Risk of Autism Associated With Hyperbilirubinemia and Phototherapy

Abstract

OBJECTIVE: 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. METHODS: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. RESULTS: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. CONCLUSIONS:After adjustment for the effects of sociodemographic factors and birth weight, neither hyperbilirubinemia nor phototherapy was an independent risk factor for ASD.

Prenatal, perinatal, and neonatal risk factors of autism spectrum disorder

“…Neonatal jaundice and ASD were not associated in our adjusted model, despite research supporting the connection (8,14,28,30,34). The results mirror recent research, finding no association between ASD and hyperbilirubinemia identified by bilirubin laboratory values (40), and suggest that confounders have an impact on previous studies linking jaundice and ASD.…”

Neonatal hyperbilirubinaemia: a global perspective

“…30,54 A growing number of studies are now exploring the risk of bilirubin-induced neurotoxicity in jaundiced infants based on unbound bilirubin rather than serum/plasma bilirubin. 37,53 Few studies have associated severe jaundice with epilepsy, 30,55 while the association with autism, [56][57][58][59] and childhood asthma [60][61][62] remains a subject of ongoing investigation and debate. In one rare longitudinal study in Finland, the authors investigated the long-term impact of severe hyperbilirubinaemia (TSB ≥20 mg/dL or 342 µmol/L) on educational, occupational and social functioning in a cohort (n=128 versus 82 controls) over a 30year period.…”

Risk of autism spectrum disorder in children with a history of hospitalization for neonatal jaundice

“…However, relevant research has resulted in inconsistent findings. Some studies demonstrated that neonatal jaundice increased the risk of ASD (12)(13)(14)(15)(16)(17)(18)27), whereas others did not (19)(20)(21). A recent population-based study objecting to investigate long-term neurodevelopmental outcomes of significant neonatal jaundice reported a 1.5 to 2-times greater risk for ASD than the reference cohort (28).…”

“…Previous studies exploring the relationship between the history of neonatal jaundice and ASD have produced conflicting results. While some studies have indicated that infants who developed neonatal jaundice are subsequently at risk of ASD (13)(14)(15)(16)(17)(18), others have failed to find any significant association (19)(20)(21). Moreover, limited research has focused mainly on the association between the history of neonatal jaundice and ASD.…”