Maternal prenatal acetaminophen use and the risk of ADHD in offspring (again)

By discussing the findings - meta-analysis findings - published by Xiaoyun Gou and colleagues [1] I once again approach the topic of whether some medicines use during pregnancy might have some important implications for offspring development. And yet again we're talking about the use of acetaminophen a.k.a paracetamol, during pregnancy and how it *might* have some important implications when it comes to offspring development (see here and see here and see here for other blogging examples on this subject).

The Gou study focused on the risk of an offspring diagnosis of attention-deficit hyperactivity disorder (ADHD) following maternal exposure to paracetamol during pregnancy. And whether timing of said exposure and/or duration of exposure showed any *association* to risk of offspring ADHD.

As per the opening sentence to this post, the Gou study was a meta-analysis, meaning that it was a synthesis of the available peer-reviewed research literature. Indeed, authors identified 8 studies published up to November 2018 that included data on nearly a quarter of a million participants in total.

Given the quite consistent consensus already seen in the science on this topic (see here for example) it's probably not unexpected that that authors concluded that: "Maternal exposure to acetaminophen during pregnancy increased the risk of attention deficit/hyperactivity disorder in offspring with a pooled adjusted risk ratio of 1.25." Further: "Children exposed prenatally to acetaminophen in the third trimester seemed to have the greatest risk of developing attention deficit/hyperactivity disorder" and "a longer duration of maternal acetaminophen use during pregnancy was correlated with a higher risk ratio."

Of course such findings, even such meta-analysis findings, come with cautions about correlation not necessarily being the same as causation given the observational nature of the studies included for review. There are also a myriad of other potential factors that seemingly impact on offspring risk for ADHD (see here and see here for some other possible examples) which perhaps require consideration at the same time.

But... this is a topic that requires a lot more investigation. Investigations into whether (a) the association is indeed a real one and not just epiphenomenal, (b) the reasons leading to paracetamol use during pregnancy which may also exert an effect on offspring risk, and (c) which biological mechanisms may be pertinent to any connection (see here and see here), are all indicated. As for where medical opinion stands on this topic at the moment, well, minus any medical or clinical advice from me, I go with the research literature on this topic [2] and would suggest that if you're in doubt, talk to your medical professional...

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[1] Gou X. et al. Association of maternal prenatal acetaminophen use with the risk of attention deficit/hyperactivity disorder in offspring: A meta-analysis. Aust N Z J Psychiatry. 2019 Jan 17:4867418823276.

[2] Andrade C. et al. Use of acetaminophen (paracetamol) during pregnancy and the risk of attention-deficit/hyperactivity disorder in the offspring. J Clin Psychiatry. 2016 Mar;77(3):e312-4.

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On postpartum paracetamol metabolites and risk of offspring ADHD: details matter

The findings reported by Yuelong Ji and colleagues [1] provide the blogging fodder today, as once again the topic of acetaminophen (a.k.a paracetamol) use during pregnancy and offspring risk of attention deficit hyperactivity disorder (ADHD) is in the spotlight. I say 'once again' because this topic has cropped up time and time again on this blog (see here for example).

On this research occasion, the starting point was the Boston Birth Cohort (a cohort that has been mentioned before) and specifically, an analysis of "maternal plasma acetaminophen metabolites levels measured within a few days after delivery and ADHD diagnosis in the offspring" as a measure of paracetamol exposure. The metabolites in question were "unchanged acetaminophen, acetaminophen glucuronide, and 3-(N-Acetyl-l-cystein-S-yl) acetaminophen." All were measured in blood plasma using one of the gold-standard chemical analytical techniques: mass spectrometry. A diagnosis of ADHD was extracted from medical records on the basis of ICD-9 and/or ICD-10 definitions.

Results: taking into account other potential confounding variables, authors reported finding "a significant positive association between maternal blood acetaminophen metabolite levels measured within 1–3 days postpartum and ADHD diagnosis in offspring." It's perhaps however important to understand how such a finding was arrived at, bearing in mind that ADHD was not the only diagnostic fruit examined in the Ji study. So: "The main exposures analyzed in this study were maternal acetaminophen metabolite levels, which were inverse normal transformed to approximate the normal distribution." What this means is that rather than reporting the specific levels of each paracetamol metabolites across different diagnoses and a 'neurotypical group' ("Children without any diagnosis of ASD [autism spectrum disorder], ADHD, developmental delays, or intellectual disabilities were classified as neurotypical (NT)"), authors chose to covert the raw values into groupings. Groupings were based around "no detection, below median, above median of detected values." I'm not altogether sure that this is the best way to report results; certainly I would have liked to have seen the raw values for each metabolite according to group as a comparator; but that's just my research preference. Researchers mention that they did not see any association between paracetamol metabolites and any other diagnostic label, and also stressed how the association remained when other potentially confounding variables were taken into account. And when it comes to ADHD, there are a few (see here for example).

How much weight can we give these results? Well, this is probably the first time that someone has looked at actual paracetamol metabolites in mums rather than just relying on maternal or doctor records of paracetamol usage during pregnancy, and that's a good thing. Authors also mention that their study was "further strengthened by the diagnosis of ADHD by both general pediatricians and developmental specialists." Add in the prospective design of the study, and you have some potentially important evidence for a *relationship* between paracetamol use and subsequent offspring development.

But... "this study only included a one-time measurement of maternal acetaminophen metabolite levels within 1–3 days postpartum." The authors rightly acknowledge that paracetamol is pretty quickly metabolised in the body so, at best, their study really only looked at recent paracetamol use immediately during or after birth. Maybe further study of archived samples during pregnancy (at multiple points during pregnancy) would provide some further information? And comments from the authors like "women with detectable levels of acetaminophen biomarkers are likely to be more regular users" really don't have any place in a scientific paper without supporting evidence. Particularly when pain relief is going to be pretty important when it comes to the process of childbirth.

Also: "our metabolite measurement method did not include acetaminophen sulfate, which accounts for 30–44% of the total metabolites of acetaminophen under the normal dosage." I don't want to go into the nitty-gritty of paracetamol metabolism, but just going back to the research looking at sulphation (sulfation) in the context of autism (see here), it would have been useful to examine both paracetamol sulphate and paracetamol glucuronide at the same time. Certainly it would have provided a more complete picture of typical paracetamol metabolism.

