JAMA Pediatrics Journal Club Slides:
Total Serum Bilirubin Levels at or
Above the ETT
Wu YW, Kuzniewicz MW, Wickremasinghe AC, et al. Risk of cerebral palsy
in infants with total serum bilirubin levels at or above the exchange
transfusion threshold: a population-based study. JAMA Pediatr. Published
online January 5, 2015. doi:10.1001/jamapediatrics.2014.3036.
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Introduction
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Background
– Exchange transfusion is recommended for newborns with total
serum bilirubin (TSB) levels thought to place them at risk for
cerebral palsy (CP).
– The excess risk of CP among these infants is unknown.
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Study Objective
– To quantify the risks of CP and CP consistent with kernicterus that
are associated with high TSB levels based on the 2004 American
Academy of Pediatrics exchange transfusion threshold (ETT)
guidelines.
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Methods
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Study Design
– Double-cohort study nested within the Late Impact of Getting
Hyperbilirubinemia or Phototherapy (LIGHT) birth cohort.
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Setting
– Kaiser Permanente Northern California.
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Patients
– Two cohorts sampled from a population of all 525 409 infants born at
≥5 weeks’ gestation at Kaiser Permanente Northern California from
January 1, 1995, through December 31, 2011.
– Exposed cohort: All 1833 infants with ≥1 TSB measurement at or
above the ETT based on age at testing, gestational age, and results
of direct antiglobulin testing.
– Unexposed cohort: 20% random sample of infants with all TSB
levels below the ETT.
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Methods
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Outcomes
– CP: nonprogressive congenital motor dysfunction with hypertonia or
dyskinesia (choreoathetosis or dystonia)
– CP consistent with kernicterus: bilateral globus pallidus injury in the
setting of dyskinetic CP.
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Limitations
– Measured maximum TSB levels are only estimates of true peak levels.
– CP diagnosis relied on clinical records (ie, patients not examined for
study).
– Brain magnetic resonance imaging performed at different ages without
a standard protocol.
– Absolute risk differences for extreme levels of hyperbilirubinemia were
calculated based on small numbers of exposed infants, thus generating
wide confidence intervals.
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Results
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1833 of 525 409 infants (0.3%) were exposed to ≥1 TSB level at or above
the ETT.
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Exposed infants were more likely to be male, Asian, and preterm.
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CP diagnosed in 7 of 1833 infants (0.4%) exposed to a TSB level at or
above the ETT compared with 86 of 104 716 unexposed infants (0.1%)
(relative risk, 4.7 [95% CI, 2.2-10.0]; P < .001).
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Risk of CP was highest for infants with most severe elevations of TSB
levels.
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No difference between the degree of elevation in TSB levels above the ETT
and the peak TSB levels in ability to predict hypertonic/dystonic CP (areas
under the receiver operating characteristic curve, 0.71 vs 0.70; P = .79).
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Results
Selection of Infants With CP Within the 2 Study Cohorts
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Results
Characteristics of Infants With and Without a TSB Level Above the EET
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Results
Risk for CP Associated With Varying Elevated TSB Levels
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Results
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7 infants had CP and a TSB Level Above the ETT
– 3 had CP consistent with kernicterus (ie, T2 hyperintensity in bilateral
globus pallidus, and dyskinetic CP).
– 4 had other causes of CP.
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Incidence of CP consistent with kernicterus was 0.57 per 100 000 births.
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All 3 infants with CP consistent with kernicterus had both of the following:
– TSB level >5 mg/dL above the ETT.
– ≥2 risk factors for neurotoxicity (ie, prematurity, glucose-6-phosphate
dehydrogenase [G6PD] deficiency, hypoalbuminemia, hypoxiaischemia, and/or sepsis).
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Results
Clinical Characteristics of 7 Infants With CP Who Were
Exposed to a TSB Level Above the ETT
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Comment
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The 2004 American Academy of Pediatrics ETT guidelines effectively
identified all cases of CP consistent with kernicterus in a large population.
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Incidence of CP due to kernicterus in United States:
– Study’s estimate (0.57 per 100 000 births) falls within the range of
previously reported estimates (0.4-2.7 per 100 000 births).
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All 3 patients with CP consistent with kernicterus had peak TSB levels >5
mg/dL above the ETT as well as ≥2 neurotoxicity risk factors.
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Although maximum TSB levels up to 5 mg/dL above the ETT were almost
always benign, infants with such levels should not be excluded from
treatment. Infants with maximum TSB levels up to 5 mg/dL above the ETT
may have good outcomes precisely because they were treated and their
TSB levels were prevented from increasing.
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Comment
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CP consistent with kernicterus was rare in this modern cohort of term and
late preterm infants and did not occur in a single infant with
hyperbilirubinemia who was otherwise healthy with no neurotoxicity risk
factors present, regardless of the severity of elevation of the TSB level.
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Findings support the suggestion that infants with hyperbilirubinemia without
neurotoxicity risk factors may have a higher tolerance than recognized in
current management guidelines.
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These data, along with estimates of risks and costs of treatment, should be
considered when developing future updated guidelines for management of
jaundice in term and late preterm newborns.
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Contact Information
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If you have questions, please contact the corresponding author:
– Yvonne W. Wu, MD, MPH, Department of Neurology, University of
California, San Francisco, 675 Nelson Rising Ln, Ste 411, San
Francisco, CA 94158 (wuy@ucsf.edu).
Funding/Support
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This study was supported by grant R01HS020618 from the Agency for
Healthcare Research and Quality.
Conflict of Interest Disclosures
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Drs Wu and Newman have provided expert consultation on cases related
to CP and/or kernicterus. No other disclosures were reported.
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