J a u n d i c e an d K e r n i c t e r u s i n th e Moderately Preterm I nfant Matthew B. Wallenstein,
MD,
Vinod K. Bhutani,
MD*
KEYWORDS Kernicterus Bilirubin-induced neurologic dysfunction Jaundice Hyperbilirubinemia Bilirubin encephalopathy Newborn jaundice Moderately preterm KEY POINTS Moderately preterm infants remain at increased risk for adverse outcomes, including acute bilirubin encephalopathy (ABE) relative to term infants. Evidence-based guidelines for the management of hyperbilirubinemia in moderately preterm infants, however, are lacking. High concentrations of unconjugated bilirubin can cause permanent neurologic damage in infants, known as chronic bilirubin encephalopathy or kernicterus. There is growing concern that exposure to even moderate concentrations of bilirubin may lead to subtle but permanent neurodevelopmental impairment (NDI), known as bilirubininduced neurologic dysfunction (BIND). Clinical manifestations of ABE in preterm infants are similar to, but often more subtle than, those of term infants. This article provides clinical strategies to operationalize the thresholds for the management of hyperbilirubinemia in moderately preterm infants, based on recently published consensus-based recommendations.
INTRODUCTION
The American Academy of Pediatrics published guidelines for management of hyperbilirubinemia in infants greater than or equal to 35 weeks’ gestational age (GA) in 2004.1 This management protocol, based on available evidence, has been widely
Funding Source: No external funding was secured for this study. Financial Disclosure: None of the authors has financial relationships relevant to this article to disclose. Conflict of Interest: None of the authors has conflicts of interest to disclose. Division of Neonatal-Developmental Medicine, Department of Pediatrics, Lucile Packard Children’s Hospital, Stanford University School of Medicine, 750 Welch Road #315, Stanford, CA 94304, USA * Corresponding author. E-mail address: [email protected] Clin Perinatol 40 (2013) 679–688 http://dx.doi.org/10.1016/j.clp.2013.07.007 perinatology.theclinics.com 0095-5108/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved.
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Wallenstein & Bhutani
accepted as standard practice and has been successfully implemented for late preterm infants.2 Similar guidelines in the United States for infants less than 35 weeks’ GA have been elusive due to absence of a rigorous standard of evidence and the practical inability to test the hypothesis of bilirubin-induced injury in vulnerable infants. As a result, management of hyperbilirubinemia in moderately preterm infants (280/7 to 346/7–wk GA) varies greatly among neonatal intensive care units (NICUs).3–5 A consensus-based recommendation was recently proposed for use of phototherapy and exchange transfusion in preterm infants less than 35 weeks’ GA.6 These practical recommendations are based on expert consensus because there are insufficient data to establish evidence-based guidelines. Posticteric complications are infrequent, with liberal and effective use of phototherapy in current clinical practice. The risk is not zero, however, and several recent studies have shown that even moderate or low total serum/plasma bilirubin (TB) levels can lead to development of kernicterus in sick premature infants.7–10 Furthermore, recent population studies suggest that moderate elevations in TB may be associated with NDI,10,11 although additional studies failed to identify increased risk of NDI with moderate TB elevation.12,13 Studies of extremely low birth weight (ELBW) infants have been informative. A recent randomized controlled trial showed that aggressive phototherapy in ELBW infants reduced NDI and hearing loss among surviving infants versus those receiving conservative phototherapy. A post hoc statistical analysis reported, however, a 5% higher mortality among those infants weighing 501 g to 750 g in the aggressive phototherapy group, although the CI included 1.0.14 This subcohort of the smallest of infants with translucent and fragile skin was exposed to light irradiance that lowered their concentration of plasma bilirubin (a powerful antioxidant). There is extensive literature on phototherapy guidelines for full-term and ELBW infants; however, management of hyperbilirubinemia in infants less than 35 weeks’ GA has not been subject to similar scientific rigor. This review outlines clinical strategies that would operationalize the management of hyperbilirubinemia in moderately preterm infants to meet the recently published consensus-based recommendations6 and examines the scope of the problem of hyperbilirubinemia in moderately preterm infants, the mechanism of brain injury, clinical manifestations of untreated and progressive hyperbilirubinemia, and the spectrum of BIND. SCOPE OF THE PROBLEM
