by multiple factors, resulting in severe jaundice. We report a case of severe jaundice due to three causes, showing the significance for the investigation of the etiology of neonatal hyperbilirubinemia., Case Presentation: At 96 h of life, a full-term and vaginal delivery male infant with yellowish discoloration of body was transferred to our hospital. When he entered neonatal intensive care unit on the fourth day after birth, he developed jaundice and the transcutaneous bilirubin was 28 mg/dl. Total bilirubin was 540.2 μmol/L, while the indirect bilirubin was 516.7 μmol/L. Both parents and the baby's blood types were O Rh(D +), and direct coomb's test was negative. But mother's indirect coomb's test was positive. Investigating for minor blood group revealed that the father's blood type of Rh was CCDee, the mather's was ccDEE, and CcDEe for the baby. After intensive phototherapy and double volume exchange transfusion, the total bilirubin remained at 303 μmol/L. At day 10, the bilirubin level was 303.5 μmol/L, intensive phototherapy was continued, and intravenous immunoglobulin was used again. The test for thyroid hormones at day 10, the TSH was 13.334mIU/L. And the screening for congenital hypothyroidism showed the TSH was 33mIU/L. Because of the palpable abdominal mass, ultrasound and MRI was done, showed a huge mass in the right adrenal gland. Brainstem auditory evoked potential was performed at day 7, which indicated hearing impairment (65db for left ear and 70db for the right). Euthyrox and intermittent phototherapy were given as following treatment. The jaundice did not subside until the 12th day., Conclusion: Even if their parents' ABO blood group and Rh (d) are consistent, a Coomb test is required for newborns with hyperbilirubinemia since they may have minor blood group incompatibilities. When bilirubin rises rapidly or the clinical treatment effect is inadequate, additional causes should be aggressively screened. Adrenal ultrasound should be performed on newborns with palpable abdominal mass, anemia and jaundice to determine whether there is adrenal hemorrhage., (© 2022. The Author(s).)

Neonatal jaundice is common and associated with delay in hospital discharge and risk of neurological sequelae if not treated. The objectives of the study were to report on our experience of the monitoring and treatment of neonatal jaundice in a home care setting and its feasibility and safety for neonates with high risk of severe hyperbilirubinemia. The 2-year study has been led in the greater Paris University Hospital At Home (Assistance Publique-Hôpitaux de Paris). The device of the intervention was the Bilicocoon® Bag, a light-emitting diode sleeping bag worn by the neonate when the total serum bilirubin value exceeds intensive phototherapy threshold, according to the guidelines from the American Academy of Pediatrics. One hundred and thirty-nine neonates had participated in the intervention and 39 (28%) were treated by phototherapy at home, as continuation of inpatient phototherapy or started at home. Seventy-five percent of the sample had more than two risk factors for development of severe hyperbilirubinemia. Twenty five percent of the cohort who received phototherapy at home had lower gestational age (p < 0.014) and had younger age at discharge from maternity (p < 0.09). Median length of stay in hospital at home was 5 days. Two patients needed readmission in conventional hospital (1%) for less than 24 h. In multivariate model, the length of stay decreased with the higher gestational age (p < 0.001) and increased significantly with the older age at discharge, the birth weight < 10th percentile, and a treatment by phototherapy at home.    Conclusion: Hospital at home, which is a whole strategy using an effective and convenient phototherapy device combined with a specialized medical follow-up, could be an alternative to conventional hospitalization for neonates at high risk of severe jaundice. The maternity discharge is facilitated, the mother-infant bonding can be promoted, and the risk of conventional rehospitalization is minimal, while guaranteeing the safety of this specific care. What is Known: • Managing neonatal jaundice is provided in conventional hospital with phototherapy. • Neonatal jaundice increases the risk of prolonged hospitalization or readmission. What is New: • Phototherapy is feasible in hospital at home for neonates with high risk of severe hyperbilirubinemia. • The care pathway of neonates from conventional hospital to hospital at home is described., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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., Competing Interests: None declared., (Thieme. All rights reserved.)

Objective: The objective of this study was to assess the prevalence and trends for neonatal hyperbilirubinemia, and the development of bilirubin neurotoxicity in the USA., Study Design: We 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., Results: The 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., Conclusions: Bilirubin 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., Impact: In 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., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

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., (Copyright © 2022 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.)

Objective: This study aimed to determine whether neonatal hyperbilirubinemia is associated with a risk of autism spectrum disorder (ASD) using a large population-based cohort., Study Design: This retrospective cohort study used data from the children's database (2000-2012) of the National Health Insurance Research Database (1996-2012) in Taiwan. We included neonates who were born between 2000 and 2004 and aged <1 month diagnosed with and without hyperbilirubinemia. The primary outcome was physician-diagnosed ASD. At the end of 2012, multivariate Cox's regression analysis was used to estimate hazard ratios (HRs)., Results: A total of 67,017 neonates were included. The neonates with hyperbilirubinemia were associated with 1.28-fold increased risk of ASD (HR = 1.28, 95% confidence interval [CI]: 1.05-1.57) compared with those without hyperbilirubinemia. In subanalysis to determine how phototherapy and exchange transfusion treatment for hyperbilirubinemia were associated with ASD showed no association between treatment and ASD, suggesting the lack of a dose-response effect of hyperbilirubinemia on the risk of ASD. Boys had a nearly six-fold higher risk of ASD than girls (HR = 5.89, 95% CI: 4.41-7.86). Additionally, neonates born with preterm birth and low birth weight were associated with a risk of ASD (HR = 1.46, 95% CI: 1.00-2.13)., Conclusion: We did not observe a dose-response effect of hyperbilirubinemia on ASD, but neonatal hyperbilirubinemia may be an independent risk factor for ASD if there is a residual confounding by other perinatal complications. Therefore, this study does not support a causal link between neonatal hyperbilirubinemia exposure and the risk of ASD., Competing Interests: None declared., (Thieme. All rights reserved.)

