Glucose-6-phosphate dehydrogenase (G6PD) is a potent antioxidant enzyme. G6PD deficiency, predominant among males, is a neonatal "neurotoxic" risk, characterized by episodic hemolysis that is sometimes infection triggered. Clinical risk among heterozygous G6PD-deficient females is often under-recognized. Recent reports of rhabdomyolysis among G6PD-deficient individuals are reviewed here. In one case, a male athlete with G6PD deficiency (<10% activity) experienced multiple, acute episodes of rhabdomyolysis, painful muscle symptomatology, injury and hemolysis after strenuous exertion. Both his mother with G6PD-deficiency (<45% activity) and maternal grandmother have chronic histories of episodic or triggered fatigue-related disruptive symptoms. Other case reports of G6PD-deficient individuals with muscle injury and exertional symptoms (with or without hemolysis) showed unique laboratory findings of elevated creatine kinase, myoglobin, lactate dehydrogenase, creatinine, and aminotransferases levels and myoglobinuria. Disrupted myocyte energetics and loss of cellular integrity can be attributed to impaired downstream pentose phosphate pathway (PPP)-related oxidant stress protection, which is a key enzymatic consequence of G6PD-deficiency. These triggered stresses may explain the muscle fatigue and propensity to exertional injury. Correlation between stress-sensitive-impaired muscle injury among all G6PD-deficient individuals, including neonates, requires further clinical validation to ascertain oxidant-stress impact of impaired PPP-dependent cellular energetics of red blood, white blood, neural, and muscle cells.

Severe neonatal hyperbilirubinemia remains a preventable cause of neonatal death and lifelong neurologic disability, yet contemporary global estimates are limited. Using Global Burden of Disease 2023 data for 204 countries, we analyzed incidence, deaths, and disability-adjusted life-years (DALYs) from extreme hyperbilirubinemia (EHB) among neonates from 2003 to 2023, applying joinpoint regression, income-stratified k-means clustering and correlation analysis, and value-per-statistical-life (VSL) and human-capital economic valuation. Globally, incident cases fell 29% (542,966-387,366) and deaths fell 66% (70,907-24,050); the mortality-to-incidence ratio halved from 13.1% to 6.2%. The average annual percent change was -1.5% for incidence and -5.0% for mortality. The Middle East and North Africa had the largest declines in cases (61%) and deaths (72%). In 2023, South Asia and Sub-Saharan Africa accounted for 68% of incident cases and 90% of deaths, lower-middle-income countries for roughly two-thirds of deaths and DALYs, and India, Pakistan, and Nigeria for about half of global mortality. Incidence and mortality were strongly correlated in low-income countries (r = 0.72) but decoupled in upper-middle-income countries (r = 0.19; P = 0.167). The 2023 burden represented $6.9-10.4 billion in VSL-based welfare losses and $13.0 billion in DALY-based human-capital losses. Progress is substantial but uneven across World Bank regions and income groups. IMPACT: Severe neonatal hyperbilirubinemia and kernicterus remain important causes of preventable neonatal death and lifelong neurologic disability. Contemporary evidence is limited on how the burden has changed across regions and income groups and whether neonatal jaundice incidence remains closely associated with mortality. Between 2003 and 2023, modeled incident cases decreased by 29%, while deaths declined by 66%. The burden was mostly concentrated in South Asia, Sub-Saharan Africa, and lower-middle-income countries. Incidence was strongly associated with mortality in low-income settings but largely decoupled from mortality in upper-middle-income settings. Future studies should link burden estimates with screening coverage, bilirubin measurement, phototherapy quality, referral capacity and long-term neurodevelopmental outcomes to identify modifiable health-system factors and guide context-specific interventions.

Infants with glucose-6-phosphate dehydrogenase (G6PD) deficiency are at increased risk for extreme hyperbilirubinemia. However, distinguishing these at-risk infants from the general population can be a diagnostic challenge for the managing pediatrician. Most instances of hyperbilirubinemia follow a benign course, which can give pediatricians a false sense of complacency regarding the likelihood of an infant having a devastating outcome. This case highlights how easily a tragedy such as kernicterus can occur, and addresses how careful application of the 2022 American Academy of Pediatrics Clinical Practice Guideline Revision can aid in the identification of infants at risk and optimization of management of infants with unknown G6PD status.

