Bilirubin Encephalopathy Research Articles

Controversies in our understanding of extreme hyperbilirubinemia in glucose-6-phosphate dehydrogenase-deficient neonates.

Despite declarations that kernicterus should be a "never-event", the condition continues to occur, glucose-6-phosphate dehydrogenase (G6PD)-deficiency being a leading cause. In this paper, we address some controversies regarding the pathophysiology and the potential for extreme hyperbilirubinemia associated with G6PD-deficiency. We present evidence to demonstrate that G6PD-deficiency-associated neonatal hyperbilirubinemia is no longer limited to countries and geographic regions to which the condition was indigenous, but is also encountered in North America and other Western countries with a low inherent G6PD-deficiency frequency. Pathophysiologically, while a diminished bilirubin conjugative component is undoubtedly present, we present evidence that there is a component of increased hemolysis as well, contributing to the extreme, exponential hyperbilirubinemia associated with G6PD-deficiency. Extreme hyperbilirubinemia in G6PD heterozygotes, while less frequent than in male hemizygotes or female deficient homozygotes, has been reported, suggesting previous underestimation of the risks of heterozygosity. Universal neonatal screening for G6PD-deficiency, while not expected to prevent acute, episodic hyperbilirubinemia, should increase awareness, thereby facilitating earlier referral for treatment, prior to the onset of bilirubin encephalopathy. Finally, we speculate as to what the future looks like for babies with G6PD-deficiency, potential therapeutic stratagems, and the effect of G6PD-deficiency on medical conditions beyond the realm of neonatal hyperbilirubinemia. IMPACT STATEMENTS: G6PD-deficiency is encountered in North America and Western countries previously thought to have a low frequency of the condition. Extreme, sudden neonatal hyperbilirubinemia is due, in the main, to increased hemolysis, an independent risk factor for neurotoxicity. Extreme hyperbilirubinemia may follow apparently resolved neonatal hyperbilirubinemia which had been treated by phototherapy. Female G6PD heterozygotes, previously thought to be unaffected clinically by G6PD-deficiency, while at low risk, may, nevertheless, develop extreme hyperbilirubinemia. Universal neonatal G6PD screening should be aimed towards increasing caretaker awareness and facilitating referral for treatment prior to the onset of bilirubin encephalopathy.

Selective Vulnerability of GABAergic Inhibitory Interneurons to Bilirubin Neurotoxicity in the Neonatal Brain.

Hyperbilirubinemia (HB) is a key risk factor for hearing loss in neonates, particularly premature infants. Here we report that bilirubin (BIL)-dependent cell death in auditory brainstem of neonatal mice of both sexes is significantly attenuated by ZD7288, a blocker for hyperpolarization-activated cyclic nucleotide-gated (HCN) channel mediated current (Ih), or by genetic deletion of HCN1. GABAergic inhibitory interneurons predominantly express HCN1, on which BIL selectively acts to increase their intrinsic excitability and mortality by enhancing HCN1 activity and Ca2+-dependent membrane targeting. Chronic BIL elevation in neonatal mice in vivo increases the fraction of spontaneously active interneurons and their firing frequency, Ih and death, compromising audition at young adult stage in HCN1+/+, but not in HCN1-/- genotype. We conclude that HB preferentially targets HCN1 to injure inhibitory interneurons, fueling a feedforward loop in which lessening inhibition cascades hyperexcitability, Ca2+ overload, neuronal death and auditory impairments. These findings rationalize HCN1 as a potential target for managing HB encephalopathy.Significance Statement This study demonstrated that bilirubin preferentially targets GABAergic interneurons where it facilitates not only gating of HCN1 channels but also targeting of intracellular HCN1 to plasma membrane in calcium-dependent manner, resulting in neuronal hyperexcitability, injury and sensory dysfunction. These findings implicate HCN1 channel not only as a potential driver for auditory abnormalities in neonatal patients with bilirubin encephalopathy, but also potential intervention target for clinical management of neurological impairments associated with severe jaundice. Selective vulnerability of interneurons to neurotoxicity may be of general significance for understanding other forms of brain injury.