Objective: To explore the changes in amplitude-integrated electroencephalography (aEEG), neuron-specific enolase (NSE), and S100B in neonates with brain injury induced by neonatal hyperbilirubinemia (NHB)., Methods: 67 neonates with brain injury induced by NHB admitted to our hospital from March 2016 to October 2018 were included in a brain injury group (BIG), and 82 neonates with NHB but without brain injury in our hospital during the same period were included in a non-BIG. The two groups were compared regarding the rates of normal and abnormal aEEG results., Results: The proportion of normal aEEG results in the BIG was significantly lower than that in the non-BIG, and the proportion of moderately and severely abnormal aEEG results in the BIG were both significantly higher than those in the non-BIG. The BIG showed significantly higher NSE and S100B levels than those of the non-BIG. The ROC curve for predicting prognosis showed that the AUC of aEEG, NSE, S100B, and the combined detection are 0.780, 0.754, 0.743, 0.788. The AUC > 0.700 indicated a good predictive value for the prognosis., Conclusion: The combination of aEEG, NSE, and S100B has good value in diagnosing injury induced by NHB and can predict prognosis moderately well.

Background: Neonatal hyperbilirubinemia is a common clinical condition that requires medical attention in newborns, which may develop into acute bilirubin encephalopathy with a significant risk of long-term neurological deficits. The current clinical challenge lies in the separation of acute bilirubin encephalopathy and non-acute bilirubin encephalopathy neonates both with hyperbilirubinemia condition since both of them demonstrated similar T1 hyperintensity and lead to difficulties in clinical diagnosis based on the conventional radiological reading. This study aims to investigate the utility of T1-weighted MRI images for differentiating acute bilirubin encephalopathy and non-acute bilirubin encephalopathy neonates with hyperbilirubinemia., Methods: 3 diagnostic approaches, including a visual inspection, a semi-quantitative method based on normalized the T1-weighted intensities of the globus pallidus and subthalamic nuclei, and a deep learning method with ResNet18 framework were applied to classify 47 acute bilirubin encephalopathy neonates and 32 non-acute bilirubin encephalopathy neonates with hyperbilirubinemia based on T1-weighted images. Chi-squared test and t-test were used to test the significant difference of clinical features between the 2 groups., Results: The visual inspection got a poor diagnostic accuracy of 53.58 ± 5.71% indicating the difficulty of the challenge in real clinical practice. However, the semi-quantitative approach and ResNet18 achieved a classification accuracy of 62.11 ± 8.03% and 72.15%, respectively, which outperformed visual inspection significantly., Conclusion: Our study indicates that it is not sufficient to only use T1-weighted MRI images to detect neonates with acute bilirubin encephalopathy. Other more MRI multimodal images combined with T1-weighted MRI images are expected to use to improve the accuracy in future work. However, this study demonstrates that the semi-quantitative measurement based on T1-weighted MRI images is a simple and compromised way to discriminate acute bilirubin encephalopathy and non-acute bilirubin encephalopathy neonates with hyperbilirubinemia, which may be helpful in improving the current manual diagnosis.

Objective: Hyperbilirubinemia is a common disease in the neonatal period, and hyperbilirubinemia may cause brain damage. Therefore, prevention and diagnosis and management of hyperbilirubinemia is very important, and vitamin D may affect bilirubin levels. To evaluate the relationship between neonatal hyperbilirubinemia and vitamin D levels., Method: The China National Knowledge Infrastructure, VIP, Wanfang, Chinese Biology Medicine Disc, PubMed, Web of Science, Cochrane Library, and Embase databases as well as clinical trial registries in China and the United States were searched for relevant studies from inception to September 2020 without restrictions on language, population, or year. The studies was screened by two reviewers independently, the data were extracted, and the risk of bias of the included studies was evaluated using the NOS. A meta-analysis was conducted on the included studies using Stata11 software., Results: Six case-control studies were included, and the methodological quality of the studies was high (grade A). The studies included 690 newborns; more than 409 were diagnosed with hyperbilirubinemia. The means and standard deviations were calculated. Meta-analysis results showed that neonatal vitamin D levels were 7.1 ng/ml lower among infants with hyperbilirubinemia than among healthy newborn levels (z = 6.95, 95% CI 9.10 ~ 5.09, P < 0.05). Subgroup analysis was conducted based on whether the bilirubin levels were concentrated in the 15 to 20 mg/dl range. Vitamin D level of infants with hyperbilirubinemia (the bilirubin levels were concentrated in the 15 to 20 mg/dl range) was 9.52 ng/ml (Z = 15.55, 95% CI-10.72~-8.32, P<0.05) lower than that of healthy infants. The bilirubin levels in four cases were not concentrated in the 15-20 mg/dl range. The results showed that the vitamin D level of hyperbilirubinemia (The bilirubin levels were not concentrated in the 15-20 mg/dl range) neonates were 5.35 ng/ml lower than that of healthy neonates (Z = 6.43, 95% CI-6.98~-3.72, P<0.05)., Conclusion: Vitamin D levels were observed to be lower in neonates with hyperbilirubinemia as compared to term neonates without hyperbilirubinemia in this study. This can possibly suggest that neonates with lower vitamin D levels are at higher risk for developing hyperbilirubinemia., Competing Interests: The authors have declared that no competing interests exist.

