Maternal diagnosis of PCOS increases the risk of offspring autism?

"We found that maternal diagnosis of PCOS [polycystic ovary syndrome] increased the risk of ASD [autism spectrum disorder], even after adjusting for potential confounders. Obesity among women with PCOS appeared to further increase the risk of ASD in the offspring. The risk associated with PCOS was similar in males and females."

Those were some of the main findings reported in the paper by Kyriaki (Sunday) Kosidou and colleagues [1] (open-access) who conducted a case-control study in Sweden looking at "23 748 ASD cases and 208 796 controls, matched by birth month and year, sex and region of birth." PCOS - an endocrine disorder characterised by polycystic ovaries, irregular periods and elevated levels of male hormones (androgens) - "was classified according to any lifetime recorded diagnosis (ICD-8: 256.90, ICD-9: 256E and ICD-10: E28.2)." The frequency of maternal PCOS alongside various other potentially confounding variables were analysed across the groups. Some media about the study can be seen here.

As per the opening paragraph, there did appear to be something to see when looking at rates of maternal PCOS where offspring autism was mentioned. One hundred and sixty-nine mothers of children with autism were found to have had a diagnosis of PCOS (0.7%) compared with 837 control mothers (0.4%). The difference (0.7% vs 0.4%) was deemed statistically significant (<0.001). That being said, and as with many factors when it comes to autism, differences were also noted across quite a few other parameters too such that 'maternal essential hypertension' was more frequently reported in mothers of children with autism compared with controls (1% vs. 0.8% respectively). Rates of diabetes mellitus were also significantly elevated (autism: 1.2% vs. controls: 0.8%). I'll come back to these findings shortly.

A few more details might also be useful to mention including: "The odds of offspring ASD were further increased among mothers with both PCOS and obesity, a condition common to PCOS that is related to more severe hyperandrogenemia." That and that fact that: "Risk estimates did not differ between sexes" and we have some potentially important results that "awaits confirmation, and exploration of potentially underlying mechanisms."

This is not the first time that the words 'PCOS' and 'autism' have graced this blog in the same entry (see here). That post from a few years back did quite a bit of speculating in terms of how mention of androgens and autism might link back to various discussions down the years talking about 'extreme male brains' and the like (bearing in mind that sweeping generalisations are not required [2]). It certainly appears that the Kosidou findings might tap into research chatter about things like testosterone and autism albeit with some provisos (see here and see here for example) and taking into account other recent findings [3].

Going back to the data on maternal hypertension and/or maternal diabetes as also showing some possible 'connection' to offspring autism, I've covered these variables before based on other independent peer-reviewed findings (see here and see here respectively). Maternal diabetes, specifically gestational diabetes, is something where the research evidence is increasingly converging in terms of an elevated risk of offspring autism. Mechanisms of effect are however, a little in short supply outside of talk about more autoimmune mediated diabetes (type 1 diabetes) and autism (see here). Maternal obesity and offspring autism has similarly figured in the peer-reviewed literature (see here).

Reiterating that there is more to do in this area of autism research, I do find the Kosidou results to be interesting. That preferential screening of offspring autism might be offered to women diagnosed with PCOS could be one consideration from such results; another might be for further research to focus on how PCOS and "elevated steroidopathic symptoms" might also feature among some people with an autism diagnosis or autistic traits in mind [4]. That being said, I must re-state that the overall numbers of diagnosed cases of PCOS in mums to children with autism was quite small...

Music: Steve - Emergency Art Rate.

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[1] 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. Molecular Psychiatry. 2015. 8 December.

[2] Joel D. et al. Sex beyond the genitalia: The human brain mosaic. Proc Natl Acad Sci U S A. 2015 Nov 30. pii: 201509654.

[3] Bilgiç A. et al. Autistic Trait, Empathy, and Attention-Deficit/Hyperactivity Symptoms in Women with Idiopathic Hirsutism. Int J Trichology. 2015 Jul-Sep;7(3):113-118.

[4] Pohl A. et al. Uncovering steroidopathy in women with autism: a latent class analysis. Mol Autism. 2014 Apr 9;5:27.

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Kosidou, K., Dalman, C., Widman, L., Arver, S., Lee, B., Magnusson, C., & Gardner, R. (2015). Maternal polycystic ovary syndrome and the risk of autism spectrum disorders in the offspring: a population-based nationwide study in Sweden Molecular Psychiatry DOI: 10.1038/mp.2015.183

A high index of suspicion for mitochondrial disease in autism?

The paper by Bradley Brown & Theodore Rais [1] (open-access available here) lies at the centre of today's brief musings and yet another interesting case report with autism in mind.

