Hypertensive disorders of pregnancy (HDP) and offspring autism and/or ADHD meta-analysed

"Pooled estimates from this systematic review and meta-analysis of 61 studies suggest that exposure to hypertensive disorders of pregnancy is associated with a small yet statistically significant increase in the odds of autism spectrum disorder and attention-deficit/hyperactivity disorder in offspring compared with no exposure."

So concluded the review and meta-analysis published by Gillian Maher and colleagues [1] that collected and analysed the current peer-reviewed research literature (up to June 2017) looking at hypertensive disorders of pregnancy (HDP) and offspring developmental outcomes. Continuing an important research theme (see here), authors observed something around "a 35% increased odds of ASD [autism spectrum disorder] compared with nonexposure" and that children were "30% more likely to have ADHD compared with unexposed offspring."

HDP according to Maher et al, covers quite a bit of diagnostic ground: "chronic hypertension (essential/secondary), white-coat hypertension, masked hypertension, transient gestational hypertension, gestational hypertension, and preeclampsia (de novo or superimposed on chronic hypertension)." The primary characteristic is "high blood pressure that either precedes pregnancy, is diagnosed within the first 20 weeks of pregnancy, or does not resolve by the 12-week postpartum checkup" [2].

There's little more to say about this area of research aside from the idea that findings "highlight the need for greater pediatric surveillance of infants exposed to HDP to allow early intervention that may improve neurodevelopmental outcome" and that more work on possible mechanism(s) need to be undertaken. On that last point the authors opine that "placental dysfunction, associated with HDP, may result in reduced placental perfusion and oxidative stress" or that: "Maternal inflammation may also play a key role." Both worthy areas for future research. The implication also, is that yet again, there may be some form of 'foetal programming' going on with regards to offspring autism that *could* be sensitive to intervention at some point...

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[1] Maher GM. et al. Association of Hypertensive Disorders of Pregnancy With Risk of Neurodevelopmental Disorders in Offspring: A Systematic Review and Meta-analysis. JAMA Psychiatry. 2018 Jun 6.

[2] Mammaro A. et al. Hypertensive Disorders of Pregnancy. Journal of Prenatal Medicine. 2009;3(1):1-5.

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More welcome research on post-exertional malaise (PEM) in ME/CFS

The findings reported by Lily Chu and colleagues [1] provide the blogging fodder today, and some further welcome research into the concept of post-extertional malaise (PEM) in the context of chronic fatigue syndrome / myalgic encephalomyelitis (CFS/ME).

PEM represents a cardinal feature of CFS/ME, where physical exertion - whether covering exercise or even just daily activities - brings about a period of (even more) exhaustion, weakness and fatigue. As per my previous discussion of the paper by McManimen and colleagues [2], there's still some ambiguity when it comes to clinically defining PEM (and indeed, whether the word 'malaise' covers the range of symptoms that the term includes). What is clear however is that PEM is real and can be absolutely disabling.

The Chu study, including the name Jose Montoya on the authorship list, set out to "describe symptoms associated with and the time course of PEM." Authors designed an online survey "asking subjects about the history and course of their ME/CFS" that asked a few questions about PEM. This included: "1) What symptoms, if any, are triggered or worsened by physical or mental activity?; 2) What symptoms are triggered or worsened by emotional distress?; 3) How soon usually after starting mental or physical exertion does your illness begin to worsen?; and 4) If you feel worse after activities, how long does this worsening usually last?" They also describe how they were careful not to actually use the word 'PEM' during the course of their research in order to "try to decrease the chances that subjects already diagnosed with ME/CFS would automatically answer our question based on their knowledge of or preconceived notions about PEM." Smart move.

Results: some 150 people as part of something called the MGEISD (Genetic Expression and Immune System Dynamics) study responded to the survey. While some of the participants were formally diagnosed with ME/CFS, the cohort also included those "waiting to be seen at the clinic, members of online ME/CFS forums, and participants of local ME/CFS support groups." Although all were telephone screened to see "if they fitted Fukuda 1994 CFS criteria" one does need to be a little careful with describing such a process as providing anything approaching a 'homogeneous' group.

"Most subjects (N = 129, 90%) experienced PEM with both physical/ cognitive exertion and emotional distress." There didn't seem to be any specific 'rules' in terms of the connection between the 'stressor' and onset of PEM, although around 40% of participants reported experiencing PEM within 24 hours. This was however subject to quite some variation. Symptoms reported in relation to the PEM questionnaire items were also variable. Fatigue is up there as one would expect, but also things like sleeping issues and headache were noted. Around 40% of participants also reported on a constellation of PEM symptoms: fatigue, sleep disturbance, pain and "at least one immune-related symptom."