Don't get me wrong, I am interested in the Ji findings and their addition to the literature on paracetamol use and offspring outcomes. This still remains an important area of investigation. I'm not however completely convinced that the evidence presented by Ji and colleagues counts as particularly strong evidence despite the important measurement of paracetamol metabolites in this context...

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[1] Ji Y. et al. Maternal Biomarkers of Acetaminophen Use and Offspring Attention Deficit Hyperactivity Disorder. Brain Sci. 2018 Jul 3;8(7). pii: E127.

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Pregnancy exposure to paracetamol and offspring developmental outcomes meta-analysed

Yes, I'm yet again talking about pregnancy paracetamol (acetaminophen) use and offspring developmental outcomes on this blog (see here and see here for other discussions on this topic). As I mentioned on another recent blogging occasion, the news regarding pregnancy paracetamol use and offspring outcomes seems to be getting worse and worse, as associations galore keep appearing in the peer-reviewed science arena. Of course one has to be a little cautious about the nature of the studies that are emerging (i.e. observational, not readily designed to look at 'cause-and-effect') but the volume of research is growing at a significant pace potentially suggestive of something to see.

Now we have the results of a "Systematic Review, Meta-Analysis, and Meta-Regression Analysis of Cohort Studies" published by Reem Masarwa and colleagues [1] on the topic of pregnancy paracetamol use and "the risk for attention deficit hyperactivity disorder (ADHD) and autistic spectrum disorder (ASD) in the offspring of women exposed to acetaminophen during pregnancy." All that meta-analysis stuff means that authors boiled down the current, existing peer-reviewed research into some sort of coherent whole. Their paper also comes complete with some lay media attention too (see here).

The findings? Well, taking into account various studies published "up to January 2017" and including some "132,738 mother and child pairs and with a follow-up period of 3-11 years", you probably won't be surprised to here that prolonged paracetamol use during pregnancy did seem to increase the risk of ADHD and/or autism in offspring to the tune of about 20-30% compared with those who did not take such medicine during pregnancy. That's not an unimportant percentage in anyone's book.

Reiterating the observational nature of the studies reviewed and boiled down (in a statistical sense) by Masarwa et al and the need for further investigations on things like possible mechanisms and indeed, whether the conditions for which paracetamol as pain relief was being taken *might* exert an effect on offspring risk, the results add to the concern. Much like other areas where various pregnancy medications are seemingly being implicated in relation to offspring outcome (see here and see here) such findings reiterate the importance of the nine months that made us and the need for much more sound research on this topic...

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[1] Masarwa R. et al. Prenatal Exposure to Acetaminophen and Risk for Attention Deficit Hyperactivity Disorder and Autistic Spectrum Disorder: A Systematic Review, Meta-Analysis, and Meta-Regression Analysis of Cohort Studies. American Journal of Epidemiology. 2018. April 24.

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ALSPAC examines... pregnancy risk factors and oppositional-defiant disorder (ODD) and conduct disorder

ALSPAC mentioned in the title of this post refers to the Avon Longitudinal Study of Parent and Children, something of quite a regular feature on this blog by all accounts (see here and see here for examples). On this blogging occasion, I'm talking about ALSPAC in relation to the research paper published by I. Hyun Ruisch and colleagues [1] who reported that: "Common and potentially preventable pregnancy risk factors were independently related to both offspring ODD [oppositional-defiant disorder] and CD [conduct disorder] symptomatology in children from the general population."

ODD and CD represent a couple of the most prevalent 'disruptive behavioural' conditions seen nowadays. Whilst subtly different from one and another both in scope and severity, both represent conditions where control and in particular, self-control in accordance with cultural rules and norms, is perhaps not as it should be. I've mentioned one or other of these conditions in previous posts on this blog (see here for example) and the heightened risk of future adverse outcomes seemingly associated with them.

As with many (nay, all) behavioural and psychiatric conditions, science is still at a bit of a loss as to how they come about, accepting that they all probably [variably] include genetic and non-genetic factors working differently in different people. Ruisch et al set about utilising data from ALSPAC to ascertain if and whether "a broad range of pregnancy factors" might play some [statistically significant] role. Their results are quite revealing...

So: "Higher ODD symptom scores were linked to paracetamol use... and life events stress... during pregnancy." Further: "Higher CD symptom scores were linked to maternal smoking..., life events stress... and depressive symptoms... during pregnancy."

It should be noted that ODD and CD symptoms scores were gathered via the Development and Well-Being Assessment (DAWBA) as per other ALSPAC research occasions (see here). Researchers also quizzed both mothers and teachers of their children; thus providing two potentially different snapshots of functioning and their related factors.

In relation to that sentence on "Common and potentially preventable pregnancy risk factors were independently related to both offspring ODD and CD symptomatology in children" my eye was immediately drawn to two variables reported as being connected to said diagnoses: pregnancy paracetamol use and maternal smoking; both of which have appeared with increasing regularity in relation to adverse offspring developmental outcomes.

First, paracetamol also known as acetaminophen to our cousins across the Pond and other parts of the world. What can I say? It seems to be going from bad to worse for this go-to over-the-counter medicine with regards to pregnancy use *associations* and offspring developmental factors (see here). Yes, I appreciate that more studies need to be done on the possible pregnancy effects of this medicine, but the emerging peer-reviewed science is starting to look quite consistent. And many of the studies pointing the finger at paracetamol, like ALSPAC, are not to be under-estimated in size or power...

Second, maternal tobacco smoking during pregnancy. Again, something that has been talked about before on this blog (see here) in the context of related clinical labels. We can't yet say that 'pregnancy smoking causes offspring CD' because proof of cause-and-effect are rarely established by such observational studies. But much like the paracetamol story, the data is becoming more and more consistent for a possible effect of pregnancy smoking on child development. And for various other reasons, smoking during pregnancy is generally not thought of being a great thing for the developing child.

More investigations are indicated but clues are starting to emerge.

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[1] Ruisch IH. et al. Pregnancy risk factors in relation to oppositional-defiant and conduct disorder symptoms in the Avon Longitudinal Study of Parents and Children. J Psychiatr Res. 2018 Feb 23;101:63-71.

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More bad news for pregnancy paracetamol use?