Detailing the experiences of a 15-year old boy diagnosed with an autism spectrum disorder (ASD) and "neurocardiogenic syncope" (fainting characterised by reduced blood circulation to the brain), authors report on how his admission to hospital for self-injury "secondary to depression" came to reveal some potentially important clinical issues.

In particular, the authors detail how some of the stressors potentially pertinent to the reasons for his admission seemed to include an awareness of his mother's "declining health due to a mitochondrial disease" and "his own concerns about his future health, given his previous “spells” (syncopal episodes secondary to his diagnosis of neurocardiogenic syncope)."

The mother of the young adult did indeed also suffer from neurocardiogenic syncope alongside various other issues including Ehlers-Danlos syndrome and "a Budd-Chiari type 2 malformation that required surgical decompression." Alongside other symptoms, her profile was considered "typical for a patient with a mitochondrial disease."

There is a degree of disconnect in the article by Brown & Rais insofar as how mitochondrial issues and autism are discussed quite a bit but as far as I can see, no specific assessment for such issues was carried out with the young man concerned. Rather, the implication is that a family history of mitochondrial issues should trigger similar assessment in those with autism save viewing such disorders as a zebra - "an obscure diagnosis that is made when a more common explanation is more likely."

I've covered some of the literature on mitochondrial issues occurring alongside autism on this blog before (see here and see here for example). Alongside more recent research talking about some fairly non-invasive ways of assessing things like "respiratory complex (RC) activities" in relation to autism [2] I'd be minded to suggest that quite a few more resources might be ploughed into this area to identify just how people on the autism spectrum might benefit from 'treatment' of said issues bearing in mind what intervention options might be available [3]. Lessons could no doubt be learned from other conditions presenting with a similar profile (at least in some cases).

One other detail also caught my eye in terms of how maternal Ehlers-Danlos syndrome (EDS) is discussed by Brown & Rais. I'm particularly interested in the idea that disorders of connective tissue might be something to look at in the context of [some] autism (see here). I say this on the basis of joint mobility issues and gait being something of potential interest to cases of autism and how issues with collagen for example, are more likely present when something like vitamin C deficiency is observed (as it has been in some cases of autism).

Physician and researchers alike perhaps should have a high index of suspicion for mitochondrial disease involvement in at least some cases of autism. And just in case this needs reiterating [4]...

Music: Major Lazer & DJ Snake - Lean On (feat. MØ).

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[1] Brown BD. & Rais T. Autism in the Son of a Woman with Mitochondrial Myopathy and Dysautonomia: A Case Report. Innov Clin Neurosci. 2015 Sep-Oct;12(9-10):29-32.

[2] Goldenthal MJ. et al. Mitochondrial enzyme dysfunction in autism spectrum disorders; a novel biomarker revealed from buccal swab analysis. Biomark Med. 2015 Oct;9(10):957-65.

[3] Parikh S. et al. A modern approach to the treatment of mitochondrial disease. Curr Treat Options Neurol. 2009 Nov;11(6):414-30.

[4] Marin SE. & Saneto RP. Neuropsychiatric Features in Primary Mitochondrial Disease. Neurol Clin. 2016 Feb;34(1):247-94.

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Brown BD, & Rais T (2015). Autism in the Son of a Woman with Mitochondrial Myopathy and Dysautonomia: A Case Report. Innovations in clinical neuroscience, 12 (9-10), 29-32 PMID: 26634179

Chronic fatigue syndrome, headaches and intracranial hypertension

Of the many important lessons that I've learned down the years of research, perhaps the most important one is that grand over-arching diagnostic labels rarely give a true reflection of the massive heterogeneity that they include in terms of clinical presentation and onwards, discussions about the possibility of differing aetiologies and pathologies. Symptoms, conditions, and diseases are compartmentalised for convenience but that does not mean that everyone shares the same experiences of that label nor arrives at it in exactly the same way.

This lesson is no better illustrated than in the paper by Nicholas Higgins and colleagues [1] (open-access here) who report on how "a 49-year-old woman with a long and debilitating history of chronic fatigue syndrome" was further inspected for "intracranial pressure because of headache, then diagnosed with borderline idiopathic intracranial hypertension after lumbar puncture and cerebrospinal fluid drainage." Further: "Stenting of both transverse sinuses brought about a life-changing remission of symptoms with no regression in 2 years of follow-up."

