Wednesday, 24 August 2016

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.


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

---------- 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

Tuesday, 23 August 2016

Autism and/or ADHD in Down's syndrome

"High rates of ASD [autism spectrum disorder] and ADHD [attention-deficit hyperactivity disorder] were found: 17 (42%) and 14 (34%) of the 41 children met DSM criteria for ASD and ADHD respectively."

That was the conclusion reached in the study by Ulrika Oxelgren and colleagues [1] looking at the "prevalence of autism spectrum disorder (ASD) and attention-deficit-hyperactivity disorder (ADHD) in a population-based group of children and adolescents with Down syndrome." The population in this case comprised 60 children and young adults diagnosed with Down's syndrome (Down syndrome if you prefer) and the gold-standards that are the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS) were the instruments of choice when arriving at decisions of whether autism might be present or not.

New news? No it's not new news that autism (whether in diagnosis or in traits) may be over-represented when it comes to Down's syndrome (see here and see here for other research-based examples). There has even been a suggestion that regression - a key part of at least some autism - may be part and parcel of some cases of Down's syndrome (see here) too.

Oxelgren et al suggest that the combination of Down's syndrome and the "intellectual disability and medical disorders" that can accompany Down's syndrome added to a possible higher rate of autism potentially make for "a severely disabled group" worthy of far greater attention when it comes to screening and intervention. I don't think anyone would disagree with such sentiments and in particular, how preferential autism screening should once again be added to a growing list of diagnoses and labels. Indeed, such data in particular directs further attention to the link between intellectual (learning) disability and autism (see here and see here).


[1] Oxelgren UW. et al. Prevalence of autism and attention-deficit-hyperactivity disorder in Down syndrome: a population-based study. Dev Med Child Neurol. 2016 Aug 9.

---------- Oxelgren UW, Myrelid Å, Annerén G, Ekstam B, Göransson C, Holmbom A, Isaksson A, Åberg M, Gustafsson J, & Fernell E (2016). Prevalence of autism and attention-deficit-hyperactivity disorder in Down syndrome: a population-based study. Developmental medicine and child neurology PMID: 27503703

Monday, 22 August 2016

"Theory of mind is not theory of emotion"

A rather interesting paper by Beth Oakley and colleagues [1] (open-access might be available here) appeared recently providing a "cautionary note on the Reading the Mind in the Eyes Test" [2], one of the premier assessments thought to offer a performance-based measure "involving mental state attribution and complex facial emotion recognition from photographs where only the eye region of the face is available."

Most people with some knowledge about autism research history will have heard about the proposal that Theory of Mind (ToM) - a term often used to cover that "mental state attribution" - might be affected in cases of autism (see here) and indeed, how careers and reputations have been made on such a generalisation. These days ToM is less and less being talked about as the heterogeneity of the autism spectrum becomes better understood and how specificity in particular, has proved to be an Achilles' heel for the concept (see here).

One of the emerging ideas to account for some of the results obtained using the Reading the Mind in the Eyes test (RMET) in cases of autism is that alexithymia - a construct characterised by an inability to describe or understand emotions - might actually be the more important issue than autism per se. The idea being that alexithymia can co-occur alongside some autism and that for those presenting with that combination, ToM and assessments like RMET might be problematic.

So Oakley et al delved a little deeper into some of the hows and whys of some of the RMET results obtained with autism in mind and whether "the RMET indexes emotion recognition, associated with alexithymia, or ToM, associated with ASD [autism spectrum disorder]." They did it on the basis of examining a small group of participants diagnosed with an ASD (n=19) alongside 24 participants without autism. Alexithymia was assessed using "the 20-item Toronto Alexithymia Scale (TAS–20)." Autism symptoms severity was measured using the Autism Spectrum Quotient (50) (oh dear..) and "current functioning" in the autism group was assessed using the gold-standard that is the Autism Diagnostic Observation Schedule (ADOS) (more like it).

Results: well bearing in mind the small participant numbers and the need for further independent replication of the findings, "Reading the Mind in the Eyes Test (RMET) performance was unaffected by autism spectrum disorder... but was negatively impacted by alexithymia." Indeed, we are told that: "Six ASD and eight control participants met the criterion for severe alexithymia, with a score of 61 or above on the 20-item Toronto Alexithymia Scale (TAS–20)." Further: "in individuals with ASD and comorbid alexithymia, it is alexithymia, rather than ASD per se, that impairs emotion recognition performance."