Assessment of Knowledge and Attitudes of Parents Regarding Neonatal Jaundice in Abia State Children's Specialist Hospital, Umuahia, Nigeria: A Cross-Sectional Study.

Background Neonatal jaundice, characterized by the yellow discoloration of an infant's skin and eyes, is a common condition that affectsnewborns. It results from an elevated level of bilirubin in the blood and,when severe, if left untreated, can lead to complications such as acute bilirubin encephalopathy and kernicterus, which can cause permanent neurological damage or even death. In low-resource settings like Nigeria, delayed recognition and inadequate management of neonatal jaundice are significant contributors to neonatal morbidity and mortality. Parental knowledge and attitudes play a critical role in the early identification and timely intervention of neonatal jaundice. However, there is limited data on the awareness, understanding, and practices of parents regarding this condition in many regions, including Abia State, Nigeria. Aim This study sought to assess the knowledge and attitudes of parents at Abia State Children's Specialist Hospital, Umuahia, Nigeria, to inform strategies for improving early detection and management of neonatal jaundice. Research methodology This descriptive cross-sectional study was conducted at Abia State Children's Specialist Hospital. The study population included 385 parents (fathers and mothers) of neonates attending the pediatric and neonatal units. A systematic random sampling technique was used to select participants. Data were collected using a structured questionnaire and analyzed using IBM SPSS Statistics for Windows, Version 25, (Released 2017; IBM Corp., Armonk, New York, United States). Results The study revealed that 226 (58.70%) of parents had heard about neonatal jaundice, with the main perceived cause being an immature liver (148, 38.44%). While 216 (56.10%) of the parents recognized neonatal jaundice as a serious condition when severe, only 72 (18.70%) were very confident in identifying its signs. Most parents (369, 95.84%) would seek medical help if they suspected jaundice in their baby, yet 288 (74.81%) believed in the effectiveness of traditional remedies. Educational level and gender were significantly associated with knowledge about neonatal jaundice (p = 0.002 and p = 0.001, respectively). Conclusion The findings highlight a moderate level of awareness but varying confidence in identifying neonatal jaundice among parents. The reliance on traditional remedies suggests a need for enhanced health education to improve knowledge of and attitudes toward neonatal jaundice management.

Correlation of Clinical Assessment of Jaundice with Total Serum Bilirubin in Neonates: Hospital-Based Cross-Sectional Study

Introduction: Neonatal jaundice is a common cause of admission in the neonatal period. Early diagnosis and treatment of neonatal jaundice prevent the bilirubin encephalopathy. There are various methods for the estimation of neonatal jaundice. Clinical assessment of neonatal jaundice can aid in the diagnosis of neonatal jaundice in low-resource settings and refer to the higher center for those who require treatment. This study aims to understand the relation between clinical assessment of jaundice and total serum bilirubin in neonates and to know the risk factors of neonatal jaundice.  Methods: The Clinical assessment of jaundice by Kramers scale can be used to assess the level of jaundice and know the progression of jaundice.  Results: This shows a significant positive relation between clinical assessment of jaundice and serum bilirubin level.  Conclusions: The study findings showed that clinical assessment of jaundice was comparable with the serum bilirubin. Clinical assessment of jaundice by Kramer‟ 's scale can be used to assess the level of jaundice and know the progression of jaundice.

Machine learning-causal inference based on multi-omics data reveals the association of altered gut bacteria and bile acid metabolism with neonatal jaundice