An article in Medical News Today titled: "Is acetaminophen really safe in pregnancy?" caught my attention recently. Highlighting various recent peer-reviewed research suggesting that pregnancy paracetamol (acetaminophen) use seems to carry some *elevated risk* for quite a few potential adverse events for offspring, the *correlation* news just seems to be getting worse for this go-to over-the-counter painkiller and fever-reducer (see here and see here).

The Medical News Today article highlights a few studies but I want to focus on one in particular, by Carl-Gustaf Bornehag and colleagues [1], which suggested that risk of language delay in female offspring *might* show some correlation with early pregnancy paracetamol use.

Based on data derived from the SELMA study (Swedish Environmental Longitudinal, Mother and child, Asthma and allergy [2]), an important initiative that has already produced quite a bit of data (see here), researchers looked at "prenatal APAP [acetyl-para-aminophenol a.k.a paracetamol] exposure in relation to language development in offspring at 30 months of age." Data from over 750 women were garnered; covering both maternal report on paracetamol usage between conception and enrolment on the study (between 8-13 weeks of pregnancy) and "APAP urinary concentration at enrollment." Yes, this study did actually test for paracetamol [metabolite] concentration(s) in urine during the early stages of pregnancy. Such data was analysed in the context of offspring language development around 30 months of age via a nurse's assessment and parental report on "the number of words the child used (<25, 25–50 and >50)."

Results: paracetamol usage during conception/early pregnancy was not uncommon (around 60% of mothers reported this). Nothing particularly shocking there. Also: "APAP was measurable in all urine samples and urinary APAP was correlated with the number of APAP taken during pregnancy (P < 0.01)." Some good news there that maternal reports of paracetamol usage seemed to correlate pretty well with the measured values of paracetamol metabolites in the urine samples analysed.

Then, although language delay - "parental report of use of fewer than 50 words, termed language delay (LD)" - was present in about 1 in 10 children with a characteristic male bias (see here), female offspring born to mothers reporting paracetamol usage more than six times during early pregnancy were approximately six times more likely to show such language delay than those reporting no paracetamol usage. In effect, the female advantage over males when it came to reported language delay disappeared when paracetamol use was put into the clinical picture. Further: "The OR [odds ratio] for LD in girls whose mothers’ urinary APAP was in the highest compared to the lowest quartile was 10.34 (95% CI 1.37–77.86)." Those girls born to mums with the highest urinary concentrations of paracetamol metabolites, compared with those born to those with some of the lowest levels, seemed also to be at greater risk of language delay.

The authors themselves note that independent replication of their results is required before any grand claims are made. Alongside more formal assessment for something like language delay, I'd also like to see how some of the other metabolites measured for [3] in the SELMA initiative (there we quite a few) might also impact on their conclusions too; particularly in the context of endocrine disrupting chemicals being noted in other studies of paracetamol - offspring development (see here). Further investigation is also required on the 'whys' of paracetamol use in the context of pregnancy: does higher use of something like paracetamol perhaps indicate that some underlying issue that is being 'treated' by such use might also/instead be correlated with offspring developmental outcomes? Pain, fever or something else?

As you can see, the Bornehag study is interesting but not without flaws. Still, set within the rising tide of peer-reviewed research talking about potential issues associated with pregnancy use (excessive use?) of paracetamol and offspring outcomes [4], it's not however something that can be easily ignored...

And whilst we're on the topic of paracetamol, I also recently came across the paper by Abdulaziz Saeedan and colleagues [5] talking about testing the hypothesis that "paracetamol (PCM) can precipitate autistic like features when used to counteract vaccine-induced fever using experimental rat pups." I know (a) this takes us into a 'hot potato' area and (b) this is a study on rats, but set against work from other authors discussing a potential role for post-vaccine paracetamol use in the context of 'risk' of autism [6], such findings also perhaps offer a few further ideas for experimental study.

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[1] Bornehag C-G. et al. Prenatal exposure to acetaminophen and children's language development at 30 months. European Psychiatry. 2018. Jan 10.

[2] Bornehag C-G. et al. The SELMA study: a birth cohort study in Sweden following more than 2000 mother-child pairs. Paediatr Perinat Epidemiol. 2012 Sep;26(5):456-67.

[3] Bornehag C-G. The SELMA study, a longitudinal study following 2,000 mother-child pairs from early pregnancy over birth and up in school age. Environ Health Perspectives. 2013: 5824: S-2-35-05.

[4] Bauer AZ. et al. Prenatal paracetamol exposure and child neurodevelopment: A review. Horm Behav. 2018 Jan 13. pii: S0018-506X(17)30454-3.

[5] Saeedan AS. et al. Effect of early natal supplementation of paracetamol on attenuation of exotoxin/endotoxin induced pyrexia and precipitation of autistic like features in albino rats. Inflammopharmacol. 2018. Jan 11.

[6] 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.

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MoBa does... prenatal exposure to acetaminophen and offspring ADHD risk

MoBa mentioned in the title of this post refers to the Norwegian Mother and Child Cohort Study, an initiative that has figured quite a few times on this blog (see here and see here and see here for examples).

This time around [1] scientific attention turned to a question of growing research importance: does acetaminophen - paracetamol to us here in Blighty - use during pregnancy affect the risk of offspring being diagnosed with attention-deficit hyperactivity disorder (ADHD)? The data thus far on the issue of this pain-relieving, antipyretic medicine and offspring health has been discussion-provoking to say the least (see here and see here)...

The findings reported by Eivind Ystrøm and colleagues [1] are based on observations for over 100,000 offspring "including 2246 with ADHD." Both "maternal use of acetaminophen during pregnancy and... paternal use before pregnancy" were included in the statistical mix designed to estimate "hazard ratios (HRs) for an ADHD diagnosis."

The results were not exactly unexpected given what has gone on before in this area of investigation. Acetaminophen use was pretty widespread across all pregnancies; approximately 50% of mums had used it at some point. Short-term use during pregnancy - less than 8 days - actually correlated with a decreased risk of offspring ADHD according to the Ystrøm findings. More chronic use of the medicine however - "more than 29 days of maternal acetaminophen use" - showed an opposite relationship, yielding something like a 200% increase in offspring ADHD "even after adjusting for indications of use, familial risk of ADHD, and other potential confounders."