This article chronicles the life of James Earl Bostic, known affectionately to his family and friends as "King James." We provide a parental and family perspective on the incredibly challenging journey he faced with his family resulting from unnecessary suffering due to kernicterus, a completely preventable disease. As his mother, I struggled to understand the significant impact of hyperbilirubinemia triggered by glucose-6-phosphate dehydrogenase (G6PD) deficiency, while also raising his sibling and navigating broken systems of care. I became a tireless advocate, pushing his educational team to assume capability and ensure he had access to robust language and literacy skills. I also repeatedly advocated for deep brain stimulation (DBS) to manage his tone, which was only granted after going before an Independent Review Board while he experienced prolonged, life-threatening dystonic crisis. My advocacy proved highly effective. DBS gave him upward and downward eye movement that enabled him to successfully access an eye gaze activated communication device, finally gaining expressive communication. He leveraged that device to validate what those who loved him knew - he had language, emotions, and a very sarcastic sense of humor! King James later addressed medical professionals during the 2019 Kernicterus Symposium at the Pediatric Academic Societies (PAS), describing how hard it was for him without communication and urging everyone to provide a meaningful education to children with special health needs. His story shows the catastrophic impact of bilirubin neurotoxicity while also emphasizing the critical importance of nurturing the whole child, assuming capability, providing equitable access to a high-quality education, and honoring self-direction.

Background: G6PD deficiency is among the leading causes of neonatal hyperbilirubinemia and kernicterus. Following a 2022 New York State Department of Health recommendation to test high-risk neonates, we implemented universal G6PD deficiency screening in the well-baby nursery. Objectives: We aimed to increase the proportion of infants screened from 0% to more than 75% within 6 months and to describe the prevalence of G6PD deficiency and the early outcomes of affected neonates. Methods: This quality improvement (QI) initiative, guided by the Model for Improvement, included a cross-sectional analysis of screening yield and early neonatal outcomes. A statistical process control p-chart tracked monthly screening. Outcomes were compared between screen-positive and screen-negative infants using the Fisher exact test. Results: Screening rose from 0% to a sustained mean of 81.1%, exceeding the 75% aim. Of 580 screened neonates, 52 (9.0%) screened positive for G6PD deficiency. Screen-positive infants were more likely than screen-negative infants to undergo repeat serum bilirubin testing (38.5% vs. 19.3%; p = 0.002) and to reach a peak bilirubin above 10 mg/dL (30.8% vs. 10.2%; p < 0.001). A higher rate of readmission for phototherapy was also observed (5.8% vs. 0.9%; p = 0.028), though based on few events. Phototherapy during the birth hospitalization, IVIG, and exchange transfusion did not differ. Conclusions: Universal G6PD screening was feasibly implemented and sustained in a high-risk well-baby nursery through routine workflow changes, without additional phlebotomy. Nearly 1 in 11 screened neonates tested positive for G6PD deficiency.

Unbound bilirubin (UB) crosses the blood-brain barrier (BBB) and accumulates in the brain, leading to astrocyte dysfunction, activated microglia-driven inflammatory responses, impaired oligodendrocyte maturation and myelination, and ultimately neurotoxicity. UB-induced molecular cascade starts with intercalation and subsequent structural and functional disruption of the plasma membrane and membrane-bound organelles including mitochondria and endoplasmic reticulum (ER). Mitochondrial membrane damage leads to depolarization, membrane potential collapse, swelling, increased reactive oxygen species (ROS) generation, ATP loss, and ultimately initiation of intrinsic apoptotic pathway through cytochrome c release. An ER insult initiates unfolded protein response (leads to adaptive response or autophagy), and increased Ca[2+] efflux into the mitochondria. Both processes converge in inducing mitochondrial apoptotic pathway through BAX/Bak translocation. Next, cytosolic release of damaged mitochondrial DNA, ATP, and ROS triggers (primarily in astrocytes and microglia) NRLP3 inflammasome formation, release of pro-inflammatory cytokines, and ultimately pyroptosis. UB can further initiate TNFR-mediated activation of NF-κB, feeding the inflammatory pathway or necroptosis. Disruption of synaptic transmission is through NMDAR-mediated glutamate excitotoxicity, subsequent Ca[2+] influx, and activation of downstream apoptotic pathways. While, at low concentration bilirubin is cytoprotective, this review deals with the detrimental subcellular consequences of UB that ultimately leads to bilirubin-induced neurologic dysfunction (BIND).

Kernicterus, also known as chronic bilirubin encephalopathy, is bilirubin-induced neurological damage that occurs most commonly in infants. Unconjugated hyperbilirubinemia can result from any condition that decreases bilirubin elimination or increases bilirubin production. Although kernicterus has classically been associated with total serum bilirubin concentrations of approximately 25 mg/dL or higher, the 2022 American Academy of Pediatrics guidelines indicate that neurotoxicity can occur at lower or higher levels based on continuous risk curves or nomograms that account for the patient’s gestational age, postnatal age, and additional neurotoxicity risk factors. Because unconjugated bilirubin is lipid-soluble, it can cross the blood-brain barrier, whereas water-soluble conjugated bilirubin cannot. Unconjugated bilirubin accumulates in brain tissue, primarily in the basal ganglia. Unconjugated bilirubin neurotoxicity can cause various neurologic sequelae.