ABSTRACT Early identification of neonatal jaundice (NJ) appears to be essential to avoid bilirubin encephalopathy and neurological sequelae. The interaction between gut microbiota and metabolites plays an important role in early life. It is unclear whether the composition of the gut microbiota and metabolites can be used as an early indicator of NJ or to aid clinical decision-making. This study involved a total of 196 neonates and conducted two rounds of “discovery-validation” research on the gut microbiome-metabolome. It utilized methods of machine learning, causal inference, and clinical prediction model evaluation to assess the significance of gut microbiota and metabolites in classifying neonatal jaundice (NJ), as well as the potential causal relationships between corresponding clinical variables and NJ. In the discovery stage, NJ-associated gut microbiota, network modules, and metabolite composition were identified by gut microbiome-metabolome association analysis. The NJ-associated gut microbiota was closely related to bile acid metabolites. By Lasso machine learning assessment, we found that the gut bacteria were associated with abnormal bile acid metabolism. The machine learning-causal inference approach revealed that gut bacteria affected serum total bilirubin and NJ by influencing bile acid metabolism. NJ-associated gut bile acids are potential biomarkers of NJ, and clinical prediction models constructed based on these biomarkers have some clinical effects and the model may be used for disease risk prediction. In the validation stage, it was found that intestinal metabolites can predict NJ, and the machine learning-causal inference approach revealed that bile acid metabolites affected NJ itself by affecting the total bilirubin content. Intestinal bile acid metabolites are potential biomarkers of NJ. By applying machine learning-causal inference methods to gut microbiome-metabolome association studies, we found NJ-associated intestinal bacteria and their network modules and bile acid metabolite composition. The important role of intestinal bacteria and bile acid metabolites in NJ was determined, which can predict the risk of NJ.

Management of Neonatal Hyperbilirubinemia: Shedding Light on the American Academy of Pediatrics 2022 Clinical Practice Guideline Revision.

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.].

Exchange Transfusion Trends and Risk Factors for Extreme Neonatal Hyperbilirubinemia over 10 Years in Shiraz, Iran.

Exchange transfusion (ET) is an effective treatment for acute bilirubin encephalopathy and extreme neonatal hyperbilirubinemia (ENH). It can reduce mortality and morbidity. This study aimed to investigate the trends and risk factors of ENH requiring ET in hospitalized neonates in Iran. A retrospective analysis of medical records of neonates who underwent ET due to ENH was conducted from 2011 to 2021, in Shiraz, Iran. Clinical records were used to gather demographic and laboratory data. The quantitative data were expressed as mean±SD, and qualitative data was presented as frequency and percentage. P<0.05 was considered statistically significant. During the study, 377 ETs were performed for 329 patients. The annual rate of ET decreased by 71.2% during the study period. The most common risk factor of ENH was glucose-6-phosphate dehydrogenase (G6PD) deficiency (35%), followed by prematurity (13.06%), ABO hemolytic disease (7.6%), sepsis (6.4%), Rh hemolytic disease (6.08%), and minor blood group incompatibility (3.34%). In 28.52% of the cases, the cause of ENH was not identified. 17 (5.1%) neonates had acute bilirubin encephalopathy, of whom 6 (35.29%) had G6PD deficiency, 6 (35.29%) had ABO incompatibility, and 2 (11.76%) had Rh incompatibility. Although the rate of ET occurrence has decreased, it seems necessary to consider different risk factors and appropriate guidelines for early identification and management of neonates at risk of ENH should be developed. The findings of the study highlighted the important risk factors of ENH in southern Iran, allowing for the development of appropriate prevention strategies.

Transcutaneous bilirubinometry for detecting jaundice in term or late preterm neonates.