Alongside the suggestion that short-term paracetamol use was associated with a decreased risk for offspring ADHD was another 'make you think' finding: "Paternal and maternal use of acetaminophen were similarly associated with ADHD." Here, a father's use of paracetamol a month or so before conception seemed also to affect the risk for offspring ADHD too. In some media interest on this paper, the authors speculate "that "it could be that fathers who use a lot of acetaminophen have a higher genetic risk for ADHD" or that long-term use of the medicine might lead to changes in sperm." I might add that given the focus on paracetamol as a pain-relieving medicine, the topic of pain and ADHD is already something present in the peer-reviewed science domain (see here). Further research is called for in an accompanying editorial on the Ystrøm paper by Mark Wolraich [2] noting the benefits of using 'big data' from initiatives such as MoBA.

Accepting that the Ystrøm results suggest correlation and not necessarily causation, not everyone has been overwhelmed by the findings. I note in that lay media piece about the research, a few critical voices have suggested that "children diagnosed with ADHD by codes in their medical records" is no substitute for the real 'diagnostic' thing. Personally, I don't see this argument as being particularly valid as anyone that reads anything about MoBA would probably realise. Scandinavian countries and their population databases have some of the best collected and kept databases in the world in terms of reliability and applicability of population health data and statistics. A quick check on PubMed regarding the amount of peer-reviewed data that has been generated from MoBA for example, illustrates that point well.

Perhaps a more pertinent issue is the question of whether longer-term use of paracetamol during pregnancy could denote a more serious underlying maternal illness/injury which might have a more powerful effect on the risk of offspring ADHD than medicine use itself. This is a similar sort of argument to that put forward in relation to pregnancy antidepressant use and various offspring outcomes detailed in the research literature (see here) and similarly, is not something that can be answered by study designs such as those used by Ystrøm.

But then other the questions arise: 'Is paracetamol use during pregnancy safe?' 'How much is safe?' and 'What are the alternatives?' At this point I'm going to stand back and say little more given my blogging caveats of no medical and/or clinical advice given or intended. I will refer you to some current opinion on this topic provided in the peer-reviewed domain [3] alongside suggesting that more large and smaller-scale investigations are required, including that on 'adjacent' diagnoses in relation to pregnancy paracetamol use too (see here)...

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[1] Ystrøm et al. Prenatal Exposure to Acetaminophen and Risk of ADHD. Pediatrics. 2017. Oct 30.

[2] Wolraich ML. An Association Between Prenatal Acetaminophen Use and ADHD: The Benefits of Large Data Sets. Pediatrics. 2017. Oct 30.

[3] Andrade C. et al. Use of acetaminophen (paracetamol) during pregnancy and the risk of attention-deficit/hyperactivity disorder in the offspring. J Clin Psychiatry. 2016 Mar;77(3):e312-4.

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Paracetamol for fever 'associated' with autism?

"In this study, we again show that acetaminophen use is associated with ASD [autism spectrum disorder]."

That was one of the results reported by Stephen Schultz & Georgianna Gould [1] (open-access available here) as part of their survey of the US "National Database for Autism Research (NDAR) of the National Institute of Mental Health (NIMH)" looking at "whether ASD is associated with acetaminophen use." Acetaminophen by the way, is another name for paracetamol, the over-the-counter pain relief medication that is going through some turbulent times at the moment (see here for example).

Shultz & Gould - one of whom has some research form in this area [2] - eventually relied on information for 118 children diagnosed with an ASD and 79 'non-ASD' children with an average age of about 11 years old. The sorts of data they looked at surrounded the parental choice of medication to treat fevers (I think) including whether paracetamol, ibuprofen or aspirin were used. I have to say that the authors could have made the methodology behind their analysis a little bit clearer in terms of how the questions were posed and to whom rather than just referring to another study with regards to participant selection for example. I had to go fishing for various details which is guaranteed to furrow my brow...

Results: well, I'm slightly puzzled it has to be said. When it came to questions about paracetamol use (I use the term paracetamol 'cos that's what us Limeys are used to) between the ASD and non-ASD groups I didn't see too much difference overall. Take for example the questions about 'only using paracetamol' for fever or 'first choice' use for fever. The percentage figures for the ASD and non-ASD group were 15% and 12% respectively for 'only use this' and 35% and 46% respectively for 'first choice'. Given the participant numbers, I'm not sure that these stats are so wildly different. Yes, I appreciate that when it came to the question about 'rarely or never using' paracetamol to treat fever, 17% of those with ASD reported positive to this question compared with only 3% of controls, but does this really tell us much about very different patterns of paracetamol use?

Further, the authors report results based on "age-adjusted models for levels of fever medication use". They observe that using "acetaminophen as a first choice was 83% less likely in children with ASD... while use of acetaminophen if other medication doesn’t bring down fever was 82% less likely in children with ASD." They interpret this to mean that compared with their previous results [2] findings were reversed in that "older children with ASD compared to control children were significantly less likely to use acetaminophen for fever; whereas, in our 2008 study, younger children with ASD compared to control children were significantly more likely to use acetaminophen at 12-18 months of age and after the MMR vaccination." The mention of immunisation in that last sentence was based on their 2008 paper suggesting that "acetaminophen use after measles-mumps-rubella vaccination was associated with autistic disorder" but I have to say that I'm left a little wanting in terms of these recent findings by Shultz & Gould.

I do think there is a 'where next?' discussion to be had when it comes to the idea that paracetamol use might be linked to 'some' autism. Given the growing research interest in paracetamol use and a 'hyperactive phenotype' of autism (see here), this stalwart of pain relief is deserving of much further inspection in relation to autism. Shultz & Gould do offer one possible research direction based on some speculation about the how the endocannabinoid system might fit into this (something mentioned by other authors too). I am interested in the hypothetical situation they conclude their paper with implicating the endocannabinoid system and how paracetamol might affect 'endocannabinoid tone' but to what extent is perhaps another question.

Just before I finish on this topic I'm minded to bring to your attention another detail from the Shultz / Gould paper with regards to the sentence: "children with ASD vs. non-ASD children are significantly more likely to show an increase in sociability when they have a fever." I've always thought the observations on behaviour and fever when it comes to [some] autism to be quite important (see here). Speculation that "this increase [in sociability] is due to anandamide activation of the endocannabinoid system in ASD children" is also ripe for further scientific investigation...

It's been a while but here is some music to close: Mrs Robinson.

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[1] Schultz ST. & Gould GG. Acetaminophen Use for Fever in Children Associated with Autism Spectrum Disorder. Autism Open Access. 2016 Apr;6(2). pii: 170.