Infants 30 to 35 weeks’ GA constitute almost one-third of all NICU admissions.15 This moderately preterm population is more vulnerable to adverse outcomes at lower TB concentrations, including ABE, relative to term infants.15–17 The prevalence of hyperbilirubinemia among preterm infants 30 to 34 weeks’ GA is difficult to quantify. The thresholds for excessive hyperbilirubinemia in this group are not standardized by GA, and clinicians often utilize lower TB thresholds to intervene with decreasing GA.18 As a result, the exact prevalence of BIND and kernicterus in preterm infants who survive to discharge is not known.19 The consequence of hyperbilirubinemia in premature infants is more severe than in term infants, with mean peak TB levels approaching 10 to 12 mg/dL (171–205 mmol/L).17 Premature infants face higher bilirubin burdens due to increased bilirubin production, decreased hepatic uptake, decreased uridinediphosphoglucuronate glucuronosyltransferase (UGT) activity, and increased enterohepatic circulation. Disorders in binding of bilirubin to albumin augment the vulnerability of both sick and healthy preterm infants. Furthermore, preterm infants are at higher risk for ABE due to their immature and developing nervous systems.20–22
Jaundice and Kernicterus
Given the prevalence of hyperbilirubinemia among preterm infants and the relative proportion of moderately preterm infants among NICU populations, neonatal health care providers are encouraged to review their institutional policies for a systemsbased approach to manage hyperbilirubinemia in these preterm infants that includes screening, diagnostic evaluation, frequency and duration of monitoring, TB thresholds for intervention adjusted for GA and presence of hemolysis, risk assessment for neurotoxicity, and effective, but judicious, use of phototherapy. Local implementation of these approaches has been successful in the apparent reduction of exchange transfusion among NICUs in the United States. Continued assessment of best practices would be helpful to minimize overtreatment or unintended consequences of bilirubin reduction strategies. MECHANISM OF BRAIN INJURY
High concentrations of unconjugated bilirubin can cause permanent neurologic damage in infants, known as chronic bilirubin encephalopathy or kernicterus. This relationship has been well established.23–26 More than half of term infants with TB greater than 30 mg/dL (513 mmol/L) develop permanent neurologic sequelae.27 Similar data are not available for moderately preterm infants. Disordered binding of bilirubin to albumin may cause increased vulnerability among preterm infants. The fraction of free bilirubin (unbound bilirubin) increases as bilirubin approaches the binding capacity of albumin. Increased unbound bilirubin levels have been linked to bilirubin neurotoxicity.28 Current evidence does not provide for precise prediction (sensitivity and/or specificity) for bilirubin neurotoxicity based on either TB or unbound (or free) bilirubin. Use of basic pharmacokinetic models of bilirubin transport and tissue uptake suggests that either unbound bilirubin alone or in combination with TB may better discriminate the risk for an individual infant.28 Diagnosis of kernicterus is made via microscopic evaluation at autopsy. History of exposure to severe or prolonged duration of hyperbilirubinemia, association of clinical signs characterized by diverse processing disorders, sensorineural hearing abnormalities (auditory brainstem-evoked responses or cochlear microphonics), and MRI in surviving infants assist clinicians in diagnosing posticteric sequelae. Classically, injury is evident in the basal ganglia (globus pallidus), central/peripheral auditory pathways, hippocampus, diencephalon, subthalamic nuclei, or midbrain, among other regions.24,29 MRI often reveals increased signal intensity in these locations. The mechanism of bilirubin neurotoxicity has not yet been elucidated. On crossing the blood-brain barrier, bilirubin may damage neurons by interfering with energy metabolism in subcellular organelles, binding to and inhibiting function of specific organelle or cyoplasmic proteins, and/or directly damaging DNA.30 In vitro studies have found that bilirubin exposure causes neuritic atrophy, cell death, decreased neuronal arborization, arrested neuritic growth, and neuritic hypoplasia.29 Acute kernicterus (or ABE) can result from unmonitored or insufficiently treated progressive hyperbilirubinemia. There is growing concern that exposure to even moderate concentrations of bilirubin may also lead to isolated neurodevelopmental injury or subtle but permanent impairment known as BIND.31 The spectrum of neurologic impairment from BIND may manifest as disturbances of myriad processes, including visual-motor, auditory, speech, cognition, and language. The effect of bilirubin on neuronal differentiation and development in vitro provides biologic plausibility for the spectrum of BIND. Evidence for a causal link between hyperbilirubinemia and subtle NDI, however, is lacking at present. Also, some evidence suggests that infants may benefit from the antioxidant properties of bilirubin, making ideal management less straightforward.13,21
