Word: Hyperbilirubinemia Management For Preterm Infants



Site ApplicabilityThis document is applicable in BC Women’s Neonatal Program related to the management of patients with hyperbilirubinemia and phototherapy treatment.Practice Level Managing hyperbilirubinemia is a basic skill within the scope of practice of all Providers and Registered Nurses caring for patients at BC Women’s and Children’s Hospital.BackgroundManagement of neonatal hyperbilirubinemia in late preterm and term neonates has been well addressed by recognized, consensus-based guidelines. The extension of these guidelines to the preterm population has been an area of uncertainty due to limited evidence. This leads to variation in clinical practice and lack of recognition of the spectrum of bilirubin-induced neurologic dysfunction (BIND) in this population with initiating and treatment of elevated bilirubin levels, BIND can be prevented. Preterm infants are metabolically immature and at higher risk of BIND at lower bilirubin levels than their term counterparts. Early use of phototherapy to eliminate BIND and minimizing exchange transfusion are the goals of treatment in premature babies. Although considered relatively safe, phototherapy does have side-effects and there is a tendency to overuse phototherapy in many neonatal intensive care units.Nearly all preterm neonates and approximately 60% of term newborns develop jaundice, (Stevenson, et al) a preventable cause of neurologic impairment in neonates. The syndrome of bilirubin-induced neurologic dysfunction (BIND) represents the range of neurologic manifestations seen in vulnerable babies who have been exposed to lower bilirubin levels than generally described. (Johnson & Bhutani) This typically occurs in the initial days of life as the blood-brain barrier (BBB) is developing, and both the bilirubin binding and clearing mechanisms are immature. A relatively high incidence of severe hyperbilirubinemia (1 in 2480 live births) has been reported in Canada (Sgro M, Campbell D, Shah). The estimation of true incidence of BIND in preterm babies is difficult due to subtle clinical features and the presence of multiple confounders during the intensive care period. Utilizing TSB as the sole marker of neurotoxicity is not reliable as the pathogenesis of BIND is multifactorial. Factors including lower birth weight, low albumin levels and presence of comorbid conditions such as sepsis or asphyxia play a crucial role in altering brain tissue susceptibility to high bilirubin levels.The pathogenesis of BIND is dependent on multiple risk factors; including 1) serum bilirubin load (circulating total and free bilirubin), 2) entry of bilirubin into the central nervous system (CNS) and 3) susceptibility of host neuron:Serum bilirubin load: Several factors specific to preterm infants’ physiology contribute to higher TSB levels when compared to term infants. These include shorter RBC lifespan (30 to 60 days), impaired conjugation of bilirubin, increased enterohepatic circulation and concurrent illnesses (hemolysis, sepsis). Other risk factors for development of severe hyperbilirubinemia possibly overlap with those described in term neonates including isoimmune hemolytic disease, cephalohematoma, previous sibling with jaundice requiring phototherapy and East Asian ethnicity (American Academy of Pediatrics). Entry of bilirubin into the CNS: The entry of bilirubin into the brain is more likely through a leaky BBB secondary to conditions such as acidosis, asphyxia, inflammation, meningitis or an abrupt increase in cerebral blood flow (including hypercarbia and seizures) ( Volpe’s Neurology of the Newborn). Bilirubin is a substrate for efflux transporter P-glycoprotein that is expressed in fetal brain endothelial cells from early in gestation (Ek et al). Susceptibility of neurons: The rapidly proliferating young neurons are highly vulnerable and the presence of co-morbid CNS injuries (such as intraventricular haemorrhage or asphyxia) put the preterm infant at much higher risk for BIND. Factors including lower gestation and birth weight, sepsis, and clinical deterioration are