[2] 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.

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Schultz ST, & Gould GG (2016). Acetaminophen Use for Fever in Children Associated with Autism Spectrum Disorder. Autism-open access, 6 (2) PMID: 27695658

ALSPAC says maybe to link between prenatal paracetamol exposure and childhood behavioural difficulties

ALSPAC - the Avon Longitudinal Study of Parents and Children - continues to give in research terms as today I approach the findings reported by Evie Stergiakouli and colleagues [1]. They observed that: "Children exposed to acetaminophen [paracetamol] prenatally are at increased risk of multiple behavioral difficulties, and the associations do not appear to be explained by unmeasured behavioral or social factors linked to acetaminophen use insofar as they are not observed for postnatal or partner’s acetaminophen use." Some media attention for the study can be found here.

Continuing the research journey on a topic not unfamiliar to this blog (see here and see here for example) that exposure to paracetamol during the nine months that made us might not be a totally benign affair, Stergiakouli et al analysed data for some 7,700 mothers included in the initiative between 1991 and 1992. Questions about paracetamol use at 18 and 32 weeks of pregnancy were asked of mothers and maternal reports of child behaviour problems at 7 years using the Strengths and Difficulties Questionnaire (SDQ) were thrown into the research mix.

Results: those behavioural difficulties potentially associated with maternal paracetamol use at both 18 and 32 weeks of pregnancy included both conduct problems and hyperactivity symptoms. Researchers were also able to record no (significant) connection between post-natal paracetamol use nor partner paracetamol use and childhood behavioural problems. They concluded that "the timing of acetaminophen use might be important" and that "the association between prenatal acetaminophen exposure and childhood behavioral problems is not explained by unmeasured familial factors linked to both acetaminophen use and childhood behavioral problems and that the findings are consistent with an intrauterine effect."

Combined with the various other studies suggesting an association between prenatal exposure to paracetamol and offspring behavioural 'issues' the case for a possible link is growing. ALSPAC has a number of methodological strengths to its design, not least "the availability of prospective information on acetaminophen use during the second and third trimesters of pregnancy and postnatally by the mother and by her partner." The fact that numerous potentially confounding variables were also controlled for is another bonus for the study results: "maternal age at birth, parity, socioeconomic status, smoking and alcohol consumption during pregnancy, prepregnancy body mass index (BMI), maternal self-reported psychiatric illness, and possible indications for acetaminophen use." This is pretty strong data (or at least as strong as the other data published on this topic).

Mechanism(s) of effect? Still something that needs a little more work I'm afraid, before any precise information is revealed. The authors go with some ideas based on the "endocrine-disrupting properties of acetaminophen" for example, but let's wait and see before anyone makes too many sweeping generalisations. I might however suggest that the possibility of a link between paracetamol exposure and asthma (see here) could be important in light of what asthma might mean for the risk of presentation of ADHD (attention-deficit hyperactivity disorder) for example (see here). Just a thought and bearing in mind the evidence linking paracetamol use and asthma is not always all on-way.

Further studies are required on this increasingly important topic. Please also bear in mind no medical or clinical advice is given or intended on this blog. Speak to your physician if you need more information about pain relief during pregnancy.

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[1] Stergiakouli E. et al. Association of Acetaminophen Use During Pregnancy With Behavioral Problems in Childhood. JAMA Pediatrics. 2016. Aug 15.

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Stergiakouli, E., Thapar, A., & Davey Smith, G. (2016). Association of Acetaminophen Use During Pregnancy With Behavioral Problems in Childhood JAMA Pediatrics DOI: 10.1001/jamapediatrics.2016.1775

Pregnancy paracetamol use and "autism spectrum symptoms" (again)

Continuing something of a research theme whereby pregnancy paracetamol (acetaminophen) use has been *correlated* with a few offspring developmental outcomes (see here and see here), the paper by Claudia Avella-Garcia and colleagues [1] (open-access available here) makes for some blogging fodder today.

Including data from some 2,600 mother-child pairs living in Spain, researchers prospectively gathered data on maternal paracetamol use ("never, sporadic, persistent") during pregnancy alongside developmental outcomes of offspring "using Childhood Autism Spectrum Test (CAST), Conner's Kiddie Continuous Performance Test (K-CPT) and ADHD-DSM-IV form list" at 1 and 5 years old ("88.8% and 79.9%, respectively" of the total cohort).

They observed that around 4 in 10 mothers in their cohort reported paracetamol use during pregnancy and for the purposes of analgesia (pain relief) in the most part. But: "Exposure (offspring exposure) was associated with lower attention function development as measured by K-CPT parameters and with presenting greater risk for more ADHD-DSM-IV hyperactivity/impulsivity symptoms. Exposure was also related to a greater number of CAST autism spectrum symptoms in male children." We're also told that boys who were described as being persistently exposed - "use of any dose in all three trimesters" - to paracetamol in-utero "presented more autism spectrum symptoms." Authors conclude by saying that: "Prenatal acetaminophen exposure was associated with a greater number of autism spectrum symptoms in males and showed adverse effects on attention-related outcomes for both genders."

Accepting that this is again *correlational* research and was "unable to evaluate the effects of dosage because of mothers’ difficulties in recalling the dose taken" the key themes of pregnancy paracetamol use and possible over-representation of ADHD (attention-deficit hyperactivity disorder) and autistic traits shines through again. Indeed, it is interesting that ADHD and autism seem to have been grouped around this particular pharmaceutical product in light of previous mention of 'a hyperactive behavioural phenotype of autism' in the emerging peer-reviewed literature (see here).

"Different mechanisms may explain acetaminophen’s harmful influence on neurodevelopment. These include the stimulation of the endocannabinoid system,... toxicity due to deficits in sulphation capacity (reduced during pregnancy and in some autistic children)... and oxidative stress. Finally, acetaminophen may act as an endocrine disruptor affecting testicular function and the production of androgens, which could interfere with fetal brain development." I personally am not going to dwell on whether these or various other factors (interfering with inflammatory signalling?) might be linked to offspring outcomes at this time. What I will say is that any potential effect is likely to include various elements and may also include some genetic predisposition too. I'd also reiterate my stance in other posts on this topic that one might need to look at other more somatic conditions as also potentially exerting an effect [2] in light of other associations that have also been made (see here).

