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Preterm neonates with increased bilirubin production loads are more likely to sustain adverse outcomes due to either neurotoxicity or overtreatment with phototherapy and/or exchange transfusion.
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Clinicians should rely on expert consensus opinions to guide timely and effective interventions until there is better evidence to refine bilirubin-induced neurologic dysfunction or benefits of bilirubin.
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There are clinical approaches that minimize the risk of bilirubin neurotoxicity.
Hyperbilirubinemia in Preterm Neonates
Section snippets
Key points
Natural bilirubin profile in preterm neonates
Previous studies suggest that preterm infants with modest TB levels can sustain long-term NDI at age 18 to 22 months,7, 15, 16, 17, 18 and infants with high TB levels can experience increased mortality and NDI associated with auditory neuropathic or visuomotor processing disorders (now characterized as BIND).7, 8, 9, 10 However, some preterm infants are resistant to relatively high bilirubin loads in the absence of increased production rates because of efficient elimination of bilirubin and
Clinical profile of subtle posticteric sequelae
As summarized by Johnson and Bhutani,8 pilot studies conducted in the pre-phototherapy era for neonates cared for in 1965 to 1966, identified altered pyschometric, audiologic, speech, language, and visuomotor disorders. Their reanalysis of 4-year and 7-year follow-up studies showed a consistent, significant correlation of low bilirubin binding reserve, with suspicious and abnormal ratings for the psychometric and audiologic examinations. An abnormal bilirubin-albumin molar ratio (BAMR) appeared
Beneficial role of bilirubin
Tissue injury from a biological, chemical, or traumatic insult usually results in a cascade of adaptive response to protect against further injury possibly through restoring vascular integrity that may include endogenously elevated TB (See Stevenson DK, Wong RJ, Arnold CC, et al. Phototherapy and the risk of photo-oxidative injury in extremely low birth weight (ELBW) infants, in this issue). Mildly elevated TB may be associated with lowered morbidity and related mortality, which could be
Bench evidence of bilirubin neurotoxicity in preterm neonates
In a recent review, Brites and Brito59 outlined the mechanisms of dysfunction and demise of neurons by unconjugated bilirubin (UCB) derived from excitotoxicity, oxidative stress, alterations in neuronal arborizations, synaptotoxicity, and apoptosis mediated by alterations in mitochondria dynamics and caspase activation, ultimately leading to cell demise. UCB decreases the expression of presynaptic proteins and was shown to cause presynaptic degeneration in the Gunn rat, an animal model of
Margins of clinical safety
Management of hyperbilirubinemia in preterm infants varies among institutions, with little evidentiary support for these differences in management.62 Because of the limited specificity of TB as a predictor for neurotoxicity, the margin of safety is narrow and unpredictable. Thus, interventions are primarily for prevention rather than for rescue. Interventions include the following: (1) alterations of preterm gut physiology and enterohepatic circulation by early initiation of feeds to alter
Timing of Interventions to Reduce Excessive Bilirubin Load
The timing of bilirubin reduction strategies impacts the outcome of preterm infants at risk for excessive hyperbilirubinemia. Early implementation of strategies to rapidly and effectively reduce the excessive bilirubin load before the onset of neurologic signs, in all likelihood, could prevent chronic posticteric sequelae or kernicterus. The initial evidence for this approach, using phototherapy, was demonstrated by a National Institute of Child Health and Development (NICHD) Neonatal Research
Follow-up of preterm infants at risk for bilirubin-induced neurologic dysfunction
Posticteric sequelae are often unrecognized, mislabeled, or misdiagnosed in preterm infants. These errors have led to prolonged diagnostic and health-seeking odysseys for families. Follow-up studies of infants enrolled in the NICHD trial of 1979 to 1985 demonstrated the challenges of follow-up in this population as well as the residual morbidities identified at late childhood and in adults. Oh and colleagues,16 through a retrospective observational analysis in infants with BW less than 1000 g,
Summary
Bilirubin, a powerful antioxidant, also can act as a powerful but silent neurotoxin at the most vulnerable stage of preterm life. The impact is long-lasting with both functional and structural neurologic injury that alters the processing of afferent input and leads to disordered efferent function. Moreover, these perturbations can potentially arrest or retard the natural neural maturation and/or lead to disordered clinical extrapyramidal function, sensory processing of hearing, visual
References (81)
- et al.
Kernicterus in sick and preterm infants (1999-2002): a need for an effective preventive approach
Semin Perinatol
(2004) - et al.
The clinical syndrome of bilirubin-induced neurologic dysfunction
Semin Perinatol
(2011) - et al.
System-based approach to management of neonatal jaundice and prevention of kernicterus
J Pediatr
(2002) - et al.
Predischarge screening for severe neonatal hyperbilirubinemia identifies infants who need phototherapy
J Pediatr
(2013) Chronic bilirubin encephalopathy: diagnosis and outcome
Semin Fetal Neonatal Med
(2010)- et al.
Relationship of serum bilirubin levels and hearing impairment in newborn infants
Early Hum Dev
(1987) - et al.
Prevalence and risk factors for auditory neuropathy spectrum disorder in a screened newborn population at risk for hearing loss
Int J Pediatr Otorhinolaryngol
(2012) - et al.
