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

Mercury, autism and mitochondrial dysfunction?

Appreciating that to mention the words 'mercury and autism' in the same sentence can lead to furrowed brows and invoke eye-rolling in some quarters, I don't want to shy away from the results reported by Shannon Rose and colleagues [1] (open-access here) and their suggestion that: "the epidemiological link between environmental mercury exposure and an increased risk of developing autism may be mediated through mitochondrial dysfunction". Further that their result: "support the notion that a subset of individuals with autism may be vulnerable to environmental influences with detrimental effects on development through mitochondrial dysfunction."

Having previously talked about research from this group (see here) based on their examinations of lymphoblastoid cell lines (LCLs) from people with autism, their latest paper seems to be something of an extension of this project. Based on investigations on LCLs from 16 autism/control pairings, mitochondrial respiration was examined as and when said cells were exposed to ethylmercury. A subgroup of LCLs from the autism group "exhibited a greater reduction in ATP-linked respiration, maximal respiratory capacity, and reserve capacity when exposed to ethylmercury, compared to control LCLs." Interestingly, the pre-administration of NAC (N-acetlycysteine) "reduced (normalized) baseline respiratory parameters and blunted the exaggerated ethylmercury-induced reserve capacity depletion." That being said: "LCLs derived from children with autism exhibit significant abnormalities in mitochondrial respiration at baseline with these abnormalities worsening following exposure to ethylmercury" so one has to be a little guarded about making too many universal judgements.

OK. Wearing the cold, dispassionate and [hopefully] objective blinkers of science, there may be a few important implications from this work. First is the idea that for some on the autism spectrum, the puzzle that is mitochondria and mitochondrial dysfunction may require quite a bit more investigation (see here). In these days of plural autisms (see here) the focus perhaps needs to be on subgroups too. Second, as per their previous efforts in this area [2] is the idea that various factors might have the ability to impact on mitochondrial function for some people on the autism spectrum. Third, although still very much a source of deep division within the autism and wider community, the suggestion that ethylmercury (a metabolite of the preservative thiomersal / thimerosal) might have the ability to impact on mitochondrial function for at least some on the autism spectrum perhaps requires further scrutiny. I say this based on the small participant numbers included in the Rose study and their specific focus on LCLs. The doses of ethylmercury used might also require further investigation in terms of translating results from lab to real world.

Finally, the idea that pre-treatment of LCLs with NAC might carry a protective role is rather interesting. Aside from the 'oxidative stress' implications of their findings, I wonder if such an observation might also carry some link to the suggestion that post-vaccination administration of paracetamol (acetaminophen) might be 'implicated' in cases of autism [3]. I say this from a rather non-expert stance in this area but with the knowledge that paracetamol has an effect on glutathione stores under certain circumstances. Glutathione by the way, is one part cysteine and has cropped up in other autism research (see here) as well as subsequently [4]. Separately, given also that glucuronidation is a primary pathway for metabolising paracetamol and with the work from Stein and colleagues [5] in mind (see here), I wonder if there may indeed be more to see here (although accepting that there may be other effects from such antipyretic use).

This is not the first time that mitochondrial dysfunction and "impaired oxidative–reduction" have been studied from the point of view of downstream metabolites of thiomersal as per the paper by Geier and colleagues [6]. Again, the focus on that occasion was cell lines and so one has again to be a little cautious about extrapolating results beyond that. That also other research, in studies of mouse models for example [7], have not tended to support a connection between thiomersal exposure and 'neurodevelopmental disorders' is an important point to make, bearing in mind that mice are mice and not people. Similar sentiments apply to the important recent results from Curtis and colleagues [8] too.

But... the Rose findings cannot be readily dismissed particularly with their focus being potentially relevant to a subgroup of those on the autism spectrum. Adding the paper from Mady Hornig (a very well-respected researcher) into the mix (again based on mice) [9]: "Host differences in maturation, metabolism, nutrition, sex, and autoimmunity influence outcomes" when it comes to the potential of "thimerosal-related neurotoxicity" and quite a bit more research is perhaps indicated.

Music then. Bobby Womack - Across 110th Street.

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[1] Rose S. et al. Increased susceptibility to ethylmercury-induced mitochondrial dysfunction in a subset of autism lymphoblastoid cell lines. J Toxicol. 2015;2015:573701.

[2] Rose S. et al. Oxidative stress induces mitochondrial dysfunction in a subset of autistic lymphoblastoid cell lines. Transl Psychiatry. 2014 Apr 1;4:e377.

[3] Schultz ST. et al. Acetaminophen (paracetamol) use, measles-mumps-rubella vaccination, and autistic disorder: the results of a parent survey. Autism. 2008 May;12(3):293-307.

[4] Abdel-Salam OME. et al. Nuclear Factor-Kappa B and Other Oxidative Stress Biomarkers in Serum of Autistic Children. OJMIP. 2015; 5: 1.

[5] Stein TP. et al. Bisphenol A Exposure in Children With Autism Spectrum Disorders. Autism Research. 2015. Jan 13.

[6] Geier DA. et al. Mitochondrial dysfunction, impaired oxidative-reduction activity, degeneration, and death in human neuronal and fetal cells induced by low-level exposure to thimerosal and other metal compounds. Toxicol Environ Chem. 2009 Jun;91(3-4):735-749.

[7] Berman RF. et al. Low-level neonatal thimerosal exposure: further evaluation of altered neurotoxic potential in SJL mice. Toxicol Sci. 2008 Feb;101(2):294-309.

[8] Curtis B. et al. Examination of the Safety of Pediatric Vaccine Schedules in a Non-Human Primate Model: Assessments of Neurodevelopment, Learning, and Social Behavior. Environ Health Perspect. 2015. Feb 18.

