Neonatal hyperbilirubinemia and autism risk (again)

Tall ships @ Paul Whiteley

The paper by Luis Lozada and colleagues [1] (open-access) brings back into focus a topic that has graced this blog before (see here) with their observation that: "Children who develop ASD [autism spectrum disorder] are more likely to have an admission with a diagnosis of jaundice in the neonatal period and more likely to require treatment for this jaundice."

Jaundice, by the way, refers to a condition marked by yellowing of the skin and eyes as a result of the build up of a compound called bilirubin. For the newborn, elevations in bilirubin can have some really negative effects when accumulating in parts of the brain.

Using a case-control study design based on data derived from the "TRICARE Management Activity’s Military Health System (MHS) database", authors set about assessing whether there was a heightened risk of autism (ASD) "among infants with a history of neonatal unconjugated hyperbilirubinemia (jaundice)." Participant numbers were in the thousands: "A total of 2917 children with ASD and 8751 matched controls were included in the study."

Using two definitions of jaundice and hence bilirubin exposure - "a diagnosis of jaundice during the hospital stay associated with birth, or during an admission within the first month of life" and/or "any phototherapy or exchange transfusion procedure in the first month of life" - authors reported that: "A history of admission with a diagnosis of neonatal jaundice was present in 640 (21.9%) of children with ASD compared with 1614 (18.4%) of controls." Further: "A procedural treatment for jaundice was documented in 107 (3.7%) of children with ASD and 221 (2.5%) of controls." On the basis of these figures and some statistical analysis, they concluded that there may be an association between bilirubin and autism (ASD). That being said, such an association was not uncomplicated. When for example, they undertook a separate analysis of those children who were born preterm - that is born before 37 weeks - the association between autism and jaundice lost its statistical significance.

These data are interesting and mirror other findings (see here) with equally large participant numbers. As the authors indicate, there are some important methodological strengths to their study that add to quality of the study findings. The one down side to the study however was the fact that the authors "did not have bilirubin levels available", so any efforts looking at "a specific dose–response relationship with ASD" are research fodder for another day.

Insofar as the possible mechanism of effect going from neonatal jaundice to autism risk, the neurotoxin angle to bilirubin is a preferred explanation for Lozada et al. As they note: "There is biologic plausibility to suggest an association between bilirubin and ASD" in terms of parts of the brain vulnerable to bilirubin toxicity and what has been identified in the large (very large) peer-reviewed literature talking about brain architecture and [some] autism. Mention is also made about the concept of BIND (bilirubin-induced neurologic dysfunction) and the possibility of an overlap with some of the core and peripheral signs and symptoms of autism.

Accepting that any link between bilirubin and autism is likely to be a complex process, the only thing I would perhaps add to speculations would be the possible intersection with the concepts of sulphation and glucuronidation - important metabolic mechanisms that have been suggested to be disrupted in some cases of autism (see here and see here respectively). I would be interested to see whether any underlying issues with such metabolic pathways might intersect with jaundice and the metabolism of bilirubin and onwards autism risk...

Music: Blackbird - The Beatles.

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[1] Lozada LE. et al. Association of Autism Spectrum Disorders With Neonatal Hyperbilirubinemia. Global Pediatric Health. 2015; 2: 2333794X15596518.

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Lozada, L., Nylund, C., Gorman, G., Hisle-Gorman, E., Erdie-Lalena, C., & Kuehn, D. (2015). Association of Autism Spectrum Disorders With Neonatal Hyperbilirubinemia Global Pediatric Health, 2 DOI: 10.1177/2333794X15596518