associated with higher incidence of BIND in preterm infants (Brown et al). Genetic variants of protein transporters lining the BBB and energy depletion can cause disturbances in protective mechanisms and may increase the susceptibility of the brain to bilirubin (Gartner et al). It is important to recognize the clinical risk factors associated with neurotoxicity in this populationThe clinical presentation of acute bilirubin encephalopathy (ABE) in preterm babies is often subtle and may occur at lower TSB levels compared to term babies. Clinical features include lethargy, decreased activity, apnea, tachycardia and hypertension, irritability, seizures, stupor, hypotonia, oculogyric movements and hyponatremia (due to inappropriate antidiuretic hormone secretion) (Bhutani, Johnson & Shapiro). The classic manifestations of ABE described in term/late preterm babies of irritability, shrill cry, opisthotonus, arching and seizures are often not seen in preterm babies.The data on long term neurodevelopmental impairment due to hyperbilirubinemia in preterm neonates is limited. There is a high likelihood of misdiagnosis and potential lack of reporting. Retrospective data suggest that TSB concentrations during the first 14 days of birth directly correlates with death, neurodevelopmental impairment (NDI) and sensorineural hearing loss (Oh et al). These are preventable with measurement and treatment of elevated bilirubin levels. ManagementProtocol-based approach: A standardized approach has several benefits including improved outcomes, decrease in ineffective or unsafe practices and support of quality improvement research (Woolf et al). Risks associated with treatment: Phototherapy is the cornerstone for management of neonatal hyperbilirubinemia. There is a tendency to over-use phototherapy in clinical practice, resulting in unnecessary exposure (Atkinson et al). Phototherapy is also associated with short-term adverse effects?including rash, hypothermia, hyperthermia, reduced bonding, interruption of breastfeeding, loose stools and increased insensible water loss (Kumar et al). In term neonates, there has been an association of a small risk between phototherapy and childhood seizures after phototherapy (Newman et al).The proposed recommendations were created by adapting the existing consensus based guidelines for management of hyperbilirubinemia in neonates (NICE UK, Maisels et al, AAP, Rennie et al, Pediatric Child Health, Van Imhoff et al, Morioka). Anticipation of severe hyperbilirubinemia:Initial screening: The timing for initial screening of TSB should be decided after detailed risk assessment based on history, physical examination and the results of antenatal red cell antibody screening tests.Prevention:Early feed initiation reduces enterohepatic circulation and decreases the bilirubin load in the initial weeks of life. Dehydration and hypovolemia contribute to the evolution of hyperbilirubinemia, and should be avoided. There is insufficient evidence to promote use of prophylactic phototherapy in preterm infants (Okwundu, Okoromah, Shah). Treatment Thresholds:For preterm infants, it is unclear at what gestation the BBB sufficiently matures, and all preterm babies are at higher risk for BIND. The goal of effective phototherapy is to eliminate BIND and minimize exchange transfusion. Phototherapy should be prescribed as a medication and the required dose (irradiance) and body surface exposed (single or double) should be documented. Ongoing laboratory testing: Repeat TSB should be checked after 3-6 hours if initial TSB levels are near ET threshold. Further testing should be based on response to phototherapy, presence of risk factors and rate of rise of TSB. Rebound bilirubin may be measured after 18-24 hours of discontinuing phototherapy based on risk factors/individualized basis.Documentation Document assessment and BIND score in progress notes, and treatments provided in Nursing Notes.ReferencesAmerican Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004;114:297–316.Atkinson LR, Escobar GJ, Takayama JI, et al. Phototherapy use in jaundiced newborns in a large managed care