What is becoming a little clearer from this and other research is that (a) PEM or whatever you want to call it is a real issue for many people diagnosed with CFS/ME and (b) the symptoms of PEM are not necessarily uniform in either character or timescale (onset, duration, etc.) What's still missing? Well, biology is still missing from quite a lot of the PEM literature; biology in terms of what PEM looks like on a physiological level and whether there may be something that can be done to alleviate it at a biological level aside from resting up (often for days at a time). I've talked about this before on this blog, in terms of biologically characterising PEM and how, for example, it might look in terms of defining recovery from ME/CFS (see here). To that end, lots more investigation in this area is implied...

And while on the topic of ME/CFS, I'll draw your attention to the paper by Karfakis [3] talking about the "biopolitics of CFS/ME." Yes, there has been and continues to be lots of that, including the phrase: "CFS/ME is an illness trapped between medicine and psychology". Discuss in 500 words.

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[1] Chu L. et al. Deconstructing post-exertional malaise in myalgic encephalomyelitis/ chronic fatigue syndrome: A patient-centered, cross-sectional survey. PLoS One. 2018 Jun 1;13(6):e0197811.

[2] McManimen SL. et al. Deconstructing post-exertional malaise: An exploratory factor analysis. Journal of health psychology. August 2016:1359105316664139.

[3] Karfakis N. The biopolitics of CFS/ME. Stud Hist Philos Biol Biomed Sci. 2018 Jun 8. pii: S1369-8486(17)30070-5.

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Constipation in kids with autism: financial as well as health implications

I've always be a little perplexed about the response to gastrointestinal (GI) issues appearing alongside autism. Time after time after time, the peer-reviewed science domain serves up evidence that both functional and more pathological bowel issues are over-represented in autism (see here and see here for examples) and cause considerable suffering. Yet some parts of the lay and research community seemingly 'gloss over' such findings. It's almost as if the acceptance that 'some' autism seems to be 'bowel-related' would shatter some people's view of autism. Perhaps it's also because there would have to be some [partial] acceptance of other related uncomfortable findings too (see here)...

The findings reported by Brandon Sparks and colleagues [1] continue the theme that functional bowel issues such as constipation are part and parcel of some autism. And not only do they have often severe health implications for the person concerned, but there may also be wider economic implications too. So, researchers concluded that: "ED [emergency department] visits by children with ASD [autism spectrum disorder] were more likely to be constipation-related compared with visits by children with other chronic conditions or children with no chronic conditions." Further: "Hospital charges were higher in children with ASD than in those without chronic conditions."

Based on data derived from the Nationwide Emergency Department Sample (NEDS), a US initiative that records diagnostic trends in ER (also known as Accident & Emergency here in Blighty) visits, authors looked for those with and without a diagnosis of autism (ASD). They observed that constipation was an important variable in those ER visits when it came to autism and continued to be important when ER visits turned into hospital admissions. They conclude by saying that there may be a need for "developing more effective outpatient therapies for constipation in children with ASD."

Constipation might not sound like a condition that requires an ER visit. But if and when it does, I guess you could probably say that it's something quite serious. Just as reports in relation to those with a learning disability have highlighted how constipation is (a) over-represented, and (b) has actually been cited as a cause of death (see here), so perhaps you can see why there should be a lot more urgency in this area of the autism research and practice landscape.

I added in the 'financial as well as health implications' bit to the title of this post to stress how, even if someone chooses to ignore the pain and physiological effects that constipation can cause, such symptoms are also placing quite a burden on resources and finances. I personally don't much like the idea of talking too much about 'how much autism costs' but if that's the only way to make people listen and actually do something about bowel issues in relation to autism, then I'm quite willing to continue to talk money and strains (no pun intended) on resources...

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[1] Sparks B. et al. Constipation in Children with Autism Spectrum Disorder Associated with Increased Emergency Department Visits and Inpatient Admissions. The Journal of Pediatrics. 2018. June 1.

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The estimated prevalence of childhood autism in Nepal (based on the AQ-10)

I read with some interest the paper by Michelle Heys and colleagues [1] talking about an estimated prevalence rate of autism in Nepal. The figure they arrived at was: "an estimated true prevalence of 3 in 1000 (95% confidence interval 2–5 in 1000)."