Background: Hyperbilirubinemia is toxic to the auditory pathways and to the central nervous system, leaving sequelae such as hearing loss and encephalopathy. The damage to the auditory system occurs primarily within the brainstem and cranial nerve VIII, and manifests clinically as auditory neuropathy spectrum disorder., Aim: to establish the relationship that exists between hyperbilirubinemia at birth as a risk factor of neonatal hearing loss in children born in ABOU-EL-REISH hospital., Materials and Methods: we carried out of 60 neonates categorized into two groups: Group (A n = 30), neonates with hyperbilirubinemia; Group (B n = 30), neonates without hyperbilirubinemia., Results: Ten neonates were boys and twenty were girls from group A and eleven boys and nigh-teen girls from group B.There was significant statistical difference between group A and group B regarding ABR (P-value = 0.001) and a statistical difference regarding OAE (P-value = 0.103 in the right ear and 0.028 in the left ear). Also, our study shows the area under the curve and the diagnostic accuracy of total serum bilirubin (TSB) level for detection of hearing screening results (ABR) at a cut-off point 21 mg/dl (P-value = 0.008 and 0.009 in the right and left ears respectively.) CONCLUSIONS: Our study showed a relevant association between bilirubin levels and abnormal hearing screening results and the importance of combined screening with OAE and ABR tests., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Indirect hyperbilirubinemia is frequently encountered during neonatal period. Although it has different causes, in some cases it can't be explained. Previous studies have illustrated that jaundice could be a major sign of urinary tract infection (UTI) in neonates., Aim of the Work: We aimed to determine the association between UTI and significant unexplained neonatal indirect hyperbilirubinemia., Methods: This prospective controlled study was performed on 150 neonates divided in two groups (100 as cases and 50 as controls) to investigate the incidence of UTI in neonates with significant unexplained hyperbilirubinemia. Urine sample was obtained using urine catheterization technique from neonates and full urine analysis was done and cases with pyuria had urine culture to confirm UTI. Immediate renal ultrasonography (USG) was performed for neonates with UTI., Results: UTI incidence was 11% in cases while none of neonates in control group had UTI with statistical significance between cases and controls (P value < 0.05). The most common (36.4%) pathogen was Escherichia coli. Posterior urethral valve with mild hydronephrosis was diagnosed in 18.2% of UTI positive patients by renal ultrasonography., Conclusion: In neonates with unexplained indirect hyperbilirubinemia, UTI should be considered as a pathological cause.

We present a new hypothesis for the pathogenesis of auditory neuropathy spectrum disorder (ANSD) in at risk neonates involving depletion of riboflavin. The association between neonatal hyperbilirubinemia and ANSD is well recognized, yet causation has not been proven. The risk of ANSD does not correlate clearly with severity of hyperbilirubinemia and ASND only occurs in a small proportion of hyperbilirubinemic neonates. Additional, perhaps co-dependent, factors are therefore likely to be involved in pathogenesis. The metabolism of bilirubin consumes riboflavin and levels of riboflavin are depleted further by phototherapy. The neonate may also be deficient in riboflavin secondary to maternal deficiency, and reduced intake or impaired absorption. We propose that riboflavin depletion may be a significant contributor to development of ANSD in at risk neonates. The basis of this hypothesis is the recent recognition that impairment of riboflavin metabolism caused by genetic mutations (SLC52A2 or AIMF1) also causes ANSD., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: Congenital sensorineural hearing loss is a heterogeneous disorder; its etiological profile varies between populations. Pathogenic variants of GJB2 gene are the major cause of non-syndromic hearing loss. Congenital cytomegalovirus infection (cCMV) is the most important prenatal etiological factor causing hearing loss and other disorders. Perinatal events, syndromes, postnatal infections or traumas are less common. Causes of the remaining one third of hearing loss cases are unknown., Objectives: To determine the etiological profile of hearing loss in pediatric cochlear implant users in Lithuanian population., Methods: The data of 122 children (70 male/52 female; aged 7.6 ± 3.3 years) cochlear implant users were analysed. Medical records of all children recruited in Santaros Clinics (Vilnius, Lithuania) were analysed to identify prenatal, perinatal, or postnatal risk factors based on the adapted list proposed by the Joint Committee of Infant Hearing. Genetic counselling and testing according to the scheme were performed to 101 children. DNA of 117 children was extracted from the DBS on Guthrie cards and CMV DNA detected using real time PCR., Results: Non-syndromic hearing loss was diagnosed in 65 cases (53.3%), 58 of which were GJB2 gene-associated; syndromic hearing loss was diagnosed to 8 children (6.6%). Perinatal (prematurity, low birth weight, hypoxia, hyperbilirubinemia, sepsis, ototoxicity, and meningitis) and postnatal (meningitis) risk factors were associated with hearing loss in 16 (13.1%) and 4 (3.3%) study participants respectively. CMV DNA was detected in 12 samples (9.8%). The cause of hearing loss remained unknown only for 17 (13.9%) children., Conclusions: The major cause of HL in the current study was GJB2 gene alterations. Only 14% of the cohort had congenital hearing loss of unknown origin., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Premature infants have a higher incidence of indirect hyperbilirubinemia than term infants. Management of neonatal indirect hyperbilirubinemia in late preterm and term neonates has been well addressed by recognized, consensus-based guidelines. However, the extension of these guidelines to the preterm population has been an area of uncertainty because of limited evidence. This leads to variation in clinical practice and lack of recognition of the spectrum of bilirubin-induced neurologic dysfunction (BIND) in this population. Preterm infants are metabolically immature and at higher risk for BIND at lower bilirubin levels than their term counterparts. Early use of phototherapy to eliminate BIND and minimize the need for exchange transfusion is the goal of treatment in premature neonates. Although considered relatively safe, phototherapy does have side effects, and some NICUs tend to overuse phototherapy. In this review, we describe the epidemiology and pathophysiology of BIND in preterm neonates, and discuss our approach to standardized management of indirect hyperbilirubinemia in the vulnerable preterm population. The proposed treatment charts suggest early use of phototherapy in preterm neonates with the aim of reducing exposure to high irradiance levels, minimizing the need for exchange transfusions, and preventing BIND. The charts are pragmatic and have additional curves for stopping phototherapy and escalating its intensity. Having a standardized approach would support future research and quality improvement initiatives that examine dose and duration of phototherapy exposure with relation to outcomes., (Copyright © 2020 by the American Academy of Pediatrics.)