I probably don't need to say too much more about this line of research and its important implications outside of perhaps the requirement to screen for alexithymia as and when autism is diagnosed. Insofar as the idea of an "alexithymia hypothesis of emotion-related deficits in ASD", this does sound like a tantalising option but again, I'd be slightly reluctant to go all-in with yet another grand theory for autism given the trials and tribulations that psychological theories in particular have faced over the years with autism in mind. As to other potential impacts from work such as this, well, assertions that a lack of empathy might the root of all evil (see here) also made by proponents of ToM might do well to take on board a role for alexithymia in any future judgements...

Minus any charges of plagiarism, I leave you with the general summary from Oakley and colleagues:

"This study suggests that a highly popular test of the ability to detect what someone else is thinking—the Reading the Mind in the Eyes Test—is instead a test of the ability to recognize another person’s emotional expression. This is important because it suggests that patients who perform badly on this test may still be able to understand another person’s mental state and that, conversely, patients who perform well on this test may still have difficulties in mental state understanding."


[1] Oakley BF. et al. Theory of mind is not theory of emotion: A cautionary note on the Reading the Mind in the Eyes Test. J Abnorm Psychol. 2016 Aug;125(6):818-23.

[2] Baron-Cohen S. et al. The “Reading the Mind in the Eyes” Test: Complete Absence of Typical Sex Difference in ~400 Men and Women with Autism. PLoS ONE. 2015; 10(8).

---------- Oakley BF, Brewer R, Bird G, & Catmur C (2016). Theory of mind is not theory of emotion: A cautionary note on the Reading the Mind in the Eyes Test. Journal of abnormal psychology, 125 (6), 818-23 PMID: 27505409

Saturday, 20 August 2016

Polycystic ovary syndrome (PCOS) and risk of psychiatric disorder

"Polycystic ovary syndrome (PCOS) is an endocrine disorder affecting 5-15% of reproductive-aged women and characterized by high levels of circulating androgens."

OK, go on.

"Women with PCOS had higher risks for a range of psychiatric disorders not shown before. Elevated risk in their siblings suggests shared familial factors between PCOS and psychiatric disorders."

So said the findings reported by Carolyn Cesta and colleagues [1] who using Swedish national register data concluded that there may be something more to see when it comes to the presentation of PCOS and risk of receipt of a comorbid psychiatric label. Included under the banner of psychiatric conditions were a variety of different labels: "schizophrenia, bipolar disorder, depressive and anxiety disorders, eating disorders, personality and gender identity disorder, autism spectrum disorder (ASD), attention-deficit hyperactivity disorder (ADHD), tics, attempted and completed suicide." Personally, I'm not so sure these days that ASD should necessarily be termed a psychiatric condition but that was a decision made by the authors and I'm sure others might disagree with me.

Participant numbers for the Cesta study were in the tens of thousands as one might expect when it comes to research using the various Scandinavian registries ("all women diagnosed with PCOS between 1990 and 2013 (n = 24,385), their full-siblings (n = 25,921), plus matched individuals (1:10/100) from the general population and their full-siblings") and results were presented as odds ratios and adjusted odds ratios (AORs).

One particular part of the Cesta results stood out for me bearing in mind the primary focus of this blog: "Significantly higher AORs were found for ASD in both brothers and sisters of women with PCOS." Added to other research by Sunday Kosidou and colleagues [2] discussed on this blog (see here), these results potentially tap into some history in autism research talking about androgens and autism (minus any sweeping generalisations).

"Health professionals treating women with PCOS should be aware that these patients – as well as their family members – are important targets for mental health care." Yet again the idea that preferential screening for something like autism and other labels appears as further clues potentially emerge as to the risk factors for autism. The familial aspect to the Cesta data also provide some ideas for research directions too and I might, speculatively, suggest at least one course of future investigation (see here).


[1] Cesta CE. et al. Polycystic ovary syndrome and psychiatric disorders: Co-morbidity and heritability in a nationwide Swedish cohort. Psychoneuroendocrinology. 2016; 73: 196-203.

[2] Kosidou K. et al. Maternal polycystic ovary syndrome and the risk of autism spectrum disorders in the offspring: a population-based nationwide study in Sweden. Mol Psychiatry. 2015 Dec 8.

---------- Cesta, C., Månsson, M., Palm, C., Lichtenstein, P., Iliadou, A., & Landén, M. (2016). Polycystic ovary syndrome and psychiatric disorders: Co-morbidity and heritability in a nationwide Swedish cohort Psychoneuroendocrinology, 73, 196-203 DOI: 10.1016/j.psyneuen.2016.08.005

Friday, 19 August 2016

Childhood inflammation and hypomanic symptoms in young adulthood?