Unless you are Nepalis or really, really interested in the epidemiology of autism worldwide (raises hand slowly), you're probably not going to be particularly 'excited' by such findings. I'm blogging about them however, because there are a couple of points of interest to take from the Heys paper. Not least that the (estimated) prevalence of autism seems to be really, really low in Nepal. I'm also quite interested in the assessment tool used - the Autism Spectrum Quotient (AQ) - and some comments made about autism from some of the parents of participants as potentially also affecting the results obtained.

The Heys study is actually a few studies included in one peer-reviewed write-up. First and foremost, researchers identified a potentially suitable population-based screening tool for autism, then adapted and translated said screening tool "in the Nepali language", then checked the acceptability of the translated assessment tool and finally, set about administering the translated assessment tool and arriving at an estimated prevalence rate. As I've already mentioned, the assessment tool settled on was the AQ-10. The decision to use this tool was taken because out of 12 assessment schedules looked at, the AQ-10 'fitted best' researchers criteria (including being free to use).

The estimated prevalence rate was arrived at on the basis of over 4000 children being 'screened' using the AQ-10. "Fourteen children scored > 6 out of 10 [on the AQ-10], indicative of elevated autistic symptomatology, of which 13 also screened positive for disability." That 'screened positive for disability' refers to the "report of social and communication difficulties, as well as physical, learning and behavioral disability using the Module on Child Functioning and Disability (MCFD) produced by UNICEF and the Washington Group on disability statistics... for use in children and young people aged 2–17 years." The authors go on to mention that those 14 children who scored 6 or greater on the AQ-10 probably reflected "children with complex needs and more likely more severe autism." Indeed they also note: "Of those children who screened positive for autism symptomatology, almost all also screened positive for physical, learning and behavioral disabilities." Yet again, autism rarely appears in some sort of diagnostic vacuum (see here).

I'll freely admit that I am ever-so-slightly critical of the AQ and its application to autism screening. I'm critical because autistic traits are not necessarily something exclusive to a diagnosis of autism (see here for one example) and short screening instruments for autism like the AQ are rarely able to tease out the possibility of other diagnoses being pertinent (perhaps even more pertinent than the label of autism). When it comes to the use of the AQ as a screener for possible adult autism, well, one only needs to look at the 'English experience' of adult prevalence estimate studies to see that results weren't exactly optimal (see here) (albeit based on the use of the AQ-20 [2]).

Do I therefore agree with the use of the AQ-10 in the Heys Nepal autism prevalence study? Well, sitting in a high-and-mighty 'with hindsight' position (😉) I would have perhaps gone with something a little more comprehensive or at least included another instrument alongside. I say this on the basis that 10 questions don't really provide enough detail when it comes to big claims about estimated autism prevalence (as per the title of the paper). The fact also that the majority of the 14 children picked up by the AQ-10 as showing 'elevated autistic symptomatology' also presented with a complex pattern of disability (including 'learning and behavioral disability) is also at odds with the typical guidance on the use of the AQ-10: "A quick referral guide for parents to complete about a child aged 4-11 years with suspected autism who does not have a learning disability." This bearing in mind also that the authors used the AQ-10 in a second wave of data collection (the MCFD was used in the first wave when such 'learning and behavioral disability' would have been initially picked up). I don't want to be too critical, but...

The second reason for blogging about the Heys paper concerns some of the comments made about autism in the context that typically Western views on autism - abilities and disabilities - are not necessarily shared the world over and might have affected the results obtained. I'm not going to recite the quotes included in the Heys study but let's just say that the point made by the authors: "would find a potential diagnosis of autism challenging to accept or endorse" kinda sums up the feelings portrayed by some parents. Bearing in mind, the AQ-10 was completed by parents or primary caregivers, and well, it's not beyond the realms of possibility that some parents may have put a more 'positive spin' on some of their responses...

There are other important points raised in the Heys paper - "children who screened positive for autism symptomatology were more likely to be stunted... Nutritional deficits in children with disabilities and learning difficulties are common and can not only be a cause of cognitive deficits, but also contribute to the failure to reach full developmental potential in the presence of a developmental condition" - but I've gone on enough for now. Suffice to say that the very conservative prevalence estimates produced by Heys et al are probably not a true reflection of the scale of autism in Nepal. Much more research is indicated.

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[1] Heys M. et al. The Estimated Prevalence of Autism in School-Aged Children Living in Rural Nepal Using a Population-Based Screening Tool. J Autism & Dev Disord. 2018. May 31.