Background: Neonatal hyperbilirubinemia (NH) may be the initial and solitary sign of infectious condition in neonates. This retrospective cohort study aims to evaluate the risk of sepsis or urinary tract infection in well-appearing infants with NH below 7 days old., Methods: All neonates (n = 8779) born in Taipei Veterans General Hospital from 2013 to 2017 were evaluated retrospectively. A total of 2523 initially well-appearing babies were admitted because of NH. After being hospitalized, patients were categorized into two groups according to the initial transcutaneous bilirubin (TCB) level. Infectious screening results, which include C-reactive protein (CRP), differential count, blood culture, urinalysis, and urine culture, were analyzed., Results: Regarding CRP, 2.7% (18/667) of neonates with NH had elevated CRP (≥1 mg/dL). Among 547 blood cultures, eight were positive, with 0.4% (2/547) non-coagulase-negative staphylococcus (CoNS) bacteremia and 1.1% (6/547) CoNS bacteremia. In urinalysis, 16.6% (182/1094) of NH neonates had pyuria, and 6.7% (25/372) had positive urine cultures. NH with a higher initial TCB level was related to an increased chance of elevated CRP (4.7% vs. 1.5%, odds ratio: 3.29, p = 0.024) and pyuria (20.6% vs. 12.6%, odds ratio: 1.79, p < 0.001). The rate of positive urine culture between the higher and lower TCB groups had no significant difference (6.6% vs. 6.9%, p > 0.99). Significant bacteriuria was more common in NH neonates admitted at later age (>2 days) (4.9% vs. 11.5%, p = 0.035)., Conclusion: In well-appearing neonates below 7 days old, NH with a higher initial TCB is associated with an increased rate in pyuria and abnormal CRP. No difference was found in the rate of positive urine culture between higher and lower TCB levels. Significant bacteriuria was more common in older NH neonates. Septicemia is rare among well-appearing neonates with NH.

Objective: To compare total serum bilirubin (TSB) levels, phototherapy usage, and hospital readmission for jaundice among neonates with Down syndrome vs controls., Study Design: A retrospective cohort study using 15 years of multihospital data. We created control reference intervals (5th, median, and 95th percentiles) for initial TSB values hourly during the first days after birth, and determined the proportion of neonates with Down syndrome whose TSB exceeded the 95th percentile control interval. We determined the proportion with an initial TSB exceeding the upper control reference interval, the highest TSB recorded, the percentage of neonates receiving phototherapy, and the rate of hospital readmission for jaundice treatment., Results: We compared 357 neonates with Down syndrome with 377 368 controls. Compared with controls, those with Down syndrome had 4.7 times the risk (95% CI, 3.9-5.7; P < .0001) of an initial TSB exceeding the 95th percentile control interval (23.5% vs 5.0%), 8.9 times (95% CI, 8.1-9.8; P < .0001) the phototherapy usage (62.2% vs 7.0%), and 3.6 times (95% CI, 1.6-8.2; P = .0075) the readmission rate for jaundice (17.4 vs 4.8 per 1000 live births)., Conclusions: Neonates with Down syndrome have a substantial risk of early hyperbilirubinemia. The American Academy of Pediatrics currently advises obtaining an early screening complete blood count from neonates with Down syndrome. We submit that assessing their TSB is also advisable., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Neonatal hyperbilirubinemia is a common clinical condition that can lead to brain encephalopathy, particularly when concurrent with acidosis due to infection, ischemia, and hypoxia. The prevailing view is that acidosis increases the permeability of the blood-brain barrier to bilirubin and exacerbates its neurotoxicity. In this study, we found that the concentration of the cell death marker, lactate dehydrogenase (LDH) in cerebrospinal fluid (CSF), is elevated in infants with both hyperbilirubinemia and acidosis and showed stronger correlation with the severity of acidosis rather than increased bilirubin concentration. In mouse neonatal neurons, bilirubin exhibits limited toxicity but robustly potentiates the activity of acid-sensing ion channels (ASICs), resulting in increases in intracellular Ca 2+ concentration, spike firings, and cell death. Furthermore, neonatal conditioning with concurrent hyperbilirubinemia and hypoxia-induced acidosis promoted long-term impairments in learning and memory and complex sensorimotor functions in vivo, which are largely attenuated in ASIC1a null mice. These findings suggest that targeting acidosis and ASICs may attenuate neonatal hyperbilirubinemia complications., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Objective: To 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 Design: We 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., Result: We 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., Conclusions: Our study stresses the importance of a systematic approach to neonatal jaundice and ongoing surveillance of extreme neonatal hyperbilirubinemia and KSD.

Background : Type 1 diabetes (T1D) is one of the most common chronic diseases of childhood. Whether neonatal hyperbilirubinaemia increases the risk of T1D remains unclear. Aim : To estimate the association between neonatal hyperbilirubinaemia and phototherapy and the risk of T1D using a large nationwide population-based cohort. Methods : This retrospective study was conducted using data from the National Health Insurance Research Database in Taiwan from 2001 until 2005. Altogether, 23,784 neonates aged <30 days diagnosed with hyperbilirubinaemia and 47,568 neonates without hyperbilirubinaemia were enrolled and frequency-matched to the hyperbilirubinaemia group by gender, age, parental occupation and urbanisation. Cox regression analysis was performed to estimate hazard ratios (HRs) and 95% confidence intervals (CI). Results : Of the 71,352 neonates included, those with hyperbilirubinaemia had a higher incidence of T1D (4.76 vs 2.68 per 10,000 person-years, p < 0.001) and an earlier mean age at onset of T1D [4.13 (2.80) vs 5.80 (2.67) years, p < 0.001] than those without hyperbilirubinaemia. After adjusting for confounding factors in multivariable analysis, the neonates with hyperbilirubinaemia had a 66% increased risk of developing T1D (HR 1.66, 95% CI 1.26-2.18). Girls had a 1.41-fold (HR 1.41, 95% CI 1.10-1.82) greater risk of T1D than boys. Additionally, neonates with a history of perinatal complications (HR 1.66, 95% CI 0.99-2.80) and neonatal infections (HR 2.13, 95% CI 1.45-3.15) had an increased subsequent risk of T1D. Conclusions : The results suggest that neonatal hyperbilirubinaemia is associated with a subsequently increased risk of childhood-onset T1D. Abbreviations: T1D, type 1 diabetes; CI, confidence interval; NHI, national health insurance; NHIA, National Health Insurance Administration; NHIRD, National Health Insurance Research Database; ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification; G6PD, glucose-6-phosphate dehydrogenase; LBW, low birthweight; HRs, hazard ratios.