organization: do clinicians adhere to the guideline? Pediatrics 2003;111:e555-561.Bhutani VK, Johnson LH, Shapiro SM. Kernicterus in sick and preterm infants (1999-2002): a need for an effective preventive approach. Semin Perinatol 2004;28:319–25.Brown AK, Kim MH, Wu PY, et al. Efficacy of phototherapy in prevention and management of neonatal hyperbilirubinemia. Pediatrics 1985;75:393–400Cockington RA. A guide to the use of phototherapy in the management of neonatal hyperbilirubinemia. J Pediatr 1979;95:281–5.Ek CJ, Wong A, Liddelow SA, et al. Efflux mechanisms at the developing brain barriers: ABC-transporters in the fetal and postnatal rat. Toxicol Lett 2010;197:51–9. Gartner LM, Lee KS, Vaisman S, et al. Development of bilirubin transport and metabolism in the newborn rhesus monkey. J Pediatr 1977;90:513–31.Guidelines for detection, management and prevention of hyperbilirubinemia in term and late preterm newborn infants (35 or more weeks’ gestation) - Summary. Paediatr Child Health 2007;12:401–18.Johnson L, Bhutani VK. The clinical syndrome of bilirubin-induced neurologic dysfunction. Semin Perinatol 2011;35:101–13. Maisels MJ, Watchko JF, Bhutani VK, et al. An approach to the management of hyperbilirubinemia in the preterm infant less than 35 weeks of gestation. J Perinatol 2012;32:660–4. Morioka I. Hyperbilirubinemia in preterm infants in Japan: New treatment criteria. Pediatr Int 2018;60:684–90. Newman TB, Wu YW, Kuzniewicz MW, et al. Childhood Seizures After Phototherapy. Pediatrics 2018Oh W, Tyson JE, Fanaroff AA, et al. Association between peak serum bilirubin and neurodevelopmental outcomes in extremely low birth weight infants. Pediatrics 2003;112:773–9.Okwundu CI, Okoromah CAN, Shah PS. Prophylactic phototherapy for preventing jaundice in preterm or low birth weight infants. Cochrane Database Syst Rev 2012;1:CD007966. Rennie J, Burman-Roy S, Murphy MS, et al. Neonatal jaundice: summary of NICE guidance. BMJ 2010;340:c2409Sgro M, Campbell D, Shah V. Incidence and causes of severe neonatal hyperbilirubinemia in Canada. CMAJ 2006;175:587–90. Stevenson DK, Fanaroff AA, Maisels MJ, et al. Prediction of hyperbilirubinemia in near-term and term infants. J Perinatol 2001;21 Suppl 1:S63-72; discussion S83-87.van Imhoff DE, Dijk PH, Hulzebos CV, et al. Uniform treatment thresholds for hyperbilirubinemia in preterm infants: background and synopsis of a national guideline. Early Hum Dev 2011;87:521–5Volpe’s Neurology of the Newborn - 6th Edition. (accessed 26 Jun 2018).Woolf SH, Grol R, Hutchinson A, et al. Potential benefits, limitations, and harms of clinical guidelines. BMJ 1999;318:527–30Related DocumentsNICU Hyperbilirubinemia Treatment Graphs: Infant Gestational age ≤24 + 6/7 weeks: Reference ToolNICU Hyperbilirubinemia Treatment Graphs: Infant Gestational age 25 – 27 + 6/7 weeks: Reference ToolNICU Hyperbilirubinemia Treatment Graphs: Infant Gestational age 28 – 29 + 6/7 weeks: Reference ToolNICU Hyperbilirubinemia Treatment Graphs: Infant Gestational age 30 – 31 + 6/7 weeks: Reference ToolNICU Hyperbilirubinemia Treatment Graphs: Infant Gestational age 32 - 33 + 6/7 weeks: Reference ToolNICU Hyperbilirubinemia Treatment Graphs: Infant Gestational age 34 – 34 + 6/7 weeks: Reference ToolHyperbilirubinemia: Phototherapy: Equipment: StandardHyperbilirubinemia: Phototherapy: ProcedureDeveloped ByBCW Neonatal Program – Senior Practice Leader, Neonatal FellowVersion HistoryDATEDOCUMENT NUMBER and TITLEACTION TAKEN06-Feb-2020C-06-07-60508 Hyperbilirubinemia Management For Preterm InfantsApproved at: Neonatal Leadership CommitteeDisclaimerThis document is intended for use?within?BC Children’s and BC Women’s Hospitals only. Any other use or reliance is at your sole risk. The content does not constitute and is not in substitution of professional medical advice. Provincial Health Services Authority (PHSA) assumes no liability arising from use or reliance on this document.?This document is protected by copyright and may only be reprinted in whole or in part with the prior written approval of PHSA.? ................
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