Risk of Autism Associated With Hyperbilirubinemia and Phototherapy.
Whether neonatal hyperbilirubinemia and/or phototherapy increase the risk of autism spectrum disorder (ASD) is unclear. We sought to quantify the risk of ASD associated with elevated total serum bilirubin (TSB) levels and with phototherapy.



In a retrospective cohort study of 525 409 infants born at ≥35 weeks' gestation in 15 Kaiser Permanente Northern California (KPNC) hospitals, 1995-2011, we obtained all TSB levels and determined which infants received phototherapy. From the KPNC Autism Registry, we identified patients with ASD diagnosed at a KPNC Autism Center, by a clinical specialist, or by a pediatrician. We calculated Cox proportional hazard ratios (HRs) for time to diagnosis of ASD, adjusting for confounding factors.



Among infants in the birth cohort, 2% had at least 1 TSB level ≥20 mg/dL, and 8% received phototherapy. The rate of ASD was 13 per 1000 births. Crude analyses revealed an association between TSB ≥20 and ASD (relative risk: 1.4; 95% confidence interval [CI]: 1.1-1.6), and between phototherapy and ASD (relative risk: 1.7; 95% CI: 1.5-1.8). After adjusting for confounders, TSB ≥20 (HR: 1.09; 95% CI: 0.89-1.35) and phototherapy (HR: 1.10; 95% CI: 0.98-1.24) were no longer significantly associated with ASD. Independent risk factors for ASD included maternal and paternal age; maternal and paternal higher education; male sex; birth weight <2500 g or ≥4200 g; and later year of birth.



After adjustment for the effects of sociodemographic factors and birth weight, neither hyperbilirubinemia nor phototherapy was an independent risk factor for ASD.
Departments of Neurology, wuy@ucsf.edu.|Pediatrics, and.|Division of Research, Kaiser Permanente Northern California, Oakland, California.
Yvonne W
YW
Wu
Pediatrics, and.|Division of Research, Kaiser Permanente Northern California, Oakland, California.
Michael W
MW
Kuzniewicz
Division of Research, Kaiser Permanente Northern California, Oakland, California.
Lisa
L
Croen
Division of Research, Kaiser Permanente Northern California, Oakland, California.
Eileen M
EM
Walsh
Epidemiology and Biostatistics, University of California, San Francisco, California; and.
Charles E
CE
McCulloch
Pediatrics, and.|Division of Research, Kaiser Permanente Northern California, Oakland, California.|Epidemiology and Biostatistics, University of California, San Francisco, California; and.
Thomas B
TB
Newman
D000328:Adult; D000067877:Autism Spectrum Disorder / Q000453:epidemiology*; D001663:Bilirubin / Q000097:blood; D001724:Birth Weight; D002140:California / Q000453:epidemiology; D015331:Cohort Studies; D004522:Educational Status; D005260:Female; D006801:Humans; D051556:Hyperbilirubinemia, Neonatal / Q000453:epidemiology*; D007231:Infant, Newborn; D007567:Jaundice, Neonatal / Q000628:therapy; D008297:Male; D008423:Maternal Age; D010331:Paternal Age; D010789:Phototherapy; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012307:Risk Factors; D012737:Sex Factors
D001663:Bilirubin