Inverse correlations between serum bilirubin level and obesity had been reported in adults. We aimed to investigate the associations between neonatal hyperbilirubinemia and childhood obesity. Data was obtained from the U.S. Collaborative Perinatal Project (CPP), a multicenter study from 1959 to 1976. Data of serum bilirubin in term newborns were used to observe the association with obesity at age of 7 years. Logistic regression models were performed to calculate adjusted odds ratios (aORs) for obesity. For children from the same mother sharing similar factors, Generalized Estimating Equation (GEE) model was used to correct for intracluster correlation. Relative to newborns with total serum bilirubin (TSB) < 3 mg/dl, there are lower risks for obesity in those with 3 mg/dl ≤ TSB < 6 mg/dl (aOR 0.91; 95%CI 0.81, 1.02), 6 mg/dl ≤ TSB < 9 mg/dl (aOR 0.88; 95%CI 0.78, 0.99), 9 mg/dl ≤ TSB<13 mg/dl (aOR 0.83; 95%CI 0.71, 0.98). By stratifying for subtypes of bilirubin, the inverse correlations only existed in exposure to unconjugated bilirubin. By using the GEE model correcting for intracluster correlations, the results are consistent. In summary, exposure to bilirubin up to 13 mg/dl is inversely associated with obesity at the age of 7 years in term infants.

Objective: To explore the effects of exchange transfusion on auditory neuropathy spectrum disorder (ANSD) in neonates with severe hyperbilirubinemia (SH)., Methods: The clinical data of 2216 SH neonates who met the standard of exchange transfusion and 732 non severe-hyperbilirubinemia (NSH) neonates in the same period who did not require exchange transfusion in the neonatology department of Childrens' Hospital of Chongqing Medical University between January 2010 and December 2015 were retrospectively analyzed. In addition, the SH neonates were further divided into the exchange transfusion group and photography group. Hearing screening was conducted on all neonates using transiently evoked otoacoustic emission (TEOAE) and auto auditory brainstem response (AABR), and neonates who failed the above screening were performed diagnostic hearing test. And then neonates diagnosed with hearing disorder were followed up for 2-5 years., Results: The pass rates of hearing screening were 80.58%, 79.71% and 87.84% in the phototherapy group, exchange transfusion group and NSH group respectively, with a significant difference(P < 0.05). Hearing loss was diagnosed in 10.15%, 12.39% and 8.54% of neonates in the phototherapy group, exchange transfusion group and NSH group. After follow-up, ultimate incidence rates of ANSD were 11.96%, 11.57% and 2.4% respectively in the 3 groups, with a significant difference (P < 0.05)., Conclusions: SH is one of risk factors for ANSD. SH neonates have a lower incidence of ANSD in the exchange transfusion group than in the phototherapy group. Neonates who meet the standards of exchange transfusion adopt this therapy in early stage, which can quickly decrease bilirubin level and ultimately reduce incidence of ANSD., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: This study was designed in order to assess the validity of the use of amplitude-integrated electroencephalogram (aEEG) in cerebral injury caused by severe neonatal hyperbilirubinemia., Methods: A total of 56 full-term neonates diagnosed with severe neonatal hyperbilirubinemia and admitted to the NICU of our hospital from July 2013 to December 2014 were continuously selected for the study. The total serum bilirubin (TSB) was higher than 342 μmol/L and was dominated by a higher amount of unconjugated bilirubin. Each patient underwent aEEG monitoring upon admission. And according to the results of the test, they were assigned into an aEEG normal group (N.=38) or an aEEG abnormal group (N.=18). Dynamic monitoring of bilirubin and blood biochemistry was also conducted for all the children after admission. Patients were treated with blue light, anti-infection agents, acidosis correction measures, transfusion exchanges, intravenous drips of albumin or globulin and other specific treatments as needed in each particular case. Brainstem auditory evoked potential (BAEP), MRI examination and a behavioral neurological assessment (NBNA) with 20-item examinations were provided within 4-17 days after admission. Follow-up observations were conducted on growth level (physical development and Gesell scores) at 3, 6, 12 and 18 months., Results: The results of all the diagnostic tests performed in the patients of both groups all yielded a significantly higher abnormality rate in the aEEG abnormal group compared to the results in the aEEG normal group. Furthermore, the results of follow-up tests showing growth and child development also showed higher abnormality rates in the aEEG abnormal group than in the aEEG normal group., Conclusions: Since the results of our aEEG monitoring were consistent with the findings of other diagnostic tests, we proved the convenience and effectivity of aEEG for guiding the treatment and prognosis of severe hyperbilirubinemia in neonates.