The authors report on how this patient had a 20-year history of fatigue that developed "after a viral illness" (there was evidence of "previous exposure to Epstein-Barr virus") and how after 3 months of "being unable to keep awake" fatigue symptoms fluctuated over several years. When presented to the authors, the woman "complained of being tired all the time, near constant headache, fogginess in the head, an inability to concentrate, muscle and joint aches, shortness of breath, and a sore throat." I had to cast a wry smile at the sentence: "She refused cognitive behavioral therapy" in light of some current goings-on with this and other 'interventions' being discussed in chronic fatigue syndrome (CFS) circles.

Kudos to the authors however and their protocol being developed whereby patients who present with chronic fatigue and headaches are "offered investigations to exclude raised intracranial pressure" as a source of their symptoms based on other studies reported by the research team [2]. Indeed, after some further investigations she showed symptoms "consistent with raised intracranial pressure." Treatment followed (although I wouldn't even begin to pretend that I understood it all) and that 'life-changing remission of symptoms' began and continued up to 2 years post diagnosis and intervention.

Not surprisingly the authors conclude that: "The unequivocally favorable outcome suggests that this is an area ripe for further study" based on this case report. Yes, one has to be careful not to generalise too much on the basis of the experiences of one patient, but given the current lack of effective interventions for something like CFS (or myalgic encephalomyelitis, ME), I'd suggest that there should be a degree of urgency to undertake additional studies in this area.

In addition to providing further evidence to suggest that we need to do more about looking at subgroups when it comes to CFS/ME (see here), I'd also be minded to suggest that this research area might also show more than a passing connection to a few other aspects covered on this blog. So for example, the idea that visual perception might be 'altered' as a symptom in at least some CFS/ME (see here) becomes potentially relevant in light of the link between idiopathic intracranial hypertension (IIH) and vision. The reports that "fogginess in the head" might also be part of the suite of cognitive effects that follow ME/CFS and are to some degree resolved by treatment of IIH in this patient group is also something that I pay quite a bit of attention to (see here). I'll finally direct you to a couple of posts I wrote about some research on Epstein-Barr virus (EBV) and some rather unusual findings (see here and see here) potentially relevant to some cases of CFS/ME with the requirement for quite a bit more research to do as part of a more multi-pronged intervention approach.

So, who is going to take up the research gauntlet and put further scientific flesh on the bones pertinent to a possible connection between IIH and [some] cases of CFS?

Music: Elle King - Ex's & Oh's.

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[1] Higgins N. et al. Borderline Intracranial Hypertension Manifesting as Chronic Fatigue Syndrome Treated by Venous Sinus Stenting. J Neurol Surg Rep. 2015 Nov;76(2):e244-e247.

[2] Higgins N. et al. Looking for idiopathic intracranial hypertension in patients with chronic fatigue syndrome. Journal of Observational Pain Medicine. 2013; 1: 28-35.

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Higgins N, Pickard J, & Lever A (2015). Borderline Intracranial Hypertension Manifesting as Chronic Fatigue Syndrome Treated by Venous Sinus Stenting. Journal of neurological surgery reports, 76 (2) PMID: 26623235

Don't give up

Appreciating that the subject matter of today's post might not necessarily align with the season that is upon us, I wanted to bring to your attention the paper by Michael Westerlund and colleagues [1] (open-access) and some rather disturbing discussions related to a young man who "decided to hang himself and to display the suicidal act" on an internet forum.

Published in the British Journal of Psychiatry, the paper set about examining how "participants on an internet forum act and react faced with suicidal communication and while witnessing the suicidal act." This was done via "a qualitative investigation of the messages that were posted before the TS's [thread starter] suicide and a combined qualitative–quantitative analysis of the messages posted during and after the suicide." A total of 30 posts before the suicide and 608 posts during and after the suicide were examined.

Several themes are discussed in the paper in terms of the authenticity of the discussions, attitudes towards the suicide, opportunities for prevention and: "Responsibility for the TS's suicide." There are some, quite frankly, awful comments discussed in this paper that I won't be repeating on this blog. Importantly however, the authors highlight a few lessons that might be learned from such events based on the fact that "the internet has developed as the main channel for suicide communication" and the possibility that lives could be potentially saved with the right tools for identifying and responding to "individuals who communicate suicide intentions on different forums on the internet." As per another quote from the paper: "the internet can be a facilitator of the suicidal process, but it can also be a venue where opportunities for prevention of suicide loom large."

Although not the main topic of this blog, suicide is something that has cropped up before (see here and see here for example). It is a complicated issue to talk about given that not only are there multiple pathways that bring someone to the position of contemplating taking their own life but also that attempted and completed acts can and do profoundly affect the people around the person in question.

