JAMA Pediatrics Journal Club Slides Total Serum Bilirubin

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. Copyright restrictions may apply

Introduction • 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. • 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. Copyright restrictions may apply

Methods • Study Design – Double-cohort study nested within the Late Impact of Getting Hyperbilirubinemia or Phototherapy (LIGHT) birth cohort. • Setting – Kaiser Permanente Northern California. • 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. Copyright restrictions may apply

Methods • 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. • 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. Copyright restrictions may apply

Results • 1833 of 525 409 infants (0. 3%) were exposed to ≥ 1 TSB level at or above the ETT. • Exposed infants were more likely to be male, Asian, and preterm. • 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). • Risk of CP was highest for infants with most severe elevations of TSB levels. • 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). Copyright restrictions may apply

Results Selection of Infants With CP Within the 2 Study Cohorts Copyright restrictions may apply

Results Characteristics of Infants With and Without a TSB Level Above the EET Copyright restrictions may apply

Results Risk for CP Associated With Varying Elevated TSB Levels Copyright restrictions may apply

Results • 7 infants had CP and a TSB Level Above the ETT – 3 had CP consistent with kernicterus (ie, T 2 hyperintensity in bilateral globus pallidus, and dyskinetic CP). – 4 had other causes of CP. • Incidence of CP consistent with kernicterus was 0. 57 per 100 000 births. • All 3 infants with CP consistent with kernicterus had both of the following: – TSB level >5 mg/d. L above the ETT. – ≥ 2 risk factors for neurotoxicity (ie, prematurity, glucose-6 -phosphate dehydrogenase [G 6 PD] deficiency, hypoalbuminemia, hypoxiaischemia, and/or sepsis). Copyright restrictions may apply

Results Clinical Characteristics of 7 Infants With CP Who Were Exposed to a TSB Level Above the ETT Copyright restrictions may apply

Comment • The 2004 American Academy of Pediatrics ETT guidelines effectively identified all cases of CP consistent with kernicterus in a large population. • 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). • All 3 patients with CP consistent with kernicterus had peak TSB levels >5 mg/d. L above the ETT as well as ≥ 2 neurotoxicity risk factors. • Although maximum TSB levels up to 5 mg/d. L 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/d. L above the ETT may have good outcomes precisely because they were treated and their TSB levels were prevented from increasing. Copyright restrictions may apply

Comment • 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. • Findings support the suggestion that infants with hyperbilirubinemia without neurotoxicity risk factors may have a higher tolerance than recognized in current management guidelines. • 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. Copyright restrictions may apply

Contact Information • 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 • This study was supported by grant R 01 HS 020618 from the Agency for Healthcare Research and Quality. Conflict of Interest Disclosures • Drs Wu and Newman have provided expert consultation on cases related to CP and/or kernicterus. No other disclosures were reported. Copyright restrictions may apply