"Higher levels of systemic inflammatory marker IL-6 in childhood were associated with hypomanic symptoms in young adulthood, suggesting that inflammation may play a role in the pathophysiology of mania."

That was the conclusion reached by Joseph Hayes and colleagues [1] (open-access available here) who drew on data derived from the excellent resource that is ALSPAC ("Charting the health of 14,500 families in the Bristol area to improve the health of future generations"). I'll be talking about other ALSPAC-derived data in upcoming posts too.

Based on a cohort of some 4600 children who provided blood samples (analysable blood samples no less) at aged 9 years old and "who completed the Hypomania Checklist (HCL-32)" at aged 22 years, researchers looked at how blood levels of C-reactive protein (CRP) and IL-6 might link in with later self-reported hypomanic symptoms.

Bearing in mind the focus on "immune activity in healthy individuals" (quite a few participants were excluded from the study as a result of reporting an infection in the week before samples were taken), researchers reported some interesting associations. As per the opening sentence: "Higher IL-6 levels in childhood were associated with adult hypomania features in a dose-response fashion." That being said: "Higher serum IL-6 levels at age 9 years were associated with female sex, non-white British ethnicity, lower SES, higher past psychological and behavioural problems and higher BMI" too. When it comes to BMI (body mass index), the observation that various immune system markers might be elevated is not necessarily a new idea.

Although childhood IL-6 levels were associated with later hypomanic symptoms (even when adjusted for the various potentially confounding variables), blood levels of CRP did not seem to show the same kind of relationship: "There was no evidence of an association between CRP levels and hypomanic symptoms." Similarly, when authors looked at the possibility of an association between the presence of atopic disease and hypomanic symptoms based on the inclusion of a parent-response question when their child participant was 10 years old - "Has a doctor ever actually said that your study child has asthma or eczema?" - the authors reported little indication of any connection.

At least one of the co-authors on the Hayes paper has some prior interest in the possible psychiatric manifestations of childhood inflammation as per other entries on this blog (see here). As much as I am intrigued by this area of research, you don't have to be a rocket scientist to understand the potential flaws in such a study where one or two biological variables are mapped on to a self-report questionnaire quite a few years later potentially excluding a myriad of factors not readily taken into account in a study like this. It would for example, be preferable to have seen multiple measures of CRP and/or IL-6 during childhood (say, every year) to see if any potential association between childhood inflammation and hypomanic symptoms holds. That also only IL-6 seemed to show some sort of connection maybe also implies that the generalised idea that 'inflammation' might tie into later psychiatric symptoms is perhaps a little bit too generalised. I could go on i.e. CRP is not the only pentraxin, IL-6 is not necessarily just a pro-inflammatory cytokine, etc.

In short, some interesting observations and yes "immunological understanding of major mental illness could potentially lead to novel approaches to diagnosis, prevention and treatment" but I think we need a lot more quality data on this topic.


[1] Hayes JF. et al. Childhood interleukin-6, C-reactive protein and atopic disorders as risk factors for hypomanic symptoms in young adulthood: a longitudinal birth cohort study. Psychol Med. 2016 Aug 1:1-11.

---------- Hayes JF, Khandaker GM, Anderson J, Mackay D, Zammit S, Lewis G, Smith DJ, & Osborn DP (2016). Childhood interleukin-6, C-reactive protein and atopic disorders as risk factors for hypomanic symptoms in young adulthood: a longitudinal birth cohort study. Psychological medicine, 1-11 PMID: 27476619

Thursday, 18 August 2016

Mercury and autism: where the science currently stands

Yes, I know that on the 'hot potato' scale, to talk about mercury and autism still moves the needle up to somewhere approaching furnace level for some people despite discussions on this heavy metal still figuring in several quarters. This is however a blog based on peer-reviewed science (for the most part) and so with mucho, mucho caveats included I want to draw your attention to the review paper by Janet Kern and colleagues [1] (open-access available here) and the observation that: "The preponderance of the evidence indicates that mercury exposure is causal and/or contributory in ASD [autism spectrum disorder]." I might add that this authorship group are no strangers to this particular topic (see here).

As per the 'review' heading accompanying the Kern paper, this was an analysis (inventory) of the up-to-date - "1999 to February 2016" - peer-reviewed studies done around the topic of mercury and autism. The authors present the data based on tissue type, ASD vs. not-ASD and various other parameters detailing the back-and-forth of relationship and no relationship that seems to percolate through the autism research scene. They conclude that "the vast majority (74%) of those studies suggest that mercury is a risk factor for ASD" and that any effect is likely to consist of "both direct and indirect effects of mercury exposure." This direct and indirect effects explanation is accompanied by a graphic highlighting the many and varied ways that mercury exposure might be linked to cases of autism. They also direct readers to a similar paper on this topic [2] that "also found that 74% of studies support a link between mercury exposure and ASD."

