Comparison of prognosis between hyperbilirubinemic infants with and without hypernatremia.

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.

High levels of pathological jaundice in the first 24 hours and neonatal hyperbilirubinaemia in an epidemiological cohort study on the Thailand-Myanmar border.

Population risks for neonatal hyperbilirubinaemia (NH) vary. Knowledge of local risks permits interventions that may reduce the proportion becoming severe. Between January 2015 and May 2016, in a resource-limited setting on the Thailand-Myanmar border, neonates from 28 weeks' gestation were enrolled into a prospective birth cohort. Each neonate had total serum bilirubin measurements: scheduled (24, 48, 72 and 144 hours of life) and clinically indicated; and weekly follow up until 1 month of age. Risk factors for developing NH were evaluated using Cox proportional hazard mixed model. Of 1710 neonates, 22% (376) developed NH (83% preterm, 19% term). All neonates born <35 weeks, four in five born 35-37 weeks, and three in twenty born ≥38 weeks had NH, giving an overall incidence of 249 per 1000 livebirths [95%CI 225, 403]. Mortality from acute bilirubin encephalopathy was 10% (2/20) amongst the 5.3% (20/376) who reached the severe NH threshold. One-quarter (26.3%) of NH occurred within 24 hours. NH onset varied with gestational age: at a median [IQR] 24 hours [24, 30] for neonates born 37 weeks or prematurely vs 59 hours [48, 84] for neonates born ≥38 weeks. Risk factors for NH in the first week of life independent of gestational age were: neonatal G6PD deficiency, birth bruising, Sgaw Karen ethnicity, primigravidae, pre-eclampsia, and prolonged rupture of membranes. The genetic impact of G6PD deficiency on NH was partially interpreted by using the florescent spot test and further genotyping work is in progress. The risk of NH in Sgaw Karen refugees may be overlooked internationally as they are most likely regarded as Burmese in countries of resettlement. Given high levels of pathological jaundice in the first 24 hours and overall high NH burden, guidelines changes were implemented including preventive PT for all neonates <35 weeks and for those 35-37 weeks with risk factors.

High levels of unbound bilirubin are associated with acute bilirubin encephalopathy in post-exchange transfusion neonates.

BACKGROUND: Although it is known that unbound bilirubin can enter the brain, there is little evidence of its association with the development of acute bilirubin encephalopathy. Here, we investigated this potential relationship in neonates who had undergone exchange transfusion. METHODS: Data from 46 newborns who underwent exchange transfusion between 2016 and 1-1 to 2018-12-31 at the First People's Hospital of Changde City in China were analyzed. The unbound bilirubin level was taken as the independent variable and the development of the acute bilirubin encephalopathy as the dependent variable. The covariates were age, birth weight, sex, red blood cell count, blood glucose, hemolytic disease, and whether the infant had received phototherapy. RESULTS: The mean age and gestational age of the neonates were 146.5 ± 86.9 h and 38.6 ± 1.3 weeks [38.7(34.6-41.1) weeks] old, respectively; 52.17% were male. Binary logistic regression analysis after adjustment for covariates showed a positive association between the levels of unbound bilirubin and the development of acute bilirubin encephalopathy (odds ratio = 1.41, 95% confidence intervals 1.05-1.91, P = < 0.05). CONCLUSION: There is a significant association between unbound bilirubin levels and the development of acute bilirubin encephalopathy in neonates. Further investigations are required to explore the mechanisms.

Early prediction of adverse outcomes in infants with acute bilirubin encephalopathy.

OBJECTIVE: Acute bilirubin encephalopathy (ABE) remains one of the important causes of neonatal mortality and child disability, early identification, and intervention which could improve outcomes. The purpose of this study was to evaluate early predictors of adverse outcomes in infants with ABE. METHODS: Newborns of gestational age ≥ 35 weeks and diagnosed with ABE were included in the study. Bilirubin-induced neurological dysfunction (BIND) score, total serum bilirubin (TSB) peak value, and serum albumin levels were determined. Adverse outcomes were defined as death or survival with auditory dysfunction and/or cerebral palsy. RESULTS: Eighty-two infants were eligible for recruitment in the study. The outcome data from 76 ABE infants (92%) were used for analysis, of which 25 infants got adverse outcomes and 51 live a normal life. Univariate analysis for BIND score, TSB peak value, bilirubin-albumin ratio (B/A), albumin level, abnormal AABR, and neonatal sepsis was performed to elucidate the association with adverse outcomes. Bivariate logistic regression analysis showed B/A (OR 10.48, 95%CI: 1.55-70.81, P = 0.02) and BIND score (OR 3.68, 95%CI: 1.39-9.72, P = 0.01) were correlated with adverse outcomes. ROC curve analysis showed that B/A (≥8.9 mg/g), BIND score (≥6) could predict adverse outcomes of ABE separately; B/A in conjunction with BIND score could increase prediction sensitivity to 100%. INTERPRETATION: Both B/A and BIND score can be used to predict adverse outcomes of ABE, and the combination of the two parameters can increase prediction sensitivity significantly.