681
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Wallenstein & Bhutani
CLINICAL MANIFESTATIONS OF HYPERBILIRUBINEMIA IN THE MODERATELY PRETERM INFANT
Clinical manifestations of ABE include changes in mental status, muscle tone, feeding, and pitch of cry, leading to progressive hypotonia, retrocollis, and opisthotonos. Mortality during ABE approaches 10%, usually due to respiratory failure or seizures refractory to antiepileptic administration.31 Kernicterus, which refers to permanent neurologic damage in infants who survive ABE, is characterized by chronic manifestations of the acute syndrome of ABE, including dystonia, athetoid cerebral palsy, gaze paralysis, and sensorineural hearing loss. Cognitive function may be spared, although some studies suggest otherwise.32 Clinical manifestations of ABE in preterm infants are similar to, but often more subtle than, those of term infants. Immature neuronal architecture and masking clinical conditions (eg, ventilatory support), however, often produce subtle clinical changes that make diagnosis of ABE a challenge in preterm infants. In a case series of preterm infants with kernicterus, only one-half displayed evidence of ABE, such as arching, seizures, posturing, abnormal muscle tone, or apnea/periodic breathing.19 A recent study identified 3 biomarkers (activin A, S100B protein, and adrenomedullin) for brain injury in preterm infants.33 Further characterization of these biomarkers may eventually aid in the diagnosis of ABE, although brain injury was defined broadly and was not specific to bilirubin-related injury in their study. The clinical spectrum of BIND, in which moderate elevations of bilirubin affect narrow neural pathways, has yet to be fully characterized in term and preterm populations. There is a persuasive theoretic support, however, for increased vulnerability to BIND among preterm populations. Several studies have found a dose-response relationship between bilirubin concentration and subtle neurodevelopmental outcomes, including minor motor/gait abnormalities, learning disabilities, autism, and developmental delay, among others.31,32,34–38 Some studies, however, found no relationship after controlling for confounding variables using logistic regression.39 Another recent study found no increase in minor neurologic dysfunction at 18 months of age among term infants with moderate hyperbilirubinemia, but they did find a significant association among infants with bilirubin concentrations above 330 mmol/L (19.3 mg/dL).40 To date, there is no direct causal relationship between moderate hyperbilirubinemia and neurotoxicity, but observational literature and a recent review support the spectrum of BIND and its relationship to subtle neurologic disorders associated with abnormal bilirubin-albumin binding.31 Future research is needed to confirm these relationships. CLINICAL MANAGEMENT OF HYPERBILIRUBINEMIA IN THE MODERATELY PRETERM INFANT
Management of hyperbilirubinemia in moderately preterm infants varies greatly among institutions, with little evidentiary support for these differences in management.3–5 This review outlines clinical strategies to operationalize the management of hyperbilirubinemia in moderately preterm infants to meet the recently published consensus-based recommendations.6 Technical aspects of effective phototherapy, including irradiance and light source, as well as method and risks of exchange transfusion are not reviewed here and have been the subject of several recent reports.3,41,42 Fig. 1 shows the recommended guidelines for initiation of phototherapy and exchange transfusion in preterm infants by postmenstrual age, for infants less than 35 weeks’ GA.
Jaundice and Kernicterus
Fig. 1. Suggested use of phototherapy and exchange transfusion in preterm infants less than 35 weeks’ GA. The operational thresholds have been demarcated by recommendations of an expert panel. The shaded bands represent the degree of uncertainty. Recommended thresholds to prepare for exchange transfusion assume that these infants are already being managed by effective phototherapy. Increase in exposure of BSA to phototherapy may inform the decision to conduct an exchange transfusion based on patient response to phototherapy. (Adapted from 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(9):660–4; with permission.)