The American Academy of Pediatrics and the Canadian Paediatric Society both advise that all newborns should undergo bilirubin screening before leaving the hospital, and this has become the standard practice in both countries. However, the US Preventive Task Force has found no strong evidence to suggest that this practice of universal screening for bilirubin reduces the occurrence of significant outcomes such as bilirubin-induced neurologic dysfunction or kernicterus. To evaluate the effectiveness of transcutaneous screening compared to visual inspection for hyperbilirubinemia to prevent the readmission of newborns (infants greater than 35 weeks' gestation) for phototherapy. We searched CENTRAL, MEDLINE, Embase, CINAHL, ClinicalTrials.gov, ICTRP, and ISRCTN in June 2023. We also searched conference proceedings, and the reference lists of included studies. We included randomized controlled trials (RCTs), quasi-randomized, cluster-randomized, or prospective cohort studies with control arm that evaluated the use of transcutaneous bilirubin (TcB) screening for hyperbilirubinemia in newborns before hospital discharge. We used standard methodologic procedures expected by Cochrane. We evaluated treatment effects using a fixed-effect model with risk ratio (RR) and 95% confidence intervals (CI) for categorical data and mean, standard deviation (SD), and mean difference (MD) for continuous data. We used the GRADE approach to evaluate the certainty of evidence. We identified one RCT that met our inclusion criteria. The study included 1858 African newborns at 35 weeks' gestation or greater who were receiving routine care at a well-baby nursery, and were randomly recruited prior to discharge to undergo TcB screening. The study had good methodologic quality. TcB screening versus visual assessment of hyperbilirubinemia in newborns: - probably reduces readmission to the hospital for hyperbilirubinemia (RR 0.25, 95% CI 0.14 to 0.46; P < 0.0001; moderate-certainty evidence); - may have little or no effect on the rate of exchange transfusion (RR 0.20, 95% CI 0.01 to 14.16; low-certainty evidence); - probably increases the number of newborns who require phototherapy prior to discharge (RR 2.67, 95% CI 1.56 to 4.55; moderate-certainty evidence). - may have little or no effect on the rate of acute bilirubin encephalopathy (RR 0.33, 95% CI 0.01 to 8.18; low-certainty evidence). The study did not evaluate or report cost of care. Moderate-certainty evidence suggests that TcB screening probably reduces hospital readmission for hyperbilirubinemia compared to visual inspection. Low-certainty evidence also suggests that TcB screening may have little or no effect on the rate of exchange transfusion compared to visual inspection. However, moderate-certainty evidence suggests that TcB screening probably increases the number of newborns that require phototherapy before discharge compared to visual inspection. Low-certainty evidence suggests that TcB screening may have little or no effect on the rate of acute bilirubin encephalopathy compared to visual inspection. Given that we have only identified one RCT, further studies are necessary to determine whether TcB screening can help to reduce readmission and complications related to neonatal hyperbilirubinemia. In settings with limited newborn follow-up after hospital discharge, identifying newborns at risk of severe hyperbilirubinemia before hospital discharge will be important to plan targeted follow-up of these infants.

Dynamic whole-transcriptome landscape of acute bilirubin encephalopathy in newborns

Hyperbilirubinemia in newborns may progress to acute bilirubin encephalopathy (ABE), posing short- and long-term health risks. Despite extensive research identifying numerous mRNAs, lncRNAs, circRNAs, and miRNAs associated with brain injury, their roles in neonatal bilirubin-induced brain injury remain elusive. This study employed whole-transcriptome sequencing to ascertain the differentially expressed (DE) RNA profiles in a newborn ABE rat model, followed by bioinformatic analysis. A time-series competing endogenous RNA (ceRNA) regulatory network was established, and the expression trends of 9 arbitrarily chosen RNAs were verified through quantitative real-time polymerase chain reaction(qRT-PCR). In comparison with the control group, we identified 595, 888, and 1448 DE mRNAs; 22, 37, and 37 DE miRNAs; 1945, 1869, and 1997 DE lncRNAs; and 31, 28, and 36 DE circRNAs at 6 h, 12 h, and 24 h, respectively. Predominantly, these DERNAs contribute to biological functions and pathways associated with inflammation, immunity, metabolism, cell death, and neurodevelopmental regulation. Moreover, we constructed ceRNA networks of DE lncRNA/circRNA-DE miRNA-DE mRNA based on time series. The qRT-PCR expression trends for the selected 9 RNAs were generally similar to the RNA-seq outcomes. This investigation uniquely delineated the temporal expression patterns of mRNA and non-coding RNA in ABE, establishing ceRNA networks and identifying potential molecular mechanisms underlying bilirubin-induced hippocampal damage. Nonetheless, further studies are warranted to corroborate these findings in humans.

Inhibition of Microglial Activation Ameliorates Inflammation, Reduced Neurogenesis in the hippocampus, and Impaired Brain Function in a Rat Model of Bilirubin Encephalopathy.