Apnea in acute bilirubin encephalopathy
Semin Perinatol
(2014) - et al.
Association between atherosclerosis and newly classified chronic kidney disease stage for Japanese patients with type 2 diabetes
Diabetes Res Clin Pract
(2009) - et al.
Low serum bilirubin concentration is a predictor of chronic kidney disease
Atherosclerosis
(2014)
Improved resistance to serum oxidation in Gilbert's syndrome: a mechanism for cardiovascular protection
Atherosclerosis
Free and albumin-bound bilirubin are efficient co-antioxidants for alpha-tocopherol, inhibiting plasma and low density lipoprotein lipid peroxidation
J Biol Chem
Phototherapy: current methods and future directions
Semin Perinatol
Blood exchange transfusion for infants with severe neonatal hyperbilirubinemia
Semin Perinatol
Chemoprevention of severe neonatal hyperbilirubinemia
Semin Perinatol
High-dose intravenous immune globulin therapy for hyperbilirubinemia caused by Rh hemolytic disease
J Pediatr
Breast-feeding, neonatal jaundice and kernicterus
Semin Neonatol
Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation
Pediatrics
Predictive ability of a predischarge hour-specific serum bilirubin for subsequent significant hyperbilirubinemia in healthy term and near-term newborns
Pediatrics
Clinical report from the pilot USA kernicterus registry (1992 to 2004)
J Perinatol
Universal bilirubin screening for severe neonatal hyperbilirubinemia
J Perinatol
Kernicterus in preterm newborns: past, present, and future
Pediatrics
Preschool IQ: prenatal and early developmental correlates
Intelligence at six years in relation to neonatal bilirubin levels: follow-up of the National Institute of Child Health and Human Development Clinical Trial of Phototherapy
Pediatrics
Bilirubin-induced neurologic dysfunction
Semin Fetal Neonatal Med
Neonatal hyperbilirubinemia and Rhesus disease of the newborn: incidence and impairment estimates for 2010 at regional and global levels
Pediatr Res
Kernicterus and prematurity
Arch Dis Child
Influence of clinical status on the association between plasma total and unbound bilirubin and death or adverse neurodevelopmental outcomes in extremely low birth weight infants
Acta Paediatr
Competitive binding of bilirubin and drugs to human serum albumin studied by enzymatic oxidation
J Clin Invest
Aggressive vs. conservative phototherapy for infants with extremely low birth weight
N Engl J Med
Association between peak serum bilirubin and neurodevelopmental outcomes in extremely low birth weight infants
Pediatrics
Serum bilirubin levels, intracranial hemorrhage, and the risk of developmental problems in very low birth weight neonates
Pediatrics
Outcomes of extremely premature infants related to their peak serum bilirubin concentrations and exposure to phototherapy
Pediatrics
Neonatal bilirubin binding capacity discerns risk of neurological dysfunction
Pediatr Res
The neuropathology of kernicterus in the premature neonate: diagnostic problems
J Neuropathol Exp Neurol
Relationship of benzyl alcohol to kernicterus, intraventricular hemorrhage, and mortality in preterm infants
Pediatrics
Kernicterus: epidemiological strategies for its prevention through systems-based approaches
J Perinatol
Neurologic sequelae of erythroblastosis fetalis
Am J Dis Child
Diagnosis of kernicterus in the neonatal period
Pediatrics
Bilirubin and brain injury
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Use of prophylactic phototherapy for RhD neonatal disease in a referral service
2023, Jornal de PediatriaCitation Excerpt :Curves with values indicating the limit between acceptable bilirubin levels and those indicating phototherapy or exchange transfusion (ET) were made available by lifetime and risk factors in each case.2 In 2016, Bhutani et al. published curves of indications for phototherapy and exchange transfusion for preterm infants with less than 35 weeks of gestational age.12 A systematic review by Cochrane (2012) on the use of prophylactic phototherapy in preterm infants concluded that implementing phototherapy soon after birth can prevent bilirubin from reaching the exchange transfusion level and reduce the risk of involving the central nervous system.
Association Between Neonatal Phototherapy Exposure and Childhood Neoplasm
2022, Journal of PediatricsExposure to air pollutants during pregnancy and after birth increases the risk of neonatal hyperbilirubinemia
2022, Environmental ResearchCitation Excerpt :Severe neonatal jaundice can lead to bilirubin encephalopathy and kernicterus, which impose substantial burdens on both society and families (Maisels et al., 2009; D 2017 Causes of Death, 2018; Lawn et al., 2014). Several recognized risk factors for neonatal jaundice have been identified, such as premature rupture of membranes (PROM) (Naeye and Peters, 1980), amniotic-fluid infection (Naeye and Peters, 1980), congenital hypothyroidism (Weldon and Danks, 1972), G6PD deficiency (Johnson et al., 2002) and premature birth (Bhutani et al., 2016). In our daily clinical work, we observed an interesting phenomenon in which more patients were diagnosed with neonatal hyperbilirubinemia in the serious air pollution days than that in low air pollution days.
Disorders in the neonatal period
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Author Disclosure: None of the authors have financial relationships relevant to this article to disclose. None of the authors have conflicts of interest to disclose.