Operational strategies 1. TB levels a. Fig. 1 is based on recommendations for operational or therapeutic TB threshold levels at, or above which, treatment is likely to do more good than harm.6 These TB levels are not based on high-quality evidence but on consensus expert opinion. b. Use TB measurements. Do not subtract direct-reacting or conjugated bilirubin from the TB. c. These TB thresholds reflect a degree of uncertainty for these recommendations. Clinicians should consider the lower range of the thresholds for infants at greater risk for bilirubin neurotoxicity, for example, (1) lower GA; (2) serum albumin levels or5 325 micromol/L who were born in Nova Scotia, Canada, between 1994 and 2000. Pediatrics 2008;122:119–24. 36. Good WV, Hou C. Sweep visual evoked potential grating acuity thresholds paradoxically improve in low-luminance conditions in children with cortical visual impairment. Invest Ophthalmol Vis Sci 2006;47:3220–4. 37. Boggs T, Hardy J, Frazier T. Correlation of neonatal serum total bilirubin concentration and evelopmental status at age eight months. Preliminary report from the collaborative project. J Pediatr 1967;71:553–60. 38. Maimburg RD, Bech BH, Vaeth M. Neonatal jaundice, autism, and other disorders of psychological development. Pediatrics 2010;126:872–8. 39. Croen LA, Yoshida CK, Odouli R. Neonatal hyperbilitubinemia and risk of autism spectrum disorders. Pediatrics 2005;115:e135–8. 40. Lunsing RJ, Pardoen WF, Hadders-Algra M. Neurodevelopment after moderate hyperbiliruinemia at term. Pediatr Res 2013;73:655–60. 41. Bhutani VK, Committee on Fetus and Newborn. Phototherapy to prevent severe neonatal hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2011;128:e1046–52. 42. National Institute for Health and Clinical Excellence. Neonatal Jaundice. National Institute for Health and Clinical Excellence. 2010. Available at: www.nice.org. uk/CG98. Accessed May 18, 2013.
687
688
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43. McDonagh AF, Maisels MJ. Bilirubin unbound: de´ja` vu all over again? Pediatrics 2006;117:523–5. 44. Ahlfors CE. Criteria for exchange transfusion in jaundiced newborns. Pediatrics 1994;93:488–94. 45. Lamola AA, Bhutani VK, Wong RJ, et al. Effect of hematocrit on efficacy of phototherapy for neonatal jaundice. Pediatr Res 2013;74(1):54–60.
MD,
Vinod K. Bhutani,
MD*
KEYWORDS Kernicterus Bilirubin-induced neurologic dysfunction Jaundice Hyperbilirubinemia Bilirubin encephalopathy Newborn jaundice Moderately preterm KEY POINTS Moderately preterm infants remain at increased risk for adverse outcomes, including acute bilirubin encephalopathy (ABE) relative to term infants. Evidence-based guidelines for the management of hyperbilirubinemia in moderately preterm infants, however, are lacking. High concentrations of unconjugated bilirubin can cause permanent neurologic damage in infants, known as chronic bilirubin encephalopathy or kernicterus. There is growing concern that exposure to even moderate concentrations of bilirubin may lead to subtle but permanent neurodevelopmental impairment (NDI), known as bilirubininduced neurologic dysfunction (BIND). Clinical manifestations of ABE in preterm infants are similar to, but often more subtle than, those of term infants. This article provides clinical strategies to operationalize the thresholds for the management of hyperbilirubinemia in moderately preterm infants, based on recently published consensus-based recommendations.
INTRODUCTION
The American Academy of Pediatrics published guidelines for management of hyperbilirubinemia in infants greater than or equal to 35 weeks’ gestational age (GA) in 2004.1 This management protocol, based on available evidence, has been widely
Funding Source: No external funding was secured for this study. Financial Disclosure: None of the authors has financial relationships relevant to this article to disclose. Conflict of Interest: None of the authors has conflicts of interest to disclose. Division of Neonatal-Developmental Medicine, Department of Pediatrics, Lucile Packard Children’s Hospital, Stanford University School of Medicine, 750 Welch Road #315, Stanford, CA 94304, USA * Corresponding author. E-mail address: [email protected] Clin Perinatol 40 (2013) 679–688 http://dx.doi.org/10.1016/j.clp.2013.07.007 perinatology.theclinics.com 0095-5108/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved.