Hyperbilirubinemia is one of the most common occurrence in newborns and is toxic to the brain, resulting in neurological sequelae such as auditory impairment, with potential to evolve to chronic bilirubin encephalopathy and long-term cognitive impairment in adults. In the early postnatal period, neurogenesis is rigorous and neuroinflammation is detrimental to the brain. What are the alterations in neurogenesis and the underlying mechanisms of bilirubin encephalopathy during the early postnatal period? This study found that, there were a reduction in the number of neuronal stem/progenitor cells, an increase in microglia in the dentate gyrus (DG) and an inflammatory state in the hippocampus, characterized by increased levels of IL-6, TNF-α, and IL-1β, as well as a decreased level of IL-10 in a rat model of bilirubin encephalopathy (BE). Furthermore, there was a significant decrease in the number of newborn neurons and the expression of neuronal differentiation-associated genes (NeuroD and Ascl1) in the BE group. Additionally, cognitive impairment was observed in this group. The administration of minocycline, an inhibitor of microglial activation, resulted in a reduction of inflammation in the hippocampus, an enhancement of neurogenesis, an increase in the expression of neuron-related genes (NeuroD and Ascl1), and an improvement in cognitive function in the BE group. These results demonstrate that microglia play a critical role in reduced neurogenesis and impaired brain function resulting from bilirubin encephalopathy model, which could inspire the development of novel pharmaceutical and therapeutic strategies.

Effect of intravenous immunoglobulin on the management of Rh- and ABO-mediated hemolytic disease of the newborn

BackgroundRegarding the close association between neonatal hyperbilirubinemia and occurrence of pathological jaundice as a cause of neurotoxicity and kernicterus, the present study aimed to evaluate the use of intravenous immunoglobulin (IVIG) in neonates with hyperbilirubinemia. MethodsA retrospective case-control study of blood group O mothers and their ABO and Rh newborns was conducted. Medical records that included total serum bilirubin levels of 79 patients with hemolytic disease of the newborn (HDN) from between 2017 and 2020 were reviewed. Neonates who were eligible to receive immunoglobulin based on the American Academy of Pediatrics (AAP) guidelines were classified as cases and the rest were included as the Control Group. ResultsThe mean total bilirubin in relation to hemoglobin levels in IVIG-treated neonates was significantly lower than in non-IVIG-treated neonates (13.98 ± 4.23 mg/dL versus 16.61 ± 2.68 mg/dL; p-value = 0.002). Although females had longer hospitalizations in both IVIG-treated (3.81 ± 1.28 versus 3.54 ± 1.30 days; p-value = 0.509) and non-IVIG-treated (3.43 ± 0.811 versus 3.19 ± 0.75 days; p-value = 0.361) groups compared to males, this difference was not significant between the groups. Although four neonates with ABO incompatibility required packed red blood cells, all infants were managed medically and no deaths occurred during the course of treatment. Moreover, no exchange transfusion or adverse effects of IVIG were observed. ConclusionThe results from the present study revealed that IVIG administration is a useful procedure for the management of bilirubin encephalopathy with greater opportunity to reduce exchange transfusion requirements for neonatal hyperbilirubinemia.

Effectiveness of phototherapy with and without probiotics for the treatment of indirect hyperbilirubinaemia in preterm neonates: a randomised controlled trial