Without courting controversy as to the sources of and relative role that mercury might have on cases of autism I was drawn to a particular conclusion made by the authors that "children with ASD are more susceptible to mercury than typically developing children." I've seen and blogged about enough autism research down the years to understand that for some people on the autism spectrum, behavioural 'symptoms' can be accompanied by various genetic and biological 'issues' linked to the handling of various toxicants and other environmental agents. I'm not yet convinced with the argument that universally people diagnosed with autism are somehow preferentially exposed to greater levels of mercury than the rest of the population but I am warming to the idea that their 'handling' of such a heavy metal (and others) might to some extent be 'impaired' and that this could have some impact on body burden levels as well as clinical presentation.

Obviously, more research is implied.


[1] Kern JK. et al. The relationship between mercury and autism: A comprehensive review and discussion. J Trace Elem Med Biol. 2016 Sep;37:8-24.

[2] Desoto MC. & Hitlan RT. Sorting out the spinning of autism: heavy metals and the question of incidence. Acta Neurobiol Exp (Wars). 2010;70(2):165-76.

---------- Kern JK, Geier DA, Sykes LK, Haley BE, & Geier MR (2016). The relationship between mercury and autism: A comprehensive review and discussion. Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS), 37, 8-24 PMID: 27473827

Wednesday, 17 August 2016

76% of youths with autism meet ADHD diagnostic criteria? No, more like 59%

"In a population of children diagnosed with ASD [autism spectrum disorder], the rate of ADHD [attention-deficit hyperactivity disorder] + ASD was 42% and the rate of ADHD + ASD + ID [intellectual disability] was 17%, resulting in a 59% total comorbidity rate of ADHD and ASD."

That was one of the important findings reported by Tara Stevens and colleagues [1] who using data from the Survey of Pathways to Diagnosis and Services (Pathways), a US initiative that has previously been discussed on this blog (see here), threw their research hat into an increasingly important part of the autism research and practice landscape.

I mentioned the percentage figure of 76% in the title of this post with reference to other, smaller scale, findings previously talked about on this blog (see here) based on the work published by Joshi and colleagues [2] and their observation of a: "high rate of comorbidity with ADHD... in psychiatrically referred youth with ASD, with a clinical presentation typical of the disorder."

The Stevens data is based on a larger sample cohort and whilst not necessarily carrying the same sort of diagnostic clout as the Joshi data ("Diagnostic interviews were administered by highly trained and closely supervised psychometricians with bachelor’s or master’s degrees in psychology or a related field") does benefit from those larger numbers included and indeed, the more naturalistic setting of data collection. That Stevens et al report that: "Average age at diagnosis was over 6 years for children with ASD + ADHD but close to 2.5 years for children with ASD only" also provides some welcome information about the experiences of a dual diagnosis of autism plus ADHD.

In these days of autism plus [3] (ESSENCE even) further focus on the idea that the label of autism rarely exists in some sort of diagnostic vacuum (see here) represents an important step towards offering appropriate - preferential - screening when autism is mentioned and also focusing minds on how comorbidity can in some cases be even more disabling than the core diagnosis of autism (see here). Although one has to be quite careful not to 'big up' the relationship between autism and ADHD, particularly in these days where a very vocal group of people talk about over-diagnosis of ADHD, I'd be minded to suggest that as per the example with other comorbidity over-represented when it comes to autism, tackling something like ADHD when it is present/diagnosed might have some important repercussions for the presentation of core autism itself and its impact on quality of life...


[1] Stevens T. et al. The comorbidity of ADHD in children diagnosed with autism spectrum disorder. Research in Autism Spectrum Disorders. 2016; 31: 11–18.

[2] Joshi G. et al. Symptom Profile of ADHD in Youth With High-Functioning Autism Spectrum Disorder: A Comparative Study in Psychiatrically Referred Populations. J Atten Disord. 2014 Aug 1. pii: 1087054714543368.

[3] Gillberg C. & Fernell E. Autism plus versus autism pure. J Autism Dev Disord. 2014 Dec;44(12):3274-6.

---------- Stevens, T., Peng, L., & Barnard-Brak, L. (2016). The comorbidity of ADHD in children diagnosed with autism spectrum disorder Research in Autism Spectrum Disorders, 31, 11-18 DOI: 10.1016/j.rasd.2016.07.003