Newborn Metabolic Profile Associated with Hyperbilirubinemia With and Without Kernicterus.

Our objective was to assess the relationship between hyperbilirubinemia with and without kernicterus and metabolic profile at newborn screening. Included were 1,693,658 infants divided into a training or testing subset in a ratio of 3:1. Forty-two metabolites were analyzed using logistic regression (odds ratios (ORs), area under the receiver operating characteristic curve (AUC), 95% confidence intervals (CIs)). Several metabolite patterns remained consistent across gestational age groups for hyperbilirubinemia without kernicterus. Thyroid stimulating hormone (TSH) and C-18:2 were decreased, whereas tyrosine and C-3 were increased in infants across groupings. Increased C-3 was also observed for kernicterus (OR: 3.17; 95% CI: 1.18-8.53). Thirty-one metabolites were associated with hyperbilirubinemia without kernicterus in the training set. Phenylalanine (OR: 1.91; 95% CI: 1.85-1.97), ornithine (OR: 0.76; 95% 0.74-0.77), and isoleucine + leucine (OR: 0.63; 95% CI: 0.61-0.65) were the most strongly associated. This study showed that newborn metabolic function is associated with hyperbilirubinemia with and without kernicterus.

Emergency release uncross-matched packed red blood cells for immediate double volume exchange transfusion in neonates with intermediate to advanced acute bilirubin encephalopathy: timely but insufficient?

Given the urgency of double volume exchange transfusion (ExT) in an infant with intermediate to advanced stages of acute bilirubin encephalopathy (ABE), it has been suggested that emergency release uncross-matched packed red blood cells (ER-PRBC) be used. The efficacy of an ExT in removing bilirubin from the brain, however, is a direct function of the mass of albumin exchanged. The very low albumin content of ER-PRBC may fail to be neuroprotective. Predicted changes in total serum bilirubin (TSB), serum albumin, the bilirubin/albumin (B/A) ratio, plasma volume (PV), and bilirubin equilibration from the extravascular space during ER-PRBC ExT are described. ExT using ER-PRBC is efficacious in lowering the TSB. However, this result is falsely reassuring as significant concurrent serum albumin loss, resultant hypoalbuminemia, contraction of PV, limited bilirubin clearance from the extravascular space, and sustained B/A ratio elevations above recommended ExT treatment thresholds suggest that bilirubin neurotoxicity will continue.

Extreme neonatal hyperbilirubinemia, acute bilirubin encephalopathy, and kernicterus spectrum disorder in children with galactosemia.

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 (TSBmax)) 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] TSBmax 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.

A neurologic dysfunction scoring protocol for jaundiced neonates requiring exchange transfusion.

AIM: To evaluate the performance of a neurologic assessment protocol among jaundiced infants requiring exchange transfusion (ET). METHODS: We identified infants in a referral children's hospital who received ET and those who met the American Academy of Pediatrics (AAP) criteria for ET based on total serum bilirubin (TSB) levels. The performance of a bilirubin-induced neurologic dysfunction (BIND-M) scoring protocol for acute bilirubin encephalopathy (ABE) in detecting infants treated with ET in both groups was investigated by logistic regression analysis and c-statistic. RESULTS: A total of 438 late-preterm and term infants were enrolled, out of which 141 (32.2%) received ET, and 155 (35.4%) met AAP criteria for ET. Infants with BIND-M scores of 3-6 (intermediate ABE) or 7-12 (advanced ABE) were significantly associated with ET in both groups, but not scores of 1-2 (mild ABE), with or without adjustment for confounding neurotoxicity risk factors. However, the discriminatory ability of BIND-M regression models was modestly satisfactory (c-statistic range: 0.693-0.791). CONCLUSIONS: Our findings suggest that BIND-M is a potentially useful decision-making tool for ET and support current recommendation for immediate ET for infants with intermediate-to-advanced stages of ABE regardless of the TSB levels.

The Bilirubin Binding Panel: A Henderson-Hasselbalch Approach to Neonatal Hyperbilirubinemia.

