Sunday, 11 May 2014

Neonatal jaundice and risk of autism?

The research of Mu-Hong Chen and colleagues from Taiwan appears on this blog quite a bit. Regular readers may already have read about the work of this group looking at various aspects on and around autism including the association with allergic and autoimmune conditions (see here) and the possibility of a link between asthma and ADHD (see here). Much of the strength of the data and results produced by this group lies in their examination of the National Health Insurance Research Database (NHIRD) which covers a large proportion of the Taiwanese population. Big data in action you might say, bearing in mind correlation and causation are not the same thing.

Chen Chengpo @ Wikipedia 
A further publication by Chen and colleagues [1] adds to the research collection from this group and their suggestion that: "Newborn exposure to hyperbilirubinemia was related to the increased risk of developing ASD [autism spectrum disorder], any developmental delay, and developmental speech or language disorder in later life". This conclusion was reached on the basis of an examination of some 2000 newborns presenting with neonatal jaundice compared with over 8000 matched controls without, following up on the subsequent rates of autism and other developmental diagnoses such as ADHD et al. Aside from the autism correlation, the authors also reported that phototherapy - treatment with light for newborn jaundice - was probably not going to be a significant factor in the suggested relationship. Just in case you need some more background about jaundice, I might refer you to quite a good, quite recent, overview (see here).

Hyperbilirubinemia leading to jaundice has been talked about a while back on this blog (see here). Since that post in early 2011, several other papers have been published which, on the whole, have suggested that jaundice might indeed be something to look at with autism risk in mind. The systematic review from Amin and colleagues [2] is quoted as suggesting: "jaundice, assessed by total serum bilirubin (TSB), was associated with ASD" based on data from several other research reports. Further, Mamidala and colleagues [3] reported that based on their analysis of pregnancy and birth-related variables in relation to autism offspring risk, the presence of neonatal jaundice was one of the more marginally significant associations found in their cohort. Even further, Froehlich-Santino and colleagues [4] talked about neonatal jaundice and autism risk in the context of sex differences: "jaundice was associated with an increased risk for ASDs in females".

Bearing in mind that not every study has reported a connection between neonatal jaundice and autism, or at least neonatal hyperbilirubinemia [5] and the quite high frequency of jaundice in newborns present in the population as a whole, one needs to treat any association with a degree of caution. That being said, data is data and results are results so some further inspection is perhaps indicated in this area.

When I posted the details of the Chen study to Facebook, it led to an interesting stream of comments and discussions about the meaning of the jaundice correlation and how it may play into some other areas in relation to autism. The genetic condition Gilbert's syndrome was mentioned as a function of jaundice being a primary manifestation there. This fairly common condition, affecting between 5-10% of the population, is not life-threatening (indeed might even be protective against the risk of other conditions). I was particularly interested in some of the biochemistry behind Gilbert's syndrome and the suggestion that the process of glucuronidation is affected in cases [6]. It jogged my memory of a recent post where I discussed the work of Stein and colleagues [7] and how reduced glucuronidation was observed in their cohort of children with autism, suggesting that sulphation might not be the only pathway with an autism connection.

Another commentator also posted an interesting question about how neonatal jaundice might also tie into the practice of breastfeeding and subsequently impact on autism risk. Just so you know, breastmilk jaundice is a recognised entity and is thought to be due to either inadequate milk intake leading to dehydration or components of breastmilk affecting the metabolism of bilirubin [8]. The discussion led to the paper by Mary Clark [9] and her opening line: "Breastfed infants are more likely to be jaundiced than infants who are formula fed" which subsequently led to the question: "does that mean that breastfeeding causes autism?". Now, I don't want to venture too far into the issue of 'bitty' and autism (see here) or make any sweeping generalisations about what may or may not be associated with the onset of autism but do feel that this question warrants more research attention. I note the paper from Al-Farsi and colleagues [10] who reported an "increased ASD risk is generally associated with suboptimal breast-feeding practices" and that's all I'm going to say on the matter at present.

If there is some take-home message from this post, it is that alongside the body of literature talking about the potential adverse effects of neonatal jaundice, hyperbilirubinemia [11] even in the very long term [12] it would perhaps be wise not to overlook some effect yet falling into the description of the autism spectrum, with the requirement for quite a bit more investigation.

Music then... since we are almost there, Summertime by Ella and Louis, best enjoyed looking out onto a sunny meadow sipping something cold and chatting about Eurovision.


[1] Chen M-H. et al. Is neonatal jaundice associated with autism spectrum disorder, attention deficit hyperactivity disorder, and other psychological development? A nationwide prospective study. Res Autism Spec Disord. 2014; 8: 625-632.

[2] Amin SB. et al. Is neonatal jaundice associated with Autism Spectrum Disorders: a systematic review. J Autism Dev Disord. 2011 Nov;41(11):1455-63.

[3] Mamidala MP. et al. Prenatal, perinatal and neonatal risk factors of Autism Spectrum Disorder: a comprehensive epidemiological assessment from India. Res Dev Disabil. 2013 Sep;34(9):3004-13.

[4] Froehlich-Santino W. et al. Prenatal and Perinatal Risk Factors in a Twin Study of Autism Spectrum Disorders. J Psychiatr Res. 2014. March 29.

[5] Croen LA. et al. Neonatal hyperbilirubinemia and risk of autism spectrum disorders. Pediatrics. 2005 Feb;115(2):e135-8.

[6] de Morais SM. et al. Decreased glucuronidation and increased bioactivation of acetaminophen in Gilbert's syndrome. Gastroenterology. 1992 Feb;102(2):577-86.

[7] Stein TP. et al. Autism and phthalate metabolite glucuronidation. J Autism Dev Disord. 2013 Nov;43(11):2677-85.

[8] Hargreaves T. & Piper RF. Breast Milk Jaundice. Arch Dis Child. Apr 1971; 46(246): 195–198.

[9] Clark M. Clinical update: understanding jaundice in the breastfed infant. Community Practitioner. 2013; 86: 42-45.

[10] Al-Farsi YM. et al. Effect of suboptimal breast-feeding on occurrence of autism: a case-control study. Nutrition. 2012 Jul;28(7-8):e27-32.

[11] Seidman DS. et al. Neonatal hyperbilirubinemia and physical and cognitive performance at 17 years of age. Pediatrics. 1991 Oct;88(4):828-33.

[12] Hokkanen L. et al. Adult neurobehavioral outcome of hyperbilirubinemia in full term neonates-a 30 year prospective follow-up study. PeerJ. 2014 Mar 4;2:e294.

---------- Chen, M., Su, T., Chen, Y., Hsu, J., Huang, K., Chang, W., Chen, T., & Bai, Y. (2014). Is neonatal jaundice associated with autism spectrum disorder, attention deficit hyperactivity disorder, and other psychological development? A nationwide prospective study Research in Autism Spectrum Disorders, 8 (6), 625-632 DOI: 10.1016/j.rasd.2014.03.006