680
Wallenstein & Bhutani
accepted as standard practice and has been successfully implemented for late preterm infants.2 Similar guidelines in the United States for infants less than 35 weeks’ GA have been elusive due to absence of a rigorous standard of evidence and the practical inability to test the hypothesis of bilirubin-induced injury in vulnerable infants. As a result, management of hyperbilirubinemia in moderately preterm infants (280/7 to 346/7–wk GA) varies greatly among neonatal intensive care units (NICUs).3–5 A consensus-based recommendation was recently proposed for use of phototherapy and exchange transfusion in preterm infants less than 35 weeks’ GA.6 These practical recommendations are based on expert consensus because there are insufficient data to establish evidence-based guidelines. Posticteric complications are infrequent, with liberal and effective use of phototherapy in current clinical practice. The risk is not zero, however, and several recent studies have shown that even moderate or low total serum/plasma bilirubin (TB) levels can lead to development of kernicterus in sick premature infants.7–10 Furthermore, recent population studies suggest that moderate elevations in TB may be associated with NDI,10,11 although additional studies failed to identify increased risk of NDI with moderate TB elevation.12,13 Studies of extremely low birth weight (ELBW) infants have been informative. A recent randomized controlled trial showed that aggressive phototherapy in ELBW infants reduced NDI and hearing loss among surviving infants versus those receiving conservative phototherapy. A post hoc statistical analysis reported, however, a 5% higher mortality among those infants weighing 501 g to 750 g in the aggressive phototherapy group, although the CI included 1.0.14 This subcohort of the smallest of infants with translucent and fragile skin was exposed to light irradiance that lowered their concentration of plasma bilirubin (a powerful antioxidant). There is extensive literature on phototherapy guidelines for full-term and ELBW infants; however, management of hyperbilirubinemia in infants less than 35 weeks’ GA has not been subject to similar scientific rigor. This review outlines clinical strategies that would operationalize the management of hyperbilirubinemia in moderately preterm infants to meet the recently published consensus-based recommendations6 and examines the scope of the problem of hyperbilirubinemia in moderately preterm infants, the mechanism of brain injury, clinical manifestations of untreated and progressive hyperbilirubinemia, and the spectrum of BIND. SCOPE OF THE PROBLEM
Infants 30 to 35 weeks’ GA constitute almost one-third of all NICU admissions.15 This moderately preterm population is more vulnerable to adverse outcomes at lower TB concentrations, including ABE, relative to term infants.15–17 The prevalence of hyperbilirubinemia among preterm infants 30 to 34 weeks’ GA is difficult to quantify. The thresholds for excessive hyperbilirubinemia in this group are not standardized by GA, and clinicians often utilize lower TB thresholds to intervene with decreasing GA.18 As a result, the exact prevalence of BIND and kernicterus in preterm infants who survive to discharge is not known.19 The consequence of hyperbilirubinemia in premature infants is more severe than in term infants, with mean peak TB levels approaching 10 to 12 mg/dL (171–205 mmol/L).17 Premature infants face higher bilirubin burdens due to increased bilirubin production, decreased hepatic uptake, decreased uridinediphosphoglucuronate glucuronosyltransferase (UGT) activity, and increased enterohepatic circulation. Disorders in binding of bilirubin to albumin augment the vulnerability of both sick and healthy preterm infants. Furthermore, preterm infants are at higher risk for ABE due to their immature and developing nervous systems.20–22
Jaundice and Kernicterus
Given the prevalence of hyperbilirubinemia among preterm infants and the relative proportion of moderately preterm infants among NICU populations, neonatal health care providers are encouraged to review their institutional policies for a systemsbased approach to manage hyperbilirubinemia in these preterm infants that includes screening, diagnostic evaluation, frequency and duration of monitoring, TB thresholds for intervention adjusted for GA and presence of hemolysis, risk assessment for neurotoxicity, and effective, but judicious, use of phototherapy. Local implementation of these approaches has been successful in the apparent reduction of exchange transfusion among NICUs in the United States. Continued assessment of best practices would be helpful to minimize overtreatment or unintended consequences of bilirubin reduction strategies. MECHANISM OF BRAIN INJURY
High concentrations of unconjugated bilirubin can cause permanent neurologic damage in infants, known as chronic bilirubin encephalopathy or kernicterus. This relationship has been well established.23–26 More than half of term infants with TB greater than 30 mg/dL (513 mmol/L) develop permanent neurologic sequelae.27 Similar data are not available for moderately preterm infants. Disordered binding of bilirubin to albumin may cause increased vulnerability among preterm infants. The fraction of free bilirubin (unbound bilirubin) increases as bilirubin approaches the binding capacity of albumin. Increased unbound bilirubin levels have been linked to bilirubin neurotoxicity.28 Current evidence does not provide for precise prediction (sensitivity and/or specificity) for bilirubin neurotoxicity based on either TB or unbound (or free) bilirubin. Use of basic pharmacokinetic models of bilirubin transport and tissue uptake suggests that either unbound