Although there remains some scientific scepticism around any correlation between pregnancy paracetamol use and offspring outcomes [3] (including in the media) there is a need for quite a few more investigations in this area. One area in particular crying out for further research is that of whether infection(s) leading to the initial use of something like pregnancy paracetamol might also elevate the risk of offspring developmental issues too (see here) and what role they may play. Although not quite in the same arena as the pretty well-established 'valproate affects developmental outcomes' hypothesis (see here) the idea that medication choice (including 'nutritional' medication) during pregnancy might *contribute* to at least some offspring outcomes seems to be gaining further peer-reviewed research ground.

One should always be cautious of such 'linking one factor to another' type of research but that doesn't mean it's all bunk...

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[1] Avella-Garcia CB. et al. Acetaminophen use in pregnancy and neurodevelopment: attention function and autism spectrum symptoms. Int J Epidemiol. 2016 Jun 28. pii: dyw115.

[2] Andersen AB. et al. Use of prescription paracetamol during pregnancy and risk of asthma in children: a population-based Danish cohort study. Clin Epidemiol. 2012; 4: 33-40.

[3] Andrade C. Use of acetaminophen (paracetamol) during pregnancy and the risk of autism spectrum disorder in the offspring. J Clin Psychiatry. 2016 Feb;77(2):e152-4.

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Avella-Garcia CB, Julvez J, Fortuny J, Rebordosa C, García-Esteban R, Galán IR, Tardón A, Rodríguez-Bernal CL, Iñiguez C, Andiarena A, Santa-Marina L, & Sunyer J (2016). Acetaminophen use in pregnancy and neurodevelopment: attention function and autism spectrum symptoms. International journal of epidemiology PMID: 27353198

What can 'big data' tell us about suicide-related behaviours?

The findings reported by Yu-Wen Lin and colleagues [1] (open-access available here) examining the "characteristics and suicide methods of patients with suicide-related behaviors" and "influential factors for repeated suicide-related behaviors and death by suicide" might not make for 'great dinner-party conversation' but are nevertheless important.

Drawing on data from one of the world's premier 'big data' research sources - the Taiwanese National Health Insurance Research Database (NHIRD) - mentioned quite a few times on this blog (see here for example), researchers scanned the database for instances where people were "hospitalized with a code indicating suicide or self-inflicted injury (E950-E959) according to the International Classification of Disease, Ninth Revision, Clinical Modification" between 1997 and 2010. They then set about looking at various factors associated with this patient population (N=57,874).

With the cold, objective spectacles of science on, various important findings are discussed. Approximately 4% of those hospitalised for suicide-related behaviours had unfortunately died. Most were male and most "had died in their first suicide attempt." The most frequently cited method of suicide was self-poisoning.

Analysis by gender revealed some important trends. Males were more likely to die by suicide but females were at "significantly increased odds of repeated suicide-related behaviors when compared with men." Further: "Those who were female, had been hospitalized for suicide-related behaviors at a younger age, had a low income, had a psychiatric disorder (i.e., personality disorder, major depressive disorder, bipolar disorder, schizophrenia, alcohol-related disorder, or adjustment disorder), had a catastrophic illness, or had been hospitalized for suicide-related behaviors that involved two methods of self-inflicted injury had a higher risk of hospitalization for repeated suicide-related behaviors." And factors for males: "had been hospitalized for suicide-related behaviors at an older age, had low income, had schizophrenia, showed repeated suicide-related behaviors, had a catastrophic illness, or had adopted a single lethal method had an increased risk of death by suicide." I might also add that the experience of being hospitalised for suicide-related behaviours at a young age also increased the risk for subsequent "repeated suicide-related behaviors."

There are some important trends emerging from this and other data. Perhaps one of the most important variables was the suggestion that a psychiatric disorder seemed to be part and parcel of that risk profile, whether for suicide-related behaviours or death by suicide. I know this is not new news but does well to reiterate how effective treatment/management of psychiatric labels should remain an absolute priority. I'd also encourage greater screening and assessment [2] among populations who might be particularly vulnerable to mental health issues too (see here for example - particularly timely in light of recent media reports).

The finding that self-poisoning was the primary method of suicide-related behaviour and completed suicides also ties in with other independent data. Accepting that one cannot control every single agent that might be used for self-poisoning, I do believe there are additional measures that can be taken. So, as per the data on the use of paracetamol as a method of suicide (which is by the way, a really horrible way to die), there are ways and means to potentially reduce risk [3] particularly when overdose is an 'impulsive' decision. One might even argue that removing such medicines from the OTC bracket might also help despite the inconvenience to other users. I suppose it depends on how much value you place on life vs. inconvenience or the use of additional resources. I'd also direct readers to some important discussions on another self-poisoning method quite frequently discussed in the research literature: pesticides (see here).  As per the findings reported by Gunnell and colleagues [4], there are solutions here too: "(a) the use of pesticides most toxic to humans was restricted, (b) pesticides could be safely stored in rural communities, and (c) the accessibility and quality of care for poisoning could be improved."

As I've discussed previously on this blog, suicide (whether attempted or completed) is a very personal thing (see here) with no magical 'one-size-fits-all' formula of what to look for in terms of risk profile or indeed, how to help. That there may however be some rough-and-ready factors generally associated with cases is a start in terms of focusing on those who might need most help, including that when it comes to the engineering of social policy [5].

And just in case you need it, there is always someone to talk to (see here).

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[1] Lin YW. et al. Influential Factors for and Outcomes of Hospitalized Patients with Suicide-Related Behaviors: A National Record Study in Taiwan from 1997-2010. PLoS One. 2016 Feb 22;11(2):e0149559.

[2] Murray D. Is it time to abandon suicide risk assessment? British Journal of Psychiatry Open. 2016; 2: e1-e2.

[3] Simkin S. et al. What can be done to reduce mortality from paracetamol overdoses? A patient interview study. QJM. 2012 Jan;105(1):41-51.

[4] Gunnell D. et al. The global distribution of fatal pesticide self-poisoning: systematic review. BMC Public Health. 2007 Dec 21;7:357.

[5] Antonakakis N. & Collins A. The impact of fiscal austerity on suicide: On the empirics of a modern Greek tragedy. Social Science & Medicine. 2014; 112: 39-50.