The idea that the internet can be a source of positive information when it comes to reducing the risk of suicide is evident in the peer-reviewed domain [2]. Sueki & Ito [3] discussed the idea of on-line gatekeeping to prevent suicide "by placing advertisements on web search pages to promote consultation service use among Internet users with suicidal ideation." Social media has also been discussed as a good tool to deliver "a range of suicide prevention activities" [4]. The trick, it seems, is getting the relevant information and expertise to those who are currently vulnerable whilst at the same time avoiding issues like possible contagion. I might add that whilst the internet might have a significant role to play in suicide, it does not and should not represent the sum total of discussions about suicide and any potentially related issues (see here).

Bearing in mind the caveats of this blog about not giving medical or clinical advice, I did wonder if it might be useful to link to something like this page containing quite a few points and further links if and when discussions about suicide are raised. For anyone here in Blighty in need, details for the Samaritans can also be found here.

A song to close from Kate Bush and Peter Gabriel.

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[1] Westerlund M. et al. Case study of posts before and after a suicide on a Swedish internet forum. Br J Psychiatry. 2015; 207: 476-482.

[2] Robert A. et al. Internet use and suicidal behaviors: internet as a threat or opportunity? Telemed J E Health. 2015 Apr;21(4):306-11.

[3] Sueki H. & Ito J. Suicide Prevention Through Online Gatekeeping Using Search Advertising Techniques. Crisis. 2015 Jul;36(4):267-73.

[4] Robinson J. et al. Social media and suicide prevention: findings from a stakeholder survey. Shanghai Arch Psychiatry. 2015 Feb 25;27(1):27-35.

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Westerlund, M., Hadlaczky, G., & Wasserman, D. (2015). Case study of posts before and after a suicide on a Swedish internet forum The British Journal of Psychiatry, 207 (6), 476-482 DOI: 10.1192/bjp.bp.114.154484

Pregnancy antidepressant use and risk of offspring autism (again)

"Use of antidepressants, specifically selective serotonin reuptake inhibitors, during the second and/or third trimester increases the risk of ASD [autism spectrum disorder] in children, even after considering maternal depression."

That was the conclusion reported in the study by Takoua Boukhris and colleagues [1] dealing with a topic which has previously graced the autism research landscape (see here and see here). Detailing the results of a "register-based study of an ongoing population-based cohort, the Québec Pregnancy/Children Cohort" covering data on all pregnancies in Québec (Canada) between 1998 and 2009 (N=145 456 singleton full-term infants born alive and whose mothers were "covered by the Régie de l’assurance maladie du Québec drug plan for at least 12 months before and during pregnancy"), the Boukhris results have created quite the media stir.

Among the 140,000+ infants followed up, just over 1000 were eventually diagnosed with an autism spectrum disorder (ASD) equating to 0.7% of the population. When researchers looked at those who were prenatally exposed to antidepressants specifically during the second or third trimester of pregnancy, the rate of ASD was calculated at 1.2%. When also controlling for potentially confounding variables such as a maternal history of depression, the elevated risk of offspring autism persisted. Ergo, there may be more to see when it comes to antidepressant use during pregnancy and offspring developmental outcomes. I might also direct readers to an editorial discussing the findings [2].

Most of the media on this latest paper have been quite sensible about the findings. They've for example, pointed out that other research studies have reported slightly less in the way of any connection between pregnancy antidepressant use and offspring autism (see here) as well as putting the results into some context with the idea of what 'elevated risk' might actually translate into (see here). That also antidepressant use during pregnancy is not normally entered into lightly without good reason is something else that I'd bring into proceedings as per other research talking about other pregnancy medication use and potentially elevated risk to offspring outcomes (see here).

The authors do suggest that more research is required to build on their findings and "to specifically assess the risk of ASD associated with antidepressant types and dosages during pregnancy." I would agree that we do need more data on this possible association (including that from animal models and related studies) in order to ascertain whether specific medicine formulations might be more strongly involved and onwards the possible mechanism(s) of effect. I'm not necessarily sold on the idea that serotonin chemistry is specifically the be-all-and-end-all of any effect on the unborn child given what we are starting to realise about the wide-ranging effects of various medicines outside of that listed on the package insert (see here). I am willing however to entertain the idea that the further reaches of tryptophan metabolism might eventually come into the frame (see here). We await further studies.

Music now, and with the imminent launch of a certain Russian Soyuz rocket, a song for Tim...

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[1] Boukhris T. et al. Antidepressant Use During Pregnancy and the Risk of Autism Spectrum Disorder in Children. JAMA Pediatrics. 2015. Dec 14.