bilirubin alone or in combination with TB may better discriminate the risk for an individual infant.28 Diagnosis of kernicterus is made via microscopic evaluation at autopsy. History of exposure to severe or prolonged duration of hyperbilirubinemia, association of clinical signs characterized by diverse processing disorders, sensorineural hearing abnormalities (auditory brainstem-evoked responses or cochlear microphonics), and MRI in surviving infants assist clinicians in diagnosing posticteric sequelae. Classically, injury is evident in the basal ganglia (globus pallidus), central/peripheral auditory pathways, hippocampus, diencephalon, subthalamic nuclei, or midbrain, among other regions.24,29 MRI often reveals increased signal intensity in these locations. The mechanism of bilirubin neurotoxicity has not yet been elucidated. On crossing the blood-brain barrier, bilirubin may damage neurons by interfering with energy metabolism in subcellular organelles, binding to and inhibiting function of specific organelle or cyoplasmic proteins, and/or directly damaging DNA.30 In vitro studies have found that bilirubin exposure causes neuritic atrophy, cell death, decreased neuronal arborization, arrested neuritic growth, and neuritic hypoplasia.29 Acute kernicterus (or ABE) can result from unmonitored or insufficiently treated progressive hyperbilirubinemia. There is growing concern that exposure to even moderate concentrations of bilirubin may also lead to isolated neurodevelopmental injury or subtle but permanent impairment known as BIND.31 The spectrum of neurologic impairment from BIND may manifest as disturbances of myriad processes, including visual-motor, auditory, speech, cognition, and language. The effect of bilirubin on neuronal differentiation and development in vitro provides biologic plausibility for the spectrum of BIND. Evidence for a causal link between hyperbilirubinemia and subtle NDI, however, is lacking at present. Also, some evidence suggests that infants may benefit from the antioxidant properties of bilirubin, making ideal management less straightforward.13,21
681
682
Wallenstein & Bhutani
CLINICAL MANIFESTATIONS OF HYPERBILIRUBINEMIA IN THE MODERATELY PRETERM INFANT
Clinical manifestations of ABE include changes in mental status, muscle tone, feeding, and pitch of cry, leading to progressive hypotonia, retrocollis, and opisthotonos. Mortality during ABE approaches 10%, usually due to respiratory failure or seizures refractory to antiepileptic administration.31 Kernicterus, which refers to permanent neurologic damage in infants who survive ABE, is characterized by chronic manifestations of the acute syndrome of ABE, including dystonia, athetoid cerebral palsy, gaze paralysis, and sensorineural hearing loss. Cognitive function may be spared, although some studies suggest otherwise.32 Clinical manifestations of ABE in preterm infants are similar to, but often more subtle than, those of term infants. Immature neuronal architecture and masking clinical conditions (eg, ventilatory support), however, often produce subtle clinical changes that make diagnosis of ABE a challenge in preterm infants. In a case series of preterm infants with kernicterus, only one-half displayed evidence of ABE, such as arching, seizures, posturing, abnormal muscle tone, or apnea/periodic breathing.19 A recent study identified 3 biomarkers (activin A, S100B protein, and adrenomedullin) for brain injury in preterm infants.33 Further characterization of these biomarkers may eventually aid in the diagnosis of ABE, although brain injury was defined broadly and was not specific to bilirubin-related injury in their study. The clinical spectrum of BIND, in which moderate elevations of bilirubin affect narrow neural pathways, has yet to be fully characterized in term and preterm populations. There is a persuasive theoretic support, however, for increased vulnerability to BIND among preterm populations. Several studies have found a dose-response relationship between bilirubin concentration and subtle neurodevelopmental outcomes, including minor motor/gait abnormalities, learning disabilities, autism, and developmental delay, among others.31,32,34–38 Some studies, however, found no relationship after controlling for confounding variables using logistic regression.39 Another recent study found no increase in minor neurologic dysfunction at 18 months of age among term infants with moderate hyperbilirubinemia, but they did find a significant association among infants with bilirubin concentrations above 330 mmol/L (19.3 mg/dL).40 To date, there is no direct causal relationship between moderate hyperbilirubinemia and neurotoxicity, but observational literature and a recent review support the spectrum of BIND and its relationship to subtle neurologic disorders associated with abnormal bilirubin-albumin binding.31 Future research is needed to confirm these relationships. CLINICAL MANAGEMENT OF HYPERBILIRUBINEMIA IN THE MODERATELY PRETERM INFANT
Management of hyperbilirubinemia in moderately preterm infants varies greatly among institutions, with little evidentiary support for these differences in management.3–5 This review outlines clinical strategies to operationalize the management of hyperbilirubinemia in moderately preterm infants to meet the recently published consensus-based recommendations.6 Technical aspects of effective phototherapy, including irradiance and light source, as well as method and risks of exchange transfusion are not reviewed here and have been the subject of several recent reports.3,41,42 Fig. 1 shows the recommended guidelines for initiation of phototherapy and exchange transfusion in preterm infants by postmenstrual age, for infants less than 35 weeks’ GA.
