Neonatal Jaundice in Association with Autism Spectrum Disorder in the Child

Background:  Several neonatal complications have been studied in association with autism spectrum disorder (ASD). The most common complication, neonatal jaundice, is inconsistently defined across studies and is also inconsistent in showing an association with ASD. However, neonatal jaundice can be indicative of high bilirubin levels that may result in neurological damage and should be appropriately investigated in association with ASD.

Objectives:  To examine associations between neonatal jaundice or hyperbilirubinemia and ASD in 2-5 year old children.

Methods: Our analysis uses the Study to Explore Early Development (SEED), a multi-site, case-control study. Children born from 2003-2006 were enrolled in SEED at 2 to 5 years of age. Developmental assessment in the clinic was used to classify children into three groups based on presence of ASD (n=702), a wide-range of non-ASD developmental delays or disorders (DD; n= 891), or non-ASD controls drawn from the general population (POP; n=983). Infants with jaundice in the first 28 days of life were identified from neonatal medical records and maternal interviews. A diagnosis was classified as definite if the infant received treatment for jaundice, as probable if there was no treatment but a diagnosis was available in the medical record, or possible if the mother reported jaundice, but there was no medical record (16%), it was not complete (19%), or it was complete but no jaundice or treatment reported (65%). Hyperbilirubinemia was classified using bilirubin levels, when available in the medical record. We examined the associations between neonatal jaundice and case status (ASD and DD groups to POP), as well as hyperbilirubinemia and case status, using adjusted multivariable logistic regression models. Odds ratios were adjusted (aOR) for sex, race/ethnicity, gestational age, maternal age, maternal education, maternal diabetes, and parity.

Results:  From a sample of 2,576, we identified 1,239 infants (48.1%) with neonatal jaundice, of which 626 (50.5%) were definite, 378 (30.5%) were probable, and 235 (19%) were possible. Of 1,419 infants born ≥35 weeks gestation with bilirubin levels available, 88 (6%) were classified as having hyperbilirubinemia (bilirubin levels in the 95^thpercentile). For neonatal jaundice in association with ASD vs. POP, we obtained an aOR=1.17 (95% confidence interval (CI) 0.93, 1.47). A slightly stronger, non-significant association with ASD vs. POP was observed for definite jaundice (aOR=1.29; 95% CI 0.95, 1.75). No associations were found for probable or possible jaundice and ASD. Significant associations were present when comparing DD vs. POP for neonatal jaundice (aOR=1.34; 95% CI 1.09, 1.65) and for definite jaundice (aOR=1.73; 95% CI 1.32, 2.27). A significant association was also observed for hyperbilirubinemia comparing DD vs. POP (aOR=1.87; 95% CI 1.03, 3.40), but non-significant comparing ASD vs. POP (aOR=1.28; 95% CI 0.65, 2.53).

Conclusions: Our results did not show a statistically significant association between neonatal jaundice and ASD or between hyperbilirubinemia and ASD. However, neonatal jaundice and hyperbilirubinemia were each significantly associated with an increased odds of DD. Further investigations are needed to confirm the association between high bilirubin levels and DD, and if there is a higher risk for any specific developmental disorder.