The reported prevalence of autism spectrum disorder (ASD) has been rising, at least partly due to increased detection and broadened diagnostic criteria, and is now estimated at 1 in 88. ASD appears to be even more prevalent among premature infants with a reported prevalence of ~8%. Neonatal clinical factors that increase the risk among premature infants are not well studied. Neonatal unconjugated hyperbilirubinemia (jaundice) may be one such factor. Jaundice is ubiquitous among premature infants and may be associated with cerebellar, hippocampal, brainstem, and basal ganglia injury, which in turn has recently been linked to autism. Recently, neonatal jaundice, assessed using total serum bilirubin levels, was found to be associated with ASD in late preterm and term infants, but its association with ASD in premature infants remains unknown. Moreover, recent studies suggest that unbound bilirubin (bilirubin not bound to protein, UB) may be a better predictor of neurodevelopmental disorder than total serum bilirubin, but no studies have evaluated whether UB is linked to ASD. This proposal is for a two year study of premature infants d 33 weeks gestational age to evaluate association between neonatal jaundice and ASD among premature infants using UB, a better bilirubin biochemical marker of neurotoxicity. The University of Rochester Medical Center has a unique opportunity to conduct the proposed prospective observational study for the following reasons: 1) A large cohort of infants d 33 weeks gestational age and enrolled in NIH-funded bilirubin study soon after birth has consented to be prospectively followed for neurodevelopmental outcomes at a later age;2) These premature infants are actively followed for neurodevelopmental outcomes by the Neonatal Developmental Program up to 10 years of age with 90% retention;3) A database has been created with requisite maternal, pregnancy, and neonatal clinical data prospectively collected on all enrolled premature infants;4) All enrolled premature infants had prospective evaluation for jaundice using measurement of UB levels, total serum bilirubin levels, and albumin levels during the first 2 weeks after birth;5) Clinical risk factors for jaundice associated neurotoxicity has been prospectively evaluated and requisite data on risk factors has been prospectively collected on all these premature infants;and 6) The site has expertise in both neonatal jaundice and ASD diagnosis. The project will involve 470 premature infants enrolled in the bilirubin-induced neurotoxicity study and who have consented for follow-up neurodevelopmental evaluation. These infants will be screened for ASD with the SCQ and those with positive screens will complete the Autism Diagnostic Observation Schedule. Establishing the association between jaundice and ASD in high-risk premature infants will suggest one preventable etiology of ASD and will lay the foundation for preventive trials to confirm the causal association between jaundice and ASD in a larger population. Ultimately, the findings of such trial will help to improv management of jaundice with secondary reduction in ASD. Not studying this established cohort with unique information on UB will be a lost opportunity.

Public Health Relevance

Very premature infants are at increased risk for autism spectrum disorder, which is becoming recognized as one of the most frequently occurring developmental disabilities worldwide with a prevalence of 1 in 8 live births. The University of Rochester Medical Center provides a unique opportunity to evaluate the association of unconjugated hyperbilirubinemia with autism spectrum disorder, and also examine the usefulness of unbound bilirubin as a predictor of jaundice associated autism spectrum disorder in premature infants using a well defined cohort enrolled soon after birth in an NIH-funded bilirubin study and followed longitudinally for long- term neurodevelopmental outcomes. The overall findings of this study have ramifications for public health globally as it will greatly impove identification of premature infants with jaundice who are at risk for autism spectrum disorder and in need of neonatal therapeutic interventions and also help to formulate guidelines for screening and close follow-up of at risk premature infants for early identification of autism spectrum disorder which is known to enhance the effectiveness of available therapy and therefore reduce cost incurred in the treatment of autism spectrum disorder.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Exploratory/Developmental Grants (R21)
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Child Psychopathology and Developmental Disabilities Study Section (CPDD)
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Kau, Alice S
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University of Rochester
School of Medicine & Dentistry
United States
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Amin, Sanjiv B (2016) Bilirubin Binding Capacity in the Preterm Neonate. Clin Perinatol 43:241-57