ABSTRACT Introduction Raised serum bilirubin levels can cause kernicterus, and premature infants are at increased risk owing to metabolic immaturity. The standard treatment for neonatal jaundice is phototherapy, but probiotics alone can reduce the duration of phototherapy and hospitalisation. Objectives To determine the effectiveness of phototherapy with and without probiotics for the treatment of indirect hyperbilirubinaemia in preterm neonates. Patients and methods The open-labelled randomised controlled trial was conducted from January 2022 to January 2023 in the neonatal unit of the University of Lahore Teaching Hospital, Pakistan. A total of 76 preterm neonates who fulfilled the selection criteria were included and divided into two groups. Both groups received standard phototherapy. In Group B, a probiotic (Saccharomyces boulardii) 125 mg, twice daily, orally (in 5 cc of whichever milk the infant was receiving) was given until discharge from hospital. The primary outcome measurements were the duration of phototherapy and the length of hospitalisation. Results The mean (SD) duration of phototherapy was 36.55 (14.25) hours in Group A and 24.61 (9.25) hours in Group B (p <0.05). The mean (SD) duration of hospital stay was 47.36 (16.51) hours in Group A and 33.13 (8.93) hours in Group B (p <0.05). Conclusion Oral probiotics (Saccharomyces boulardii) have a significant effect on the duration of phototherapy for neonatal hyperbilirubinaemia, and they decrease the chances of nosocomial infection. Exploration of clinical outcomes by investigating faecal flora and undertaking large randomised controlled trials of various probiotics are needed. Abbreviations ABE: acute bilirubin encephalopathy; CNS: central nervous system;GA: gestational age; IVIG: intravenous immunoglobulin; KSD: kernicterus;NNU: neonatal unit; RCT: randomised controlled trial; S. boulardii: Saccharomyces boulardii.

Enhancing Acute Bilirubin Encephalopathy Diagnosis with Multi-Modal MRI: A Deep Learning Approach

Background: Acute Bilirubin Encephalopathy (ABE) is a major cause of infant mortality and disability, making early detection and treatment essential to prevent further progression and complications. Methods: To enhance the diagnostic capabilities of multi-modal Magnetic Resonance Imaging (MRI) for ABE, we proposed a deep learning model integrating an attention module (AM) with a central network (CentralNet). This model was tested on MRI data from 145 newborns diagnosed with ABE and 140 non-ABE newborns, utilizing both T1-weighted and T2-weighted images. Results: The findings indicated the following: (1) In single-modality experiments, the inclusion of AM significantly improved all the performance metrics compared to the models without AM. Specifically, for T1-weighted MRI, the accuracy was 0.639 ± 0.04, AUC was 0.682 ± 0.037, and sensitivity was 0.688 ± 0.09. For the T2-weighted images, the accuracy was 0.738 ± 0.039 and the AUC was 0.796 ± 0.025. (2) In multi-modal experiments, using T1 + T2 images, our model achieved the best accuracy of 0.845 ± 0.018, AUC of 0.913 ± 0.02, and sensitivity of 0.954 ± 0.069, compared to models without an AM and CentralNet. The specificity remained relatively stable, while the precision and F1 scores significantly increased, reaching 0.792 ± 0.048 and 0.862 ± 0.017, respectively. Conclusions: This study emphasizes the effectiveness of combining attention modules with CentralNet, significantly enhancing the accuracy of multi-modal MRI in classifying ABE. It presents a new perspective and possibility for the clinical application of multi-modal MRI imaging in the diagnosis of ABE.

Bilirubin impairs neuritogenesis and synaptogenesis in NSPCs by downregulating NMDAR-CREB-BDNF signaling.

Neonatal jaundice is one of the most common disorders in the first 2 wk after birth. Unconjugated bilirubin (UCB) is neurotoxic and can cause neurological dysfunction; however, the underlying mechanisms remain unclear. Neurogenesis, neuronal growth, and synaptogenesis are exuberant in the early postnatal stage. In this study, the impact of UCB on neuritogenesis and synaptogenesis in the early postnatal stage was evaluated both in vitro and in vivo. Primary culture neuronal stem and progenitor cells (NSPCs) were treated with UCB during differentiation, and then the neurite length and synapse puncta were measured. In the bilirubin encephalopathy (BE) animal model, DCX+-marked developing neurons were used to detect apical length and dendritic arborization. According to the data, UCB significantly reduced neurite length and synapse density, as well as decreased the apical dendrite length and dendritic arborization. Furthermore, the NMDAR subunit NR2B was downregulated in NSPCs, while pCREB expression in the hippocampus progressively decreased during disease progression in the BE model. Next, we tested the expression of NR2B, pCREB, mBDNF, and p-mTOR in NSPCs in vitro, and found that UCB treatment reduced the expression of these proteins. In summary, this suggests that UCB causes chronic neurological impairment and is related to the inhibition of NMDAR-CREB-BDNF signaling in NSPCs, which is associated with reduced neuritogenesis and synaptogenesis. This finding may inspire the development of novel pharmaceuticals and treatments.