[2] King BH. Assessing Risk of Autism Spectrum Disorder in Children After Antidepressant Use During Pregnancy. JAMA Pediatrics. Dec 14.

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Boukhris, T., Sheehy, O., Mottron, L., & Bérard, A. (2015). Antidepressant Use During Pregnancy and the Risk of Autism Spectrum Disorder in Children JAMA Pediatrics DOI: 10.1001/jamapediatrics.2015.3356

Exercise as medicine by diagnostic label

I consider the paper by Pedersen & Saltin [1] (open-access available here) to be pretty good scientific value insofar as their providing the reader "with the up-to-date evidence-based basis for prescribing exercise as medicine in the treatment of 26 different diseases."

Including various psychiatric labels - "depression, anxiety, stress, schizophrenia" - as an addition to their previous review in this area [2], the authors have quite comprehensively trawled through the available peer-reviewed literature to arrive at a summary of what the research evidence suggests, the possible mechanism(s) of action of exercise use and where discussed, the type of training that might best fit with the label.

I'd prefer not to dwell too long on the findings in their entirety because there are quite a lot of them. Given however that topics such as depression, anxiety and schizophrenia have been discussed on this blog before with physical activity and exercise in mind (see here and see here for example) I thought it might be useful to mention a few points bearing in mind my blogging caveats about not giving anything that looks, sounds or smells like clinical advice.

Depression: "some, but modest evidence of a positive effect of physical training on depression symptoms." Bearing in mind that the label 'depression' covers quite a bit of diagnostic ground, specific recommendations about a best type of exercise were not made as were details on how exercise might specifically act upon cases of depression. This last point has however been explored in other research [3]. The authors did however suggest that: "more sessions have a larger effect on depression score than a smaller number of sessions" and "resistance and mixed training may be more effective than aerobic training."

Anxiety: again, bearing in mind that anxiety comes in various different guises, there was "some, but limited knowledge about the effects of physical activity as a treatment for anxiety." Anxiety when coincidental to various chronic diseases such as cardiovascular disease or chronic obstructive pulmonary disease (COPD) did seem to be positively affected by physical activity based on some meta-analyses. The authors were able to be a little more specific in the potential best types of exercise in the context of anxiety such that "individualised" and exercise under supervision might be a useful start. Small group training was also suggested, initially starting with "low-intensity aerobic physical activity" including walking, swimming and cycling.

Schizophrenia: accepting that the physical health of those diagnosed with schizophrenia has been an area crying out for further research, the authors highlight several pertinent issues when it comes to physical activity and schizophrenia in relation to the issue of comorbidity ("People with schizophrenia often have accompanying symptoms, such as anxiety and stress") and the possible impact that certain pharmacotherapy used for schizophrenia might have on factors affecting/affected by physical activity and exercise. They do however report that exercise does seem to impact on the presentation of schizophrenia: "Psychiatric symptoms were significantly reduced by interventions using around 90 min of moderate-to-vigorous exercise per week. This amount of exercise was also reported to improve functioning, co-morbid disorders, and cognition." Further: "It is important for the training to take into account the individual situation of the person in terms of physical environment, a recognizable structure and level of social participation" with a recommendation "to start with low-intensity aerobic exercise and gradually increase to moderate intensity, with a gradual increase in duration."

There is a need to build upon such reviews and further zoom in on what might be the optimal exercise pattern for labels and indeed, for individual people. Set within the context of other health promoting regimes (affecting diet, smoking and drinking habits and other aspects of health for example) and without coming across as too 'nanny state', the authors conclude: "it is now time that the health systems create the necessary infrastructure to ensure that supervised exercise can be prescribed as medicine."

To close, yes yet another Force Awakens trailer as this week all is revealed...

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[1] Pedersen BK. & Saltin B. Exercise as medicine - evidence for prescribing exercise as therapy in 26 different chronic diseases. Scand J Med Sci Sports. 2015 Dec;25 Suppl 3:1-72.

[2] Pedersen BK. & Saltin B. Evidence for prescribing exercise as therapy in chronic disease. Scand J Med Sci Sports. 2006 Feb;16 Suppl 1:3-63.

[3] Schuch FB. et al. Neurobiological effects of exercise on Major Depressive Disorder: A systematic review. Neuroscience & Biobehavioral Reviews. 2015. 2 Dec.

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Pedersen BK, & Saltin B (2015). Exercise as medicine - evidence for prescribing exercise as therapy in 26 different chronic diseases. Scandinavian journal of medicine & science in sports, 25 Suppl 3, 1-72 PMID: 26606383