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Lin YW, Huang HC, Lin MF, Shyu ML, Tsai PL, & Chang HJ (2016). Influential Factors for and Outcomes of Hospitalized Patients with Suicide-Related Behaviors: A National Record Study in Taiwan from 1997-2010. PloS one, 11 (2) PMID: 26900930

Pendulum swings... prenatal antidepressant exposure not linked to autism or ADHD

"Multiple studies have examined the risk of prenatal antidepressant exposure and risk for autism spectrum disorder (ASD) or attention-deficit hyperactivity disorder (ADHD), with inconsistent results."

And...

"These results suggest that prior reports of association between prenatal antidepressant exposure and neurodevelopmental disease are likely to represent a false-positive finding, which may arise in part through confounding by indication."

'These results' refers to the findings reported by Castro and colleagues [1] (open-access available here) who looked at the records of over 1200 children diagnosed with ASD and ~1700 children diagnosed with ADHD compared with over 3400 and 3700 controls respectively with regards to antidepressant exposure during pregnancy and maternal antidepressant use before pregnancy. Based on exposures identified "using e-prescribing data in the EHR [electronic health records], both inpatient and outpatient, which record number of pills, frequency and refill number, allowing calculation of exposure period" researchers were, with reasonable confidence, able to test the idea that a diagnosis of ASD or ADHD might be elevated following prenatal exposure to said pharmaceutics.

The headline that most media discussing this study picked up on was the lack of any significant association between antidepressant use during pregnancy and risk of offspring autism or ADHD. This finding kinda contrasts with other recent independent reports that have been covered on this blog (see here). Indeed the authors - including one Isaac Kohane (see here) - suggest that their results, bearing in mind certain limitations, highlight how 'false-positive' might indeed be a good description of some of the previous data in this area.

But just before any sweeping generalisations are made about this class of pharmaceutic being 'off the hook' there were some other potentially important findings also reported by Castro et al. To quote once again: "For both ASD and ADHD, pre-pregnancy antidepressant use was associated with greater risk, even after adjustment for maternal major depression." The risk reported was significant insofar as what it might mean for offspring autism and/or ADHD and also how "the requirement for maternal antidepressant treatment, rather than the medication itself, may be associated with risk for neurodevelopmental disorders in offspring".

As I've discussed before, the idea that antidepressant use during pregnancy might be linked to offspring developmental outcomes is a complicated area. That such medicines use is not generally entered into lightly is something to bear in mind given what depression can do to a person and those around them. I cannot readily account for the discrepancy between these and other reports on this topic outside of the idea that the question of a connection or not may not be as simple as 'yes' or 'no' but rather a slightly more convoluted story where genetics and other more 'environmental' factors might play some role. The idea that there may be specific phenotypes of autism associated with such medication use has received a boost in other independent studies [2] looking at other medicines. I suppose such confusion kinda sums up autism research when it comes to questions of such exposure and the range of pharmaceutics that have been correlated with offspring risk (see here and see here).

Music: Björk - It's Oh So Quiet. Shhh.

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[1] Castro VM. et al. Absence of evidence for increase in risk for autism or attention-deficit hyperactivity disorder following antidepressant exposure during pregnancy: a replication study. Transl Psychiatry. 2016 Jan 5;6:e708.

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Castro VM, Kong SW, Clements CC, Brady R, Kaimal AJ, Doyle AE, Robinson EB, Churchill SE, Kohane IS, & Perlis RH (2016). Absence of evidence for increase in risk for autism or attention-deficit hyperactivity disorder following antidepressant exposure during pregnancy: a replication study. Translational psychiatry, 6 PMID: 26731445

Pregnancy paracetamol use and the 'hyperactive behavioral phenotype' of autism

"Prenatal use of acetaminophen was associated with an increased risk of ASD [autism spectrum disorder] accompanied by hyperkinetic symptoms..., but not with other ASD cases."

I was rather interested to read that conclusion presented in the study by Zeyan Liew and colleagues [1] talking about how acetaminophen (or paracetamol as it is known here in Blighty) use during pregnancy might have some rather important connections to offspring outcomes specifically with autism and hyperkinetic symptoms in mind.

Interested not only because I've discussed other research talking about how we might need to be a little more cautious about how OTC pain relief such as paracetamol is used in certain circumstances with potential offspring outcomes in mind (see here and see here) but also because it makes reference to a quite specific effect to the "hyperactive behavioral phenotype" of autism. That hyperkinetic behavioural phenotype by the way, plugs into a growing body of peer-reviewed evidence talking about the over-representation of ADHD (attention-deficit hyperactivity disorder) symptoms in relation to [some] autism (see here).

Liew et al "followed 64,322 children and mothers enrolled in the Danish National Birth Cohort (DNBC; 1996–2002) for average 12.7 years to investigate whether acetaminophen use in pregnancy is associated with increased risk of ASD in the offspring." Details about paracetamol use during pregnancy were "collected prospectively from three computer-assisted telephone interviews" and offspring outcomes with labels like autism were compared. This follows a similar methodological template from some of this research team (see here).

Some 1.6% of children included in the analysis were eventually diagnosed with as ASD. Roughly a third of that 1.6% of children were also diagnosed with hyperkinetic disorders (which seems to tally with other independent data analysis [2]). Perhaps unsurprisingly, paracetamol use during pregnancy was pretty widespread in the cohort (~50%) but, despite this, authors detailed something of a potentially important relationship between pregnancy paracetamol use and offspring "ASD accompanied by hyperkinetic symptoms." That there also appeared to be a relationship between length of use of paracetamol and risk of offspring autism with hyperkinetic symptoms, seems to strengthen details of a possible association.

Accepting that this was a study plotting pregnancy medication use and offspring outcomes and hence findings need to be treated with a degree of caution (as with other studies on other medicines), set within the other research talking about paracetamol use during pregnancy I'm coming around the idea that more investigation is required in this area [3]. I could, once again, start talking about how pregnancy paracetamol use might link into childhood asthma symptoms [4] (albeit with some cautions attached [5]) and what that might mean for the behavioural 'associations' noted in some cases of asthma (see here) as a possible angle for future research. I would however temper such musings within the context of autism (see here); although the preliminary suggestion that prenatal exposure to certain drugs used to treat asthma might also affect risk of offspring autism is also interesting [6].