[2] Brugha TS. et al. Validating two survey methods for identifying cases of autism spectrum disorder among adults in the community. Psychol Med. 2012 Mar;42(3):647-56.

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'Growing out of autism' was talked about way back in 1993

I appreciate that for some people mention of the words 'growing out of autism' in the title of this post will be met with a furrowed brow. I appreciate that the very sweeping generalisation that all autism that is, has been or ever will be, is lifelong and immutable is something that some people adhere to almost religiously, as words like 'oh, they weren't autistic in the first place' ring out in some quarters to counter such 'growing out of' sentiments. I'm certainly not going to be able to change anyone's mind, and neither do I seek to.

But the idea that autism, for some, is not lifelong is something that is very evident in the peer-reviewed science domain and beyond. I've talked about it on a few occasions on this blog (see here and see here) and how 'subsequently not fulfilling the diagnostic criteria for autism' having previously done so, may have some quite profound implications beyond just the core presentation of autism (see here).

Recently PubMed decided to list the paper by Anne-Liis von Knorring & Bruno Hägglöf [1] published way back in 1993 (the year we were all asked to 'Shake the Room'). Theirs is an interesting paper insofar as providing a window on autism research decades back; even referring to a time when the term 'childhood psychosis' was still being used.

They report 'follow-up' results of a group of children and young adults residing in Northern Sweden. Previously diagnosed with childhood psychosis, all cases were re-evaluated and: "According to DSM-III-R, 38 children met the criteria of "autistic disorder"." Authors reported on various aspects of behaviour some 8-9 years later for 34 of the original 38 participants, and what happened to signs and symptoms in terms of things like stability.

For most participants, there was little change in their diagnostic status. Autism for the majority, was lifelong and indeed for some, showed "a mildly deteriorating course" but typically with some improvements in language and communication. The authors also mention how: "In one case symptoms of schizophrenia developed" which kinda taps into another area of increasing interest these days concerning the over-representation of psychiatric comorbidity in the context of autism (see here).

But then, something interesting: "Only one boy had "grown out of" autism without showing any autistic-like symptoms at all." Yes, it's only 1 out of 34 (two others from the original cohort who did not take part in the follow-up study were reported to be "well-functioning employed adult young men living by themselves") but nonetheless...

I've often pondered why 'growing out of autism' has not been received with open arms by some. I've come to the conclusion that there are likely a few reasons why.

So first, the idea of 'autistic identity' - where autism is seen as so much more than a diagnosis - might have something to do with it. Although identities change, modify and adapt throughout the lifespan, there is perhaps something 'safe' about the idea that being defined as 'autistic' is a constant, and the sense of belonging that perhaps follows, alongside terms like 'neurodiversity' gaining popularity. The evidence suggesting that such a constant might not be a universal constant for everyone is perhaps jarring for some. Indeed, from a neurodiversity point of view, those who are no longer autistic should perhaps then be viewed as transitioning to neurotypical perhaps...?

Allied to this sense of 'identity' I do wonder if some of the terminology associated with 'growing out of autism' might also play a role in how the concept has been viewed down the years. Take for example the term 'optimal outcome' made in reference to those who were were once autistic but at a later point don't hit clinical cutoff points. The insinuation is that where a diagnosis of autism or the presentation of significant autistic traits persists, there is an opposite: 'not optimal'. You can perhaps see how this paints autism, particularly in the context of that autistic identity. And it is indeed timely that there is research chatter about 'reframing optimal outcome' [2] recently...

Similarly, the idea of 'growing out of autism' also taps into the 'medicalisation' of the label. So, minus making too many direct comparisons, when individuals don't meet the clinical thresholds for the label (having previously done so), one could argue that this is evidence that some autism is akin to other medical diagnostic labels that wax and wane, whether naturally or following intervention. I daresay also that autism as seemingly being transient for some, also sits in the same domain of autism being 'acquired' for some. Y'know, those various examples in the peer-reviewed literature that suggest that infection (viral, bacterial, etc) can lead to autism (see here) or that autism appearing alongside various inborn errors of metabolism (see here) is a reality too.

I'm just opining as an outsider looking in, but these are some of the reasons that spring to mind for the seeming lack of interest (even disdain in some quarters) for such a group. Minus any sweeping generalisations from me, all of those previous points have collectively been noted in another context: sexuality...