The review article discusses current knowledge of iron-mediated oxidative cell death (ferroptosis) and its potential role in the pathogenesis of neuronal dysfunction induced by neonatal hemolytic hyperbilirubinemia. The connection between metabolic conditions related to hemolysis (iron and bilirubin overload) and iron-induced lipid peroxidation is highlighted. Neurotoxicity of iron and bilirubin is associated with their release from destructed erythrocytes in response to hemolytic disease. Iron overload initiates lipid peroxidation through the reactive oxygen species production resulting to oxidative damage to cells. Excessive loading of immature brain cells by iron-induced formation of reactive oxygen species contributes to the development of various neurodevelopmental disorders. The causal relationship between iron overload and susceptibility of brain cells to oxidative damage by ferroptosis appears to be associated not only with the amount of redox-active iron involved in oxidative cell damage but also with the degree of maturity of the neonatal brain. Neuronal dysfunction induced by neonatal hemolytic disease can represent a specific model of ferroptosis. The mechanism by which iron overload triggers ferroptosis is not completely explained. However, hemolysis of neonatal red blood cells appears to be a determining factor. Potential therapeutic strategy with iron-chelating agents to inhibit ferroptosis has a promising future in postnatal care., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Galactosemia has not been recognized as a cause of extreme neonatal hyperbilirubinemia, although growing evidence supports this association., Methods: In a retrospective cohort study, we identified children with galactosemia due to GALT deficiency using the Danish Metabolic Laboratory Database. Among these, we identified children with extreme neonatal hyperbilirubinemia or symptoms of ABE. Extreme neonatal hyperbilirubinemia was defined as maximum total serum bilirubin (TSB max) ) level ≥450 µmol/L and a ratio of conjugated serum bilirubin/TSB <0.30., Results: We identified 21 children with galactosemia (incidence:1:48,000). Seven children developed extreme neonatal hyperbilirubinemia (median [range] TSB max level: 491 [456-756] µmol/L), accounting for 1.7% of all extreme neonatal hyperbilirubinemia cases. During the first 10 days of life, hyperbilirubinemia was predominantly of unconjugated type. Four children developed symptoms of intermediate/advanced ABE. One additional child had symptoms of intermediate/advanced ABE without having extreme neonatal hyperbilirubinemia. On follow-up, one child had KSD., Conclusions: Galactosemia is a potential cause of extreme neonatal hyperbilirubinemia, ABE, and KSD. It is crucial that putative galactosemic children are treated aggressively with phototherapy to prevent ABE and KSD. Thus it is important that galactosemia is part of the work up for unconjugated hyperbilirubinemia.

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.

Background: Neonatal hyperbilirubinaemia is one of the commonest causes of hospital visit in the neonatal period. When severe, it is a leading cause of irreversible neurological and musculoskeletal disability. Prompt recognition and timely interventions are imperative for a drastic reduction in complications associated with severe hyperbilirubinaemia in newborns., Methods: We report a 4-year descriptive and longitudinal study to determine the causes, clinical presentations and long-term outcomes in newborns admitted for severe neonatal jaundice., Methods: Newborns admitted and managed for severe neonatal jaundice at the Enugu State University Teaching Hospital during a 4-year period were enrolled and followed up for 2 years., Results: A total of 1920 newborns were admitted during the study period and 48 were managed for severe hyperbilirubinaemia giving an in-hospital incidence rate of 25 (95% CI 18-32) per 1000 admitted newborns. The mean age of onset was 3.4 ± 0.5 days (range 1-8 days) and hospital presentation from time of first notice was 4.3 ± 0.4 days (range 1-9 days). The total and unconjugated admission serum bilirubin ranged from 7.1 to 71.1 (mean 26 ± 2.5 mg/dl) and 4.2 to 46.3 mg/dl (mean 18.3 ± 9.2) respectively. Earliest sign of severe hyperbilirubinaemia in newborns were: refusal to suck (15.2%) and depressed primitive reflexes (24.5%) while the commonest signs included high pitch cry (11.9%), convulsion and stiffness (6.9%) and vomiting (6.3%) in addition to the former signs. The major causes of severe hyperbilirubinaemia were idiopathic (33.3%), sepsis (35.3%), ABO incompatibility (17.6%) and glucose-6-phosphate dehydrogenase (G6PD) deficiency (11.8%). Long-term sequelae on follow-up included delayed developmental milestone attainment, postural deformities, visual and seizure disorders., Conclusions: There is urgent need for continued education for mothers, families and healthcare workers on the danger newborns with jaundice could face if not brought early to the hospital for timely diagnosis and management.

Background: Indirect neonatal hyperbilirubinemia (INH) is a common neonatal disorder worldwide which can remain benign if prompt management is available. However there is a higher morbidity and mortality risk in settings with limited access to diagnosis and care. The manuscript describes the characteristics of neonates with INH, the burden of severe INH and identifies factors associated with severity in a resource-constrained setting., Methods: We conducted a retrospective evaluation of anonymized records of neonates hospitalized on the Thai-Myanmar border. INH was defined according to the National Institute for Health and Care Excellence guidelines as 'moderate' if at least one serum bilirubin (SBR) value exceeded the phototherapy threshold and as 'severe' if above the exchange transfusion threshold., Results: Out of 2980 records reviewed, 1580 (53%) had INH within the first 14 days of life. INH was moderate in 87% (1368/1580) and severe in 13% (212/1580). From 2009 to 2011, the proportion of severe INH decreased from 37 to 15% and the mortality dropped from 10% (8/82) to 2% (7/449) coinciding with the implementation of standardized guidelines and light-emitting diode (LED) phototherapy. Severe INH was associated with: prematurity (< 32 weeks, Adjusted Odds Ratio (AOR) 3.3; 95% CI 1.6-6.6 and 32 to 37 weeks, AOR 2.2; 95% CI 1.6-3.1), Glucose-6-phosphate dehydrogenase deficiency (G6PD) (AOR 2.3; 95% CI 1.6-3.3), potential ABO incompatibility (AOR 1.5; 95% CI 1.0-2.2) and late presentation (AOR 1.8; 95% CI 1.3-2.6). The risk of developing severe INH and INH-related mortality significantly increased with each additional risk factor., Conclusion: INH is an important cause of neonatal hospitalization on the Thai-Myanmar border. Risk factors for severity were similar to previous reports from Asia. Implementing standardized guidelines and appropriate treatment was successful in reducing mortality and severity. Accessing to basic neonatal care including SBR testing, LED phototherapy and G6PD screening can contribute to improve neonatal outcomes.