I do like that Liew and colleagues talked about the idea of a specific behavioural phenotype potentially linked to pregnancy paracetamol exposure as providing a guide for more targeted investigation and perhaps to some degree bypassing the need for the sweeping generalisations about 'all autism' (we've had enough of those down the years). I believe there is quite a bit of research traction in this area with the notion of the autisms (see here) in mind.

Music: Elvis Presley - If I Can Dream.

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[1] Liew Z. et al. Maternal use of acetaminophen during pregnancy and risk of autism spectrum disorders in childhood. Autism Research. 2015. Dec 21.

[2] Berenguer-Forner C. et al. Comorbidity of autism spectrum disorder and attention deficit with hyperactivity. A review study. Rev Neurol. 2015 Feb 25;60 Suppl 1:S37-43.

[3] de Fays L. et al. Use of paracetamol during pregnancy and child neurological development. Dev Med Child Neurol. 2015 Aug;57(8):718-24.

[4] Eyers S. et al. Paracetamol in pregnancy and the risk of wheezing in offspring: a systematic review and meta-analysis. Clin Exp Allergy. 2011 Apr;41(4):482-9.

[5] Cheelo M. et al. Paracetamol exposure in pregnancy and early childhood and development of childhood asthma: a systematic review and meta-analysis. Arch Dis Child. 2015 Jan;100(1):81-9.

[6] Gidaya NB. et al. In utero Exposure to β-2-Adrenergic Receptor Agonist Drugs and Risk for Autism Spectrum Disorders. Pediatrics. 2016. 6 Jan.

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Liew Z, Ritz B, Virk J, & Olsen J (2015). Maternal use of acetaminophen during pregnancy and risk of autism spectrum disorders in childhood: A Danish national birth cohort study. Autism research : official journal of the International Society for Autism Research PMID: 26688372

Baby teeth and autism research

"This report provides evidence that teeth can be useful biomarkers of early life exposure for use in epidemiologic case-control studies seeking to identify differential unbiased exposures during development between those with and without specific disorders such as autism."

That was one of the conclusions reached in the paper by Raymond Palmer and colleagues [1] (open-access available here) who played science tooth fairy with 71 deciduous teeth (baby teeth) provided by children with autism from a "tooth repository consisting of 928 children’s deciduous teeth." As per other reports with autism in mind using these potentially important biological samples [2], there is quite a lot of information potentially available from baby teeth assuming one knows how to handle such samples.

For Palmer et al the analytical methods of choice were "liquid chromatography tandem mass spectrometry and gas chromatography" echoing other autism biomarker research discussed on this blog (see here) and fairly commonly appearing in the peer-reviewed literature [3]. Levels of various compounds were assessed in the pulverised baby teeth samples including "acetaminophen [paracetamol], ARA [arachidonic acid], DEET [diethyl-m-toluamide], TCPy [3,5,6-trichloro-2-pyridinol], IMPy [2-isopropyl-6-methyl-4-pyrimidinol], and MEHP [mono-2-ethylhexyl phthalate]." Just in case you aren't an organic chemist, many of those compounds are metabolites of "pesticides, plastics, or medications" and were studied in light of previous work from this authorship group [4] and the suggestion that some of them might be relevant to autism risk and/or onset (see here for example) or at least serving up an interesting correlation.

Consistent with that previous report, Palmer and colleagues "demonstrated that specific semivolatile organic chemicals relevant to autism etiology can be detected in deciduous teeth." Drawing on information from both US children with autism (a "collection of deciduous teeth through collaborative efforts with the Interactive Autism Network (IAN)") and Mexican children with autism, various results are presented. "Despite demographic differences in the two samples, there were similar rates of detection for all chemicals" was one of the primary findings. So, round about 40% of samples from both geographic groups were detected to have traces of acetaminophen (paracetamol) in them for example. This finding tallied to some degree with parent report about paracetamol use during pregnancy and infancy. Other results can be seen in some of the accompanying tables (see here for example).

Importantly, Palmer and colleagues discuss what their findings do and do not mean. "While we have demonstrated that chemicals relevant to ASD [autism spectrum disorders] can be detected in deciduous teeth and are associated with mothers’ self-reported exposures, our results are limited in generalizability—largely due to the sample consisting entirely of children with ASD." In other words, the sole focus on baby teeth from children with autism does not necessarily mean that any compounds detected 'cause' autism given the snapshot view of their study and the lack of appropriate asymptomatic control samples analysed. Further work is indicated in this area to "include more diverse participants and neurotypical children as controls will allow case/control comparisons."

The use of baby teeth represents an interesting addition to tissue analysis when it comes to autism. Given the availability of such teeth, the timing of their availability and the relatively non-invasive way that such samples can be collected, there are quite a few positives to the use of such as resource in autism research. Combined with other fairly non-invasively collected samples such as urine (see here), saliva samples (see here) and potentially even things like nail clippings [5], there is quite a bit of information potentially available for autism research. That being said, the word 'biomarker' with autism in mind, needs to be rather carefully used in light of things like plurality...

Music: Maroon 5 - Sugar.

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[1] Palmer RF. et al. Organic Compounds Detected in Deciduous Teeth: A Replication Study from Children with Autism in Two Samples. J Environ Public Health. 2015;2015:862414.

[2] Adams JB. et al. Mercury, lead, and zinc in baby teeth of children with autism versus controls. J Toxicol Environ Health A. 2007 Jun;70(12):1046-51.

[3] Wang H. et al. Potential serum biomarkers from a metabolomics study of autism. J Psychiatry Neurosci. 2015 Sep 22;40(5):140009.

[4] Camann DE. et al. Acetaminophen, pesticide, and diethylhexyl phthalate metabolites, anandamide, and fatty acids in deciduous molars: potential biomarkers of perinatal exposure. Journal of Exposure Science and Environmental Epidemiology. 2013; 23: 190–196.

[5] Shu I. et al. Detection of Drugs in Nails: Three Year Experience. J Anal Toxicol. 2015 Oct;39(8):624-8.

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Palmer, R., Heilbrun, L., Camann, D., Yau, A., Schultz, S., Elisco, V., Tapia, B., Garza, N., & Miller, C. (2015). Organic Compounds Detected in Deciduous Teeth: A Replication Study from Children with Autism in Two Samples Journal of Environmental and Public Health, 2015, 1-9 DOI: 10.1155/2015/862414

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