Jaundice and Kernicterus
Fig. 1. Suggested use of phototherapy and exchange transfusion in preterm infants less than 35 weeks’ GA. The operational thresholds have been demarcated by recommendations of an expert panel. The shaded bands represent the degree of uncertainty. Recommended thresholds to prepare for exchange transfusion assume that these infants are already being managed by effective phototherapy. Increase in exposure of BSA to phototherapy may inform the decision to conduct an exchange transfusion based on patient response to phototherapy. (Adapted from 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(9):660–4; with permission.)
Operational strategies 1. TB levels a. Fig. 1 is based on recommendations for operational or therapeutic TB threshold levels at, or above which, treatment is likely to do more good than harm.6 These TB levels are not based on high-quality evidence but on consensus expert opinion. b. Use TB measurements. Do not subtract direct-reacting or conjugated bilirubin from the TB. c. These TB thresholds reflect a degree of uncertainty for these recommendations. Clinicians should consider the lower range of the thresholds for infants at greater risk for bilirubin neurotoxicity, for example, (1) lower GA; (2) serum albumin levels or5 325 micromol/L who were born in Nova Scotia, Canada, between 1994 and 2000. Pediatrics 2008;122:119–24. 36. Good WV, Hou C. Sweep visual evoked potential grating acuity thresholds paradoxically improve in low-luminance conditions in children with cortical visual impairment. Invest Ophthalmol Vis Sci 2006;47:3220–4. 37. Boggs T, Hardy J, Frazier T. Correlation of neonatal serum total bilirubin concentration and evelopmental status at age eight months. Preliminary report from the collaborative project. J Pediatr 1967;71:553–60. 38. Maimburg RD, Bech BH, Vaeth M. Neonatal jaundice, autism, and other disorders of psychological development. Pediatrics 2010;126:872–8. 39. Croen LA, Yoshida CK, Odouli R. Neonatal hyperbilitubinemia and risk of autism spectrum disorders. Pediatrics 2005;115:e135–8. 40. Lunsing RJ, Pardoen WF, Hadders-Algra M. Neurodevelopment after moderate hyperbiliruinemia at term. Pediatr Res 2013;73:655–60. 41. Bhutani VK, Committee on Fetus and Newborn. Phototherapy to prevent severe neonatal hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2011;128:e1046–52. 42. National Institute for Health and Clinical Excellence. Neonatal Jaundice. National Institute for Health and Clinical Excellence. 2010. Available at: www.nice.org. uk/CG98. Accessed May 18, 2013.
687
688
Wallenstein & Bhutani
43. McDonagh AF, Maisels MJ. Bilirubin unbound: de´ja` vu all over again? Pediatrics 2006;117:523–5. 44. Ahlfors CE. Criteria for exchange transfusion in jaundiced newborns. Pediatrics 1994;93:488–94. 45. Lamola AA, Bhutani VK, Wong RJ, et al. Effect of hematocrit on efficacy of phototherapy for neonatal jaundice. Pediatr Res 2013;74(1):54–60.