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 (BTotal), which is currently used to guide clinical care; the bilirubin binding capacity (BBC); and the concentration of non-albumin bound or free bilirubin (BFree). The fourth component is the bilirubin-albumin equilibrium dissociation constant, KD, which is calculated from BTotal, BBC, and BFree 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 BTotal) are needed to expedite the clinical use of bilirubin binding. At any BTotal, the BFree and the relative risk of bilirubin neurotoxicity increase as the KD/BBC ratio increases (ie, bilirubin binding worsens). Comparing the KD/BBC ratio of newborns with BTotal of concern with that typical for the population helps determine whether the risk of bilirubin neurotoxicity varies significantly from the inherent risk at that BTotal Furthermore, the bilirubin binding panel individualizes care because it helps to determine how aggressive intervention should be at any BTotal, irrespective of whether it is above or below established BTotal guidelines. The bilirubin binding panel may reduce anxiety, costs, unnecessary treatment, and the likelihood of undetected bilirubin neurotoxicity.

Bilirubin-Induced Neurological Dysfunction: A Clinico-Radiological-Neurophysiological Correlation in 30 Consecutive Children.

The clinical expression of bilirubin-induced neurological dysfunction varies according to severity and location of the disease. Definitions have been proposed to describe different bilirubin-induced neurological dysfunction subtypes. Our objective was to describe the severity and clinico-radiological-neurophysiological correlation in 30 consecutive children with bilirubin-induced neurological dysfunction seen over a period of 5 years. Thirty children exposed to acute neonatal bilirubin encephalopathy were included in the study. The mean peak total serum bilirubin level was 625 µmol/L (range 480-900 µmol/L). Acoustic brainstem responses were abnormal in 73% (n = 22). Pallidal hyperintensity was observed on magnetic resonance imaging in 20 children. Peak total serum bilirubin levels correlated with motor severity (P = .03). Children with severe motor impairment were likely to manifest severe auditory neuropathy (P < .01). We found that in a resource-constrained setting, classical kernicterus was the most common bilirubin-induced neurological dysfunction subtype, and the majority of children had abnormal acoustic brainstem responses and magnetic resonance imaging.

Serum unbound bilirubin as a predictor for clinical kernicterus in extremely low birth weight infants at a late age in the neonatal intensive care unit.

BACKGROUND: This study aimed to evaluate peak serum total bilirubin (TB) and unbound bilirubin (UB) levels in preterm infants with clinical kernicterus (KI) who were diagnosed by clinical findings during infancy. DESIGN/SUBJECTS: For this multicenter retrospective study, 18 Japanese extremely low birth weight (ELBW) infants with clinical KI were included. Clinical KI was diagnosed based on the presence of motor developmental impairment with/without athetosis, and abnormal magnetic resonance imaging or brainstem auditory evoked potential findings during infancy. High and low TB or UB levels were defined as serum TB levels ⩾ and <15 mg/dL or serum UB levels ⩾ and <0.8 µg/dL, respectively. The clinical characteristics of KI preterm infants were analyzed. The proportion of infants with high or low serum TB levels and with high or low serum UB levels was then investigated. Sensitivity and specificity were calculated. RESULTS: In 18 KI infants, the median age when serum TB levels peaked was 28 days after birth. In eight KI infants with low serum TB levels, 88% of them had high serum UB levels. For comparison of the number of infants who had high or low serum TB and UB levels, the sensitivity was 90% and specificity was 13%. CONCLUSIONS: Serum TB and UB levels peak at a later age than expected. Chronic serum UB monitoring may be helpful for identifying ELBW infants at risk for developing KI, even when they do not have high serum TB levels.

Audiologic impairment associated with bilirubin-induced neurologic damage.

Hyperbilirubinemia occurs commonly in neonates and is usually mild and transient, with no long-lasting sequelae. However, bilirubin-induced neurologic damage may occur in some infants. The auditory pathway is the most sensitive part of the central nervous system to bilirubin-induced toxicity, and permanent sequelae may result from only moderately elevated total serum/plasma bilirubin levels. The damage to the auditory system occurs primarily within the brainstem and cranial nerve VIII, and manifests clinically as auditory neuropathy spectrum disorder.

Discrepancies between transcutaneous and serum bilirubin measurements.

