Current Pediatric Reviews - Volume 13, Issue 3, 2017

Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency triggered and low-bilirubin kernicterus persist despite current prevention strategies. Objective: Review efforts to eradicate bilirubin induced brain injury in these two conditions including novel approaches to risk assessment and hyperbilirubinemia evaluation. Result and Conclusion: In the case of G6PD deficiency, a heightened awareness of populations at risk and an expanded kernicterus prevention strategy focused on intensified parental engagement, education and counselling on neonatal jaundice is needed. In the case of low-bilirubin kernicterus, a renewed focus on identifying infants with hypoalbuminemia and implementation of hyperbilirubinemia treatment thresholds based on the bilirubin/albumin ratio is needed. Bilirubin binding panels when commercially available will prove valuable.

Background: Conjunctival icterus is a largely neglected physical sign that may be helpful in identifying neonates with clinically relevant hyperbilirubinemia by practitioners in the hospital and outpatient clinic or parents at home. Objective: A recent NICU based study reported that conjunctival icterus is often a sign of significant (TSB ≥ 17 mg/dl) hyperbilirubinemia and TSB levels ≥ 76^th-95^th percentile on the Bhutani nomogram. In contrast, others report that conjunctival icterus, although frequently present at high TSB levels, may also be detected at lower TSB concentrations; suggesting instead that its absence may help to rule out significant hyperbilirubinemia. Result and Conclusion: The current review details the nature of conjunctival icterus and presents new data on its clinical occurrence in relation to TSB levels that re-affirm its correlation with elevated TSB concentrations and use to trigger TSB measurement in the jaundiced neonate.

Background: Even relatively low serum bilirubin concentrations can cause neurodevelopmental impairment in extremely low birth weight (EBWL) infants, while sequelae from hyperbilirubinemia in late preterm and term infants are rare and occur only at very high serum bilirubin levels. Phototherapy is the current treatment of choice. Objective: To present an update on the most important issues involved in phototherapy for jaundiced infants. Results: Light absorption by bilirubin in the skin transforms the native Z,Z-bilirubin to conformational photoisomers Z,E-bilirubin and E,Z-bilirubin and structural photoisomers E,Z-lumirubin and E,E-lumirubin. Formation and excretion of Z,E-bilirubin and E,Z-lumirubin are both important routes of elimination of bilirubin through bile and urine, although the precise contributions of the various photoisomers to the overall elimination of bilirubin are unknown. It appears that the photoisomers of bilirubin are predominantly formed in the plasma, and the rate of formation is affected by the hemoglobin concentration. Phototherapy lights with an emission spectrum of 460-490 nm provide the most efficient bilirubin-reducing light. LEDs should replace fluorescent tubes and halogen spotlights as the preferred light sources. Recent data raise concerns that sick ELBW infants under prolonged phototherapy may have an increased risk of death, though survivors may benefit from reduced rates of neurodevelopmental impairment. Comparison of the efficacy of cycled vs. continuous phototherapy has given divergent results. Changing the infant's position does not increase the efficacy of phototherapy. Conclusion: During the last decade, we have made progress in our understanding of how and where phototherapy works and in its practical applications.

Extreme hyperbilirubinemia and kernicterus, though rare, continue to occur despite the adoption of universal screening. Unless they are known to have glucose-6-phosphate dehydrogenase deficiency, infants who currently develop kernicterus in high resource countries are often otherwise healthy newborns discharged from the well-baby nursery. In this review, we highlight risk factors that increase the risk of a newborn ≥35 weeks gestational age developing severe hyperbilirubinemia, as well as the risk factors that increase the hyperbilirubinemic infant’s risk of kernicterus.

The suicidal death of erythrocytes should be considered a possible cause of hemolysis and plasma bilirubin overload when there is no evidence of an immune-mediated hemolytic anemia, no consumptive red blood cell disorder, no morphologic or laboratory data to suggest a problem of the red cell membrane, and no evidence of a quantitative or qualitative defect in hemoglobin synthesis. In neonatal period, xenobiotics, cytokines, osmotic shock, energy depletion, oxidative stress, and variation of temperature may induce an alteration of balance between damaging and protecting factors which can be followed by red cell death. The intraerythrocyte redox balance plays a pivotal role in orchestrating the complex molecular mechanisms leading to eryptosis. Neonatal erythrocytes are a target of extracellular free radicals and, at the same time, are themselves generators of free radicals through the Fenton reaction. This review clarifies the complex mechanisms underlying the susceptibility of neonatal erythrocytes to increased oxidative stress.

Background: Hyperbilirubinemia is a benign transitional phenomenon that occurs in 60% to 80% of all term infants. The degree of hyperbilirubinemia and hence risk for developing bilirubin-induced neurologic dysfunction or BIND is dependent upon two major processes: (i) bilirubin production and its elimination. Objective: The aim of this review is to address the importance of hemolysis and its clinical detection in neonates with hyperbilirubinemia. Results: In newborns, an increased bilirubin production rate due to hemolysis is often the primary cause of hyperbilirubinemia during the first week of life. If undiagnosed or untreated, it may lead to an increased risk for BIND. Therefore, the ability to identify infants with hemolytic disease is important in assessing those at risk for developing BIND. In addition, an infant’s genetic profile and bilirubin binding status can also affect their overall capacity to cope with the resultant tissue bilirubin load and affect risk and guide appropriate management strategies. Conclusion: Therefore, the determination of a newborn’s bilirubin production rate is critical to the assessment of a newborn’s risk for developing unpredictable extreme hyperbilirubinemia and preventing BIND.

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.

Background: Kernicterus is a common cause of death and morbidity in many Low- Middle-income Countries (LMICs) and still occurs in affluent nations. In either case, the immediate cause is delayed treatment of severe hyperbilirubinemia. In the West, a provider driven “systems approach” has been widely adopted to identify babies at risk prior to discharge from birthing centers with follow up monitoring based on the serum bilirubin level at time of discharge. The situation is more complicated in regions of the world where kernicterus is endemic, especially in LMICs where Glucose-6-phosphate Dehydrogenase Deficiency (G6PDd) is common and the system of jaundice management is often fragmented. Objective: To examine reasons for errors in jaundice management leading to kernicterus and the potential beneficial role of enlisting more parental participation in management decisions. Method: We searched world literature related to pitfalls in jaundice management including deficiencies in providers’ and parents’ knowledge and behavior. Perspectives from mothers of children with kernicterus supplemented the literature review. Result: System failures contributing to kernicterus in affluent countries include a lack of follow up planning, bad advice by providers, and a delay in care seeking by parents. In many LMICs, the majority of births occur at home with unskilled attendants. Traditional practices potentiate hemolysis in G6PDd babies. The danger of severe jaundice is frequently underestimated both by parents and care providers, and cultural and economic barriers as well as ineffective therapies delay care seeking. The failure to provide parents information about identifying severe jaundice and knowledge about the risks and treatment of hyperbilirubinemia has contributed to delayed treatment in both affluent and low-middle-income countries. A recent non-randomized clinical trial, supports teaching all parents skills to monitor jaundice, signs of early neurotoxicity, the importance of breast feeding, avoidance of ineffective or dangerous practices, and when/where to seek help. Conclusion: Empowering parents allow them to participate more fully in care decisions and to confront obstacles to care when provider services fail.