To examine the origin of seizures induced by severe neonatal hyperbilirubinemia, The EEG characteristics of seizures were analyzed in newborns with and without severe neonatal hyperbilirubinemia. Fisher's exact test was used to determine the specificity. In total, 931 patients had a total serum bilirubin (TSB) level of 340-425 μmol/L, only 2 of whom had seizures. Compared to patients with hyperbilirubinemia and a TSB level of 340-425 μmol/L, those with a TSB level >425 μmol/L had a significant risk of seizure (OR = 213.2, 95% CI = 113.0-405.8, P<0.001). Of all 28 patients with severe hyperbilirubinemia and seizure, 26 had seizures that originated in the temporal and/or occipital lobe. In seizure patients without severe hyperbilirubinemia, origination in the temporal/occipital and other lobes occurred in 19 and 117 cases, respectively. Compared to the risk of seizure origination in the temporal and/or occipital lobe in other diseases, the risk in patients with severe hyperbilirubinemia was increased by approximately 80 times (OR = 80.1, 95% CI = 28.3-226.4, P<0.001). Severe neonatal hyperbilirubinemia can selectively induce temporal and occipital lobe seizures. This is the first report of a new syndrome with the same etiology and electrophysiological features as epilepsy.

Objective: ABO hemolytic disease occurs among neonates with blood groups A or B delivered to group O women. Extreme neonatal hyperbilirubinemia due to ABO disease has been reported, but its frequency is not well known. We sought to determine the odds of developing severe ABO hemolytic disease in the 13 years since adopting universal bilirubin screening/management in the Intermountain Healthcare system., Study Design: We conducted a retrospective analysis of neonates born between 2004 and 2016, defining "severe hemolytic disease" as; (1) total serum bilirubin (TSB) >25 mg/dL, or (2) hospital readmission for jaundice, or (3) bilirubin encephalopathy. Neonates born to group O (+) mothers were included and considered either; (1) Controls (not at risk for ABO disease because they were group O), (2) Study subjects (at risk for ABO disease because they were group A or B)., Results: Of 400,531 live births, 47% were to group O women; 86% of whom were group O (+). Overall, 42,529 (27%) neonates born to group O (+) women had their blood group determined; 29,729 (68%) were O, 10,682 (25%) A, and 3109 (7%) B. Peak TSBs during the first 10 days were higher in group A (11.0 ± 4.2 mg/dL) and B (11.5 ± 4.3) than group O neonates (10.3 ± 4.1). However the relative risks of a TSB ≥25 mg/dL, readmission for jaundice, or kernicterus, were the same in the control vs. study groups., Conclusions: In our health system, severe hemolytic disease in neonates born to group O (+) woman is not more likely in group A or B neonates than in controls (group O). We recognize that in other practices, particularly those who do not have a universal bilirubin screening/management program, ABO hemolytic disease severity might be different than in our system.

Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common enzyme deficiency affecting more than 300 million individuals worldwide. Extreme neonatal hyperbilirubinemia, with its severe sequelae of bilirubin neurotoxicity and the potential of death, is the most devastating manifestation of G6PD deficiency. In a recent review of Favism, Luzzatto and Arese state that the pathophysiology of jaundice in G6PD-deficient neonates is different from that of favism, as there is little evidence of hemolysis in these infants., Objectives: To explore the role of hemolysis in neonatal hyperbilirubinemia associated with G6PD deficiency., Methods: Previously published works including studies of endogenous production of carbon monoxide (CO), an index of heme catabolism, in hyperbilirubinemic G6PD-deficient neonates were reviewed to determine the role of hemolysis in this condition., Results: Three studies demonstrated that endogenous CO production is elevated in G6PD-deficient neonates with extreme hyperbilirubinemia., Conclusions: Hemolysis is an important pathogenetic factor in G6PD deficiency-associated neonatal hyperbilirubinemia., (© 2018 S. Karger AG, Basel.)

Background and Objectives: Significant hyperbilirubinemia (SHB) may cause chronic auditory toxicity (auditory neuropathy spectrum disorder and/or sensorineural hearing loss); however, total serum bilirubin (TSB) does not discriminate neonates at risk for auditory toxicity. Our objective was to compare TSB, bilirubin albumin molar ratio (BAMR), and unbound bilirubin (UB) for their association with chronic auditory toxicity in neonates with SHB (TSB ≥20 mg/dL or TSB that met criteria for exchange transfusion)., Methods: Infants ≥34 weeks' gestational age (GA) with SHB during the first 2 postnatal weeks were eligible for a prospective longitudinal study in India. Comprehensive auditory evaluations were performed at 2 to 3 months of age by using auditory brainstem response, tympanometry, and an otoacoustic emission test and at 9 to 12 months of age by using audiometry. The evaluations were performed by an audiologist unaware of the degree of jaundice., Results: A total of 93 out of 100 infants (mean GA of 37.4 weeks; 55 boys, 38 girls) who were enrolled with SHB were evaluated for auditory toxicity. Of those, 12 infants (13%) had auditory toxicity. On regression analysis controlling for covariates, peak UB (but not peak TSB or peak BAMR), was associated with auditory toxicity (odds ratio 2.41; 95% confidence interval: 1.43-4.07; P = .001). There was significant difference in the area under the receiver operating characteristic curves between UB (0.866), TSB (0.775), and BAMR (0.724) for auditory toxicity ( P = .03) after controlling for covariates., Conclusions: Unconjugated hyperbilirubinemia indexed by UB (but not TSB or BAMR) is associated with chronic auditory toxicity in infants ≥34 weeks' GA with SHB., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2017 by the American Academy of Pediatrics.)