[9] Hornig M. et al. Neurotoxic effects of postnatal thimerosal are mouse strain dependent. Mol Psychiatry. 2004 Sep;9(9):833-45.

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Rose, S., Wynne, R., Frye, R., Melnyk, S., & James, S. (2015). Increased Susceptibility to Ethylmercury-Induced Mitochondrial Dysfunction in a Subset of Autism Lymphoblastoid Cell Lines Journal of Toxicology, 2015, 1-13 DOI: 10.1155/2015/573701

Bisphenol A Exposure in Children With Autism

The paper by T. Peter Stein and colleagues [1] suggesting an "association" between BPA (Bisphenol-A) and autism spectrum disorder (ASD) was always bound to create some interest. Reporting results based on the analysis of urine samples from a group of children diagnosed with an autism spectrum disorder (ASD) (n=46) compared to controls (n=52), authors concluded that: "there is an association between BPA and ASD." Association... note that word.

C'mon. Let's go see how much
we're going for on eBay

BPA has been around for quite a few years. An important chemical in the production of certain plastics and resins, in more recent times quite a volume of science has suggested that caution should be applied to the use of and exposure to BPA particularly with reference to its potential estrogenic properties [2]. As with everything in life, the effects or not of BPA continue to be the source of some discussion, with concerns even been raised about the alternatives to BPA (see here) being put forward. In short, it's very, very complicated.

Stein and colleagues started from the premise that: "The major pathway for BPA metabolism and excretion is via glucuronidation." Glucuronidation involves the addition of glucuronic acid to a particular metabolite thus aiding the removal of said metabolite from the body. Those of you who have come across the whole sulphation and autism story might remember how glucuronidation and sulphation share some history with [some] autism in mind as per papers like the one from Alberti and colleagues [3]. Stein et al have some research form when it comes to glucuronidation and autism as per papers such as this one [4] (open-access) that concluded that: "The glucuronidation pathway may differ in some children with ASD." They reported lower levels of glucuronidation which impacted on the metabolism of phthalates among other things (see here).

Anyhow, the analytical weapon of choice in the BPA-autism study by Stein et al was mass spectrometry (MS). Again, this research group have some interest/experience in this area as per other research of theirs which has crossed my blogging path (see here). Looking at those urine samples from participants with ASD vs asymptomatic controls, researchers reported a few important details including that: "about 20% of the ASD children had BPA levels beyond the 90th percentile (>50 ng/mL) of the frequency distribution for the total sample of 98 children." They also reported "significant differences (P < 0.05) between the groups in total and % bound BPA" (bound BPA referring to BPA glucuronide). Reiterating their conclusion: "The results suggest there is an association between BPA and ASD."

Bearing in mind how the word 'chemical' has been mis-represented down the years, there is quite a body of work emerging suggestive that there is quite a bit more to do when it comes to environmental exposures potentially linking into at least some cases of autism. This is not the first time that BPA has been examined with autism in mind as per discussions like the one from de Cock and colleagues [5] and some animal model work such as that from Wolstenholme et al [6]. The paper from Kaur and colleagues [7] suggesting that: "BPA may act as an environmental risk factor for autism in genetically susceptible children by inducing oxidative stress and mitochondrial dysfunction" offers some tantalising areas of further research tallying with other non-autism research [8]. I might also bring your attention to the paper by Lichtensteiger and colleagues [9] (thanks to @autismepi) perhaps providing another important area for further research.

Further study is of course implied from the Stein work and other research in this area. That and quite a bit more investigation of the biological systems implicated in any effect from BPA on cases of autism brings the focus back to a model of genes and environment [variably] interacting on the very wide autism spectrum...

Music: Madonna - Papa Don't Preach. Well, preaching is what we do best!

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[1] Stein TP. et al. Bisphenol A Exposure in Children With Autism Spectrum Disorders. Autism Research. 2015. Jan 13.

[2] Sharpe RM. Is it time to end concerns over the estrogenic effects of bisphenol A? Toxicol Sci. 2010 Mar;114(1):1-4.

[3] Alberti A. et al. Sulphation deficit in "low-functioning" autistic children: a pilot study. Biol Psychiatry. 1999 Aug 1;46(3):420-4.

[4] Stein TP. et al. Autism and Phthalate Metabolite Glucuronidation. J Autism Dev Disord. Nov 2013; 43(11): 2677–2685.

[5] de Cock M. et al. Does perinatal exposure to endocrine disruptors induce autism spectrum and attention deficit hyperactivity disorders? Review. Acta Paediatr. 2012 Aug;101(8):811-8.

[6] Wolstenholme JT. et al. Gestational exposure to low dose bisphenol A alters social behavior in juvenile mice. PLoS One. 2011;6(9):e25448.

[7] Kaur K. et al. Bisphenol A induces oxidative stress and mitochondrial dysfunction in lymphoblasts from children with autism and unaffected siblings. Free Radic Biol Med. 2014 Nov;76:25-33.

[8] Veiga-Lopez A. et al. Impact of Gestational Bisphenol A on Oxidative Stress and Free Fatty Acids: Human Association and Interspecies Animal Testing Studies. Endocrinology. 2015. Jan 20.

[9] Lichtensteiger W. et al. Differential Gene Expression Patterns in Developing Sexually Dimorphic Rat Brain Regions Exposed to Anti-androgenic, Estrogenic, or Complex Endocrine Disruptor Mixtures: Glutamatergic Synapses as Target. Endocrinology. 2015 Jan 21: en20141504.

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Stein, T., Schluter, M., Steer, R., Guo, L., & Ming, X. (2015). Bisphenol A Exposure in Children With Autism Spectrum Disorders Autism Research DOI: 10.1002/aur.1444

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.

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[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.

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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