Safety of Macitentan for the Treatment of Portopulmonary Hypertension: Real-World Evidence from the Combined OPUS/OrPHeUS Studies.

Portopulmonary hypertension (PoPH) carries a worse prognosis than other forms of pulmonary arterial hypertension (PAH). Data regarding use of PAH-specific therapies in patients with PoPH are sparse as they are usually excluded from clinical trials. This analysis describes patient characteristics, treatment patterns, outcomes, and safety profiles in patients with PoPH newly initiating macitentan in the USA using the OPUS/OrPHeUS combined dataset. OPUS was a prospective, US, multicenter, observational drug registry (April 2014-June 2020); OrPHeUS was a retrospective, US, multicenter chart review (October 2013-March 2017). Additional information regarding patients' liver disease was retrospectively collected for patients with PoPH in OPUS. The OPUS/OrPHeUS dataset included 206 patients with PoPH (median age 58years; 52.4% female), with baseline cirrhosis and liver test abnormalities reported in 72.8% and 31.6% of patients respectively. Macitentan was initiated as combination therapy in 74.8% of patients and median (Q1, Q3) exposure to macitentan was 11.9 (3.1, 26.0) months. One-year Kaplan-Meier estimates (95% confidence limit, CL) of patients free from all-cause hospitalization and survival were 48.6% (40.7, 56.0) and 82.2% (75.1, 87.4). Of the 96 patients with PoPH in OPUS, 29.2% were classified as in need of liver transplant due to underlying liver disease during the study; transplant waitlist registration was precluded because of PAH severity for 32.1% and 17.9% were transplanted. Hepatic adverse events (HAE) were experienced by 49.0% of patients; the most common being increased bilirubin (16.0%), ascites (7.3%), and hepatic encephalopathy (5.8%); 1.5% and 21.8% of patients discontinued macitentan as a result of HAE and non-hepatic adverse events. There were no unexpected safety findings in patients with PoPH treated with macitentan. These data add to the evidence supporting the safety and tolerability of macitentan in patients with PoPH. A graphical abstract is available with this article. OPsumit® Users Registry (OPUS): NCT02126943; OPsumit® Historical Users cohort (OrPHeUS): NCT03197688; www. gov .

Comparison of prognosis between hyperbilirubinemic infants with and without hypernatremia.

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. 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. 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%). 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.

Unbound Bilirubin and Acute Bilirubin Encephalopathy in Infants Born Late Preterm and Term with Significant Hyperbilirubinemia

To compare the association of unbound bilirubin (UB), total serum bilirubin (TSB), and bilirubin:albumin molar ratio (BAMR) with acute bilirubin encephalopathy (ABE), as assessed by bilirubin-induced neurologic dysfunction (BIND) score, in infants with significant hyperbilirubinemia (TSB ≥20mg/dL or underwent exchange transfusion). In this prospective cohort study, infants ≥34weeks of gestational age with significant hyperbilirubinemia during the first 2 postnatal weeks were eligible, unless they had craniofacial malformations, chromosomal disorders, TORCH (toxoplasmosis, other infections, rubella, cytomegalovirus and herpes simplex) infections, surgery, or a family history of congenital deafness. TSB, serum albumin, and UB were measured at hospital admission using the colorimetric, bromocresol green, and modified peroxidase method, respectively. Infants were evaluated on admission for ABE using a standardized neurologic examination and assigned a BIND score by trained physicians. Infants with a total BIND score of 0 were deemed to not have ABE, whereas those with a score ≥1 were deemed to have ABE. A total of 151 infants were studied, among whom 37 (24.5%) had ABE. Of these, 19 had mild ABE (BIND score 1-3) and 18 had moderate-to-severe ABE (BIND score 4-9). On logistic regression, UB, but not TSB or BAMR, was associated with ABE (aOR 1.64; 95% CI 1.17-2.3). On ordered logistic regression, UB, but not TSB or BAMR, was associated with severity of ABE (aOR 1.76; 95% CI 1.28-2.4). Our findings of the association between UB and ABE indicate that BIND scoring may be useful for evaluation of ABE in infants ≥34weeksof gestational age.