Background: Severe hyperbilirubinemia is toxic during central nervous system development. Prolonged and uncontrolled high levels of unconjugated bilirubin lead to bilirubin-induced neurological damage and eventually death by kernicterus. Bilirubin neurotoxicity is characterized by a wide array of neurological deficits, including irreversible abnormalities in motor, sensitive and cognitive functions, due to bilirubin accumulation in the brain. Despite the abundant literature documenting the in vitro and in vivo toxic effects of bilirubin, it is unclear which molecular and cellular events actually characterize bilirubin-induced neurodegeneration in vivo., Methods: We used a mouse model of neonatal hyperbilirubinemia to temporally and spatially define the response of the developing cerebellum to the bilirubin insult., Results: We showed that the exposure of developing cerebellum to sustained bilirubin levels induces the activation of oxidative stress, ER stress and inflammatory markers at the early stages of the disease onset. In particular, we identified TNFα and NFKβ as key mediators of bilirubin-induced inflammatory response. Moreover, we reported that M1 type microglia is increasingly activated during disease progression. Failure to counteract this overwhelming stress condition resulted in the induction of the apoptotic pathway and the generation of the glial scar. Finally, bilirubin induced the autophagy pathway in the stages preceding death of the animals., Conclusions: This study demonstrates that inflammation is a key contributor to bilirubin damage that cooperates with ER stress in the onset of neurotoxicity. Pharmacological modulation of the inflammatory pathway may be a potential intervention target to ameliorate neonatal lethality in Ugt1 -/- mice.

Classically, genetically decreased bilirubin conjugation and/or hemolysis account for the mechanisms contributing to neonatal hyperbilirubinemia associated with glucose-6-phosphate dehydrogenase (G6PD) deficiency. However, these mechanisms are not involved in most cases of this hyperbilirubinemia. Additional plausible mechanisms for G6PD deficiency-associated hyperbilirubinemia need to be considered. Glutathione S-transferases (GST) activity depends on a steady quantity of reduced form of glutathione (GSH). If GSH is oxidized, it is reduced back by glutathione reductase, which requires the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH). The main source of NADPH is the pentose phosphate pathway, in which G6PD is the first enzyme. Rat kidney GSH, rat liver GST, and human red blood cell GST levels have been found to positively correlate with G6PD levels in their respective tissues. As G6PD is expressed in hepatocytes, it is expected that GST levels would be significantly decreased in hepatocytes of G6PD-deficient neonates. As hepatic GST binds bilirubin and prevents their reflux into circulation, hypothesis that decreased GST levels in hepatocytes is an additional mechanism contributing to G6PD deficiency-associated hyperbilirubinemia seems plausible. Evidence for and against this hypothesis are discussed in this article hoping to stimulate further research on the role of GST in G6PD deficiency-associated hyperbilirubinemia., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

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., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Moderate neonatal jaundice is the most common clinical condition during newborn life. However, a combination of factors may result in acute hyperbilirubinemia, placing infants at risk of developing bilirubin encephalopathy and death by kernicterus. While most risk factors are known, the mechanisms acting to reduce susceptibility to bilirubin neurotoxicity remain unclear. The presence of modifier genes modulating the risk of developing bilirubin-induced brain damage is increasingly being recognised. The Abcb1 and Abcc1 members of the ABC family of transporters have been suggested to have an active role in exporting unconjugated bilirubin from the central nervous system into plasma. However, their role in reducing the risk of developing neurological damage and death during neonatal development is still unknown.To this end, we mated Abcb1a/b-/- and Abcc1-/- strains with Ugt1-/- mice, which develop severe neonatal hyperbilirubinemia. While about 60% of Ugt1-/- mice survived after temporary phototherapy, all Abcb1a/b-/-/Ugt1-/- mice died before postnatal day 21, showing higher cerebellar levels of unconjugated bilirubin. Interestingly, Abcc1 role appeared to be less important.In the cerebellum of Ugt1-/- mice, hyperbilirubinemia induced the expression of Car and Pxr nuclear receptors, known regulators of genes involved in the genotoxic response.We demonstrated a critical role of Abcb1 in protecting the cerebellum from bilirubin toxicity during neonatal development, the most clinically relevant phase for human babies, providing further understanding of the mechanisms regulating bilirubin neurotoxicity in vivo. Pharmacological treatments aimed to increase Abcb1 and Abcc1 expression, could represent a therapeutic option to reduce the risk of bilirubin neurotoxicity., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Poor plasma bilirubin binding increases the risk of bilirubin neurotoxicity in newborns with hyperbilirubinemia. New laboratory tests may soon make it possible to obtain a complete bilirubin binding panel when evaluating these babies. The 3 measured components of the panel are the plasma total bilirubin concentration (B Total ), which is currently used to guide clinical care; the bilirubin binding capacity (BBC); and the concentration of non-albumin bound or free bilirubin (B Free ). The fourth component is the bilirubin-albumin equilibrium dissociation constant, K D , which is calculated from B Total , BBC, and B Free The bilirubin binding panel is comparable to the panel of components used in the Henderson-Hasselbalch approach to acid-base assessment. Bilirubin binding population parameters (not prospective studies to determine whether the new bilirubin binding panel components are better predictors of bilirubin neurotoxicity than B Total ) are needed to expedite the clinical use of bilirubin binding. At any B Total , the B Free and the relative risk of bilirubin neurotoxicity increase as the K D /BBC ratio increases (ie, bilirubin binding worsens). Comparing the K D /BBC ratio of newborns with B Total of concern with that typical for the population helps determine whether the risk of bilirubin neurotoxicity varies significantly from the inherent risk at that B Total Furthermore, the bilirubin binding panel individualizes care because it helps to determine how aggressive intervention should be at any B Total , irrespective of whether it is above or below established B Total guidelines. The bilirubin binding panel may reduce anxiety, costs, unnecessary treatment, and the likelihood of undetected bilirubin neurotoxicity., (Copyright © 2016 by the American Academy of Pediatrics.)