Neonatal hyperbilirubinemia is common, but bilirubin-induced neurologic dysfunction (BIND) remains an important cause of preventable morbidity, particularly in preterm infants. Japan has developed a distinctive approach centered on unbound bilirubin (UB), the biologically active fraction. Nakamura and colleagues pioneered neonatal UB measurement in the 1970s and incorporated UB measurements into the Kobe University (Nakamura) criteria in 1991. With improved survival of extremely preterm infants, bilirubin encephalopathy was still observed despite modest total serum bilirubin (TSB) levels that persisted beyond the first postnatal week. These observations led Morioka to revise the criteria in 2017, incorporating gestational age (GA), corrected GA, UB levels, and staged treatment throughout the prolonged neonatal course. Clinical experience suggests that this approach may reduce phototherapy exposure without increasing UB levels or exchange transfusion, although multicenter evidence with long-term neurodevelopmental outcomes remains limited. The Japanese experience emphasizes longitudinal monitoring and bilirubin-albumin binding characteristics beyond TSB levels alone. Transcutaneous bilirubin, albumin, and bilirubin-albumin molar ratio may facilitate screening, while emerging fluorescence-based methods may improve UB accessibility. UB measurement should be viewed as a framework for individualized risk assessment, with principles adaptable to diverse populations and clinical settings.

Hemolytic Disease of the Fetus and Newborn (HDFN) is caused by the placental transfer of maternal red blood cell (RBC) alloantibodies into the fetal circulation which then targets paternally derived RBC antigens expressed on the fetal RBC. The resulting anemia in the fetus/newborn can lead to grave clinical consequences including hydrops fetalis, kernicterus, and perinatal demise. We have utilized the human KEL transgenic mouse model to study the induction of anti-KEL RBC alloantibodies through pregnancy as well as transfusion and the subsequent placental transfer of anti-KEL RBC alloantibodies into the fetal circulation, causing anemia, hydrops, and fetal/neonatal demise. Here, we describe the methods used to establish the KEL transgenic mouse HDFN model and the assays that evaluate the key pathologic features of HDFN.

Bilirubin is a bile pigment widely present in the human body. At appropriate concentrations, it functions as an antioxidant, reduces obesity risk, and helps prevent cardiovascular diseases. However, excessive levels of unconjugated bilirubin (UCB) in the bloodstream can cross the blood-brain barrier, potentially causing kernicterus and irreversible neurological damage. Therefore, the accurate detection of bilirubin concentrations in human blood is of great significance for evaluating liver function and metabolic health status. Herein, we synthesized fluorescent gold nanocluster (AuNCs) probes using thiolated-cyclic β-cyclodextrin (β-CD) as the ligand. The as-synthesized β-CD-AuNCs exhibit intense fluorescence emission at 760 nm in the near-infrared (NIR) region. Notably, the fluorescence emission intensity of β-CD-AuNCs decreases significantly with the increase of bilirubin concentration, which is mainly attributed to the host-guest recognition interaction between β-cyclodextrin and bilirubin, as well as the inner filter effect (IFE). Within the linear range of 0-50 μM, the sensor shows a distinct concentration-dependent fluorescence response to bilirubin, achieving a detection limit (LOD) of 0.32 μM. This sensitivity is considerably lower than the normal concentration range of free bilirubin in human serum. Finally, the fluorescent sensor was applied to the detection of UCB in a murine hemolytic hyperbilirubinemia model, and the detection results were consistent with those obtained by the commercial kit. Hence the reported UCB sensing probe can serve as a powerful diagnostic tool to research UCB functions and to investigate UCB related diseases.

Albumin is the crux of the exchangeable (i.e., miscible) bilirubin pool, controlling via its high affinity binding the distribution of bilirubin within and across the intravascular and extravascular spaces. It follows that clinicians should leverage the administration of bilirubin free albumin in the management of hazardous hyperbilirubinemia to avoid or reverse bilirubin neurotoxicity. A standard double volume exchange transfusion does exactly that via the albumin laden fresh frozen plasma used to reconstitute the blood infused during the procedure. Albumin priming - the infusion of bilirubin-free albumin prior to a double volume exchange transfusion - augments the infant's pre-exchange albumin mass and albumin bilirubin binding capacity. As such, albumin priming can enhance bilirubin clearance over the course of the subsequent exchange transfusion and provide an immediate stepwise gain in neuroprotection during the pre-exchange period. The potential for neuroprotection against worsening bilirubin-induced neurological dysfunction is the principal reason to albumin prime and prime early when caring for a neonate with signs of intermediate to advanced stage acute bilirubin encephalopathy. Albumin priming should also be considered in asymptomatic infants whose bilirubin - albumin molar ratios approach or exceed albumin's saturable binding limits, as a preventive measure to attenuate bilirubin neurotoxicity risk.