OBJECTIVE: To characterize discrepancies between transcutaneous bilirubin (TcB) measurements and total serum bilirubin (TSB) levels among newborns receiving care at multiple nursery sites across the United States. METHODS: Medical records were reviewed to obtain data on all TcB measurements collected during two 2-week periods on neonates admitted to participating newborn nurseries. Data on TSB levels obtained within 2 hours of a TcB measurement were also abstracted. TcB--TSB differences and correlations between the values were determined. Data on demographic information for individual newborns and TcB screening practices for each nursery were also collected. Multivariate regression analysis was used to identify characteristics independently associated with the TcB--TSB difference. RESULTS: Data on 8319 TcB measurements were collected at 27 nursery sites; 925 TSB levels were matched to a TcB value. The mean TcB--TSB difference was 0.84 ± 1.78 mg/dL, and the correlation between paired measurements was 0.78. In the multivariate analysis, TcB--TSB differences were 0.67 mg/dL higher in African-American newborns than in neonates of other races (P < .001). The TcB--TSB difference also varied significantly based on brand of TcB meter used and hour of age of the infant. For 2.2% of paired measurements, the TcB measurement underestimated the TSB level by ≥ 3 mg/dL. CONCLUSIONS: During routine clinical care, TcB measurement provided a reasonable estimate of TSB levels in healthy newborns. Discrepancies between TcB and TSB levels were increased in African-American newborns and varied based on brand of meter used.

The clinical syndrome of bilirubin-induced neurologic dysfunction.

Clinicians have hypothesized a spectrum of minor neurologic manifestations, consistent with neuroanatomical reports and collectively termed as a "syndrome of bilirubin-induced neurologic dysfunction (BIND)," which can occur in the absence of classical kernicterus. The current review builds on these initial reports with a focus on clinical signs and symptoms that are assessed by standardized tools and manifest from neonatal age to childhood. These clinical manifestations are characterized by the following domains: (i) neuromotor signs; (ii) muscle tone abnormalities; (iii) hyperexcitable neonatal reflexes; (iv) variety of neurobehavior manifestations; (v) speech and language abnormalities; and (vi) evolving array of central processing abnormalities, such as sensorineural audiology and visuomotor dysfunctions. Concerns remain that the most vulnerable infants are likely to acquire BIND, either because their exposure to bilirubin is not identified as severe enough to need treatment or is prolonged but slightly below current threshold levels for intervention. Knowing that a total serum/plasma bilirubin (TB) level is not the most precise indicator of neurotoxicity, the role of expanded biomarkers or a "bilirubin panel" has yet to be validated in prospective studies. Future studies that correlate early "toxic" bilirubin exposure to long-term academic potential of children are needed to explore new insights into bilirubin's effect on the structural and functional maturation of an infant's neural network topology.

Impact of Rhesus disease on the global problem of bilirubin-induced neurologic dysfunction.

Clinical experience with Rhesus (Rh) disease and its post-icteric sequelae is limited among high-income countries because of nearly over four decades of effective prevention care. We hypothesized that Rh disease is prevalent in other regions of the world because it is likely that protection is limited or non-existent. Following a worldwide study, it has been concluded that Rh hemolytic disease is a significant public health problem resulting in stillbirths and neonatal deaths, and is a major cause of severe hyperbilirubinemia with its sequelae, kernicterus and bilirubin-induced neurologic dysfunction. Knowing that effective Rh-disease prophylaxis depends on maternal blood-type screening, healthcare afforded to the high-risk mothers needs to be free of bottlenecks and coupled with unfettered access to effective Rh-immunoglobulin. Future studies that match the universal identification of Rh-negative status of women and targeted use of immunoprophylaxis to prevent childhood bilirubin neurotoxicity are within reach, based on vast prior experiences.

Bilirubin-induced neural impairment: a special focus on myelination, age-related windows of susceptibility and associated co-morbidities.

Bilirubin-induced neurologic dysfunction (BIND) and classical kernicterus are clinical manifestations of moderate to severe hyperbilirubinemia whenever bilirubin levels exceed the capacity of the brain defensive mechanisms in preventing its entrance and cytotoxicity. In such circumstances and depending on the associated co-morbidities, bilirubin accumulation may lead to short- or long-term neurodevelopmental disabilities, which may include deficits in auditory, cognitive, and motor processing. Neuronal cell death, astrocytic reactivity, and microglia activation are part of the bilirubin-induced pathogenesis. Less understood is how abnormal growth and maturation of oligodendrocytes may impact on brain development, affecting the formation of myelin tracts. Based on in-vitro and in-vivo models, as well as in clinical cases presented here, we propose the existence of impaired myelination by bilirubin with long-term sequelae, mainly in pre-term infants. Sensitive time-windows are highlighted and centered on the different developmental-dependent impairments determined by bilirubin, and the influence of sepsis and hypoxia is reviewed.