Antenatal jaundice instruction and acute bilirubin encephalopathy in Nigeria

BackgroundAcute Bilirubin Encephalopathy (ABE) is common in Nigeria. Parents’ inability to recognize jaundice and delays in seeking care are significant barriers to its prevention.MethodsWe compared associations of (1) interactive antenatal maternal jaundice instruction with postnatal reinforcement, (2) standard postnatal instruction, and (3) no maternal instruction with the incidence of ABE among 647 jaundice admissions stratified for risk factors identified in initial descriptive analysis.ResultsEighty-three (83/647;12.8%) admissions developed ABE including eleven jaundice-related deaths. ABE was present at admission in 20/22 (90.9%) if mothers received no jaundice instruction and no antenatal care, 42/182 (23.1%) if received antenatal care but no instruction, 16/95 (16.8%) if received postnatal instruction only, and 4/337 (1.2%) if mothers received both antenatal and postnatal instruction (p < .001). ABE was highly associated with out-of-hospital delivery, number of antenatal clinic visits, and birth attendant, but these risks were mitigated by antenatal/postnatal instruction. Admission rates with bilirubin levels below treatment guidelines (12 mg/dL) were higher following instruction (30.7%) than with no instruction (14.4%). Limiting subjects to those meeting admission criteria increased ABE rates in all groups without altering conclusions.ConclusionInteractive antenatal instruction with postnatal reinforcement resulted in timely care seeking and a lower incidence of ABE.ImpactEmpowering mothers to participate in neonatal jaundice management is critical in low-income countries where jaundice monitoring and follow up are unreliable.Instructing mothers about jaundice in antenatal clinics with postnatal reinforcement is more effective than standard postpartum instruction in facilitating jaundice detection, timely care seeking, and lowering the incidence of acute bilirubin encephalopathy (ABE).Antenatal training also mitigates risks for ABE associated with out-of-hospital deliveries, limited antenatal care, and unskilled birth attendants.Impact: Adding structured jaundice instruction in antenatal clinics could greatly reduce bilirubin induced brain injury in countries where ABE is common.

Demystifying non-invasive approaches for screening jaundice in low resource settings: a review.

All national and international pediatric guidelines universally prescribe meticulous bilirubin screening for neonates as a critical measure to mitigate the incidence of acute bilirubin encephalopathy (ABE) and Kernicterus. The prevailing gold standard for jaundice detection in neonates necessitates invasive blood collection, followed by subsequent biochemical testing. While the invasive procedure provides dependable bilirubin measurements and continues to be the sole gold standard diagnostic method for assessing bilirubin concentration. There exists a pressing need to innovate non-invasive screening tools that alleviate the sampling stress endured by newborns, mitigate iatrogenic anemia, and expedite the turnaround time for obtaining results. The exploration of non-invasive modalities for bilirubin measurements is gaining momentum, driven by the overarching goal of minimizing the number of pricks inflicted upon neonates, thereby rendering screening a swift, efficient, comfortable, and dependable process. This comprehensive review article delves extensively into the array of non-invasive approaches and digital solutions that have been proposed, implemented, and utilized for neonatal bilirubin screening, with a particular emphasis on their application in low-resource settings. Within this context, the review sheds light on the existing methodologies and their practical applications, with a specific focus on transcutaneous bilirubin meters. Moreover, it underscores the prevailing open challenges in this domain and outlines potential directions for future research endeavors. Notably, the review underscores the imperative need for robust educational programs targeted at both families and healthcare personnel to expedite the process of seeking timely care for neonatal jaundice. Additionally, it underscores the necessity for the development of enhanced screening and diagnostic tools that can offer greater accuracy in clinical practice.

Magnetic resonance spectroscopy and auditory brain-stem response audiometry as predictors of bilirubin-induced neurologic dysfunction in full-term jaundiced neonates

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 hyperbilirubinemiaWhat 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.