Personally, I don't see such 'growing out of autism' cases as a threat to either identity or any other aspect of autism. You've probably heard of the term 'if you've met one autistic person, you've met one person with autism' and well, that goes as much for those who 'lose' their diagnosis as it does for anyone else. Anyone with some scientific curiosity should really be asking the question 'why?' Why do some people manifest autism (and reach all the diagnostic cutoff points for autism) at one part in their life but not another? Is it about masking or are there more complicated processes - psychological, biological, genetics - at work?  What role does intervention play (if any)? And what lessons can we learn from such a group outside of the idea that autism is a truly heterogeneous label?

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[1] von Knorring AL. & Hägglöf B. Autism in northern Sweden. A population based follow-up study: Psychopathology. Eur Child Adolesc Psychiatry. 1993 Apr;2(2):91-97.

[2] Georgiades S. & Kasari C. Reframing Optimal Outcomes in Autism. JAMA Pediatrics. 2018. June 25.

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Headline fail: "Autism traits could be 'edited' out genetic trial suggests"

The Telegraph June 25 2018

"Autism traits could be 'edited' out genetic trial suggests" was one of the headlines that accompanied the publication of the findings by Bumwhee Lee and colleagues [1].

The Lee article details some interesting science following the use of something called CRISPR-Cas9 gene editing (see here) or more precisely the use of a new-ish development to this technique - "CRISPR–Gold, a nonviral delivery vehicle for the CRISPR–Cas9 ribonucleoprotein." CRISPR is one of the hottest things in science at the moment, as the words 'find, cut and paste' move to a genetic level (see here) and promises so much. In the Lee study, the target was the metabotropic glutamate receptor 5 (mGluR5) gene as a move to "efficiently reduce local mGluR5 levels in the striatum."

Oh, did I also mention that this research was done using mice? Indeed, this was a study of mice engineered to display some of the molecular and behavioural characteristics of a condition called Fragile X syndrome (FXS). As such, authors reported that the use of CRISPR-Gold injections into the striatum of said FXS mice correlated with a reduction in certain behaviours such as obsessive digging and leaping into the air. The authors opine that such behaviours 'overlap' with those noted in autism (FXS has a 'connection' to autism) and voilà, a link to autism is made.

Aside from that brief overview of the findings from Lee et al just mentioned, I'm not going to go too much into the nitty-gritty of the actual results. A cobbler should stick to his last and all that, and others have done a far better job than I ever could in discussing the science (see here). I do however want to make a case that the 'autism traits could be edited out' headline represents a fail when covering the Lee findings.

I say 'headline fail' in the title of this post because well, it is. Not only does it assume that obsessive digging and sporadic leaping into the air made by mice are singularly autistic traits, it takes a few sentences before the word 'mice' is even mentioned in the coverage. I've talked before about the caution(s) needed when translating animal findings to real people (see here) and how autism in particular, seems to be a label ripe for mass sweeping generalisations from 'autistic animals' to autistic people. I'm not saying that some of the features of autism are uniquely human (see here) but rather that is it premature to even imply that the traits of autism can be 'edited out' on the basis of a single mouse or other animal genetic study.

I've already mentioned about a 'connection' between FXS and autism but it is perhaps also important to realise that there seem to be many routes that bring someone to a diagnosis of autism. FXS is one condition that manifests autistic traits but it is not the only one and certainly science does not yet know everything there is to know about the genetics of autism and FXS. And just before anyone starts talking about autism being universally 'in-born' and 'genetic' as it is [assumed] in FXS, well, the peer-reviewed research evidence might just disagree with you (see here for one example)...

Finally there's another aspect to this work that requires sensitive media handling: the ethics of 'editing out' autistic traits. I know this is a 'hot potato' area, as an increasingly vocal - certainly on social media - group of people on the autism spectrum talk about their strengths as well as their disabilities. Much of this discussion is framed around the notion that autism is not something separate from who they are but rather a fundamental part of who they are. If one takes this viewpoint, it is logical to assume that 'editing out' autistic traits might mean something rather ominous to some people...

The point I'm trying to get across is that the Lee paper is seemingly good science. It faithfully reported the results of an exciting new technology that holds promise for many different labels, conditions and diseases (see here). The issue however, is that the reporting of such research needs to be accurate and responsible. Headlines in particular, need to mention the word 'mouse' if it was a mouse study. They need to avoid sweeping generalisations that infer that digging and leaping behaviour in animals are generalisable as autistic traits (certainly the latest ICD-11 schedule says nothing about such behaviours), and they need to be sensitive to the fact that 'editing out' may very well provoke significant anxiety among some people on the autism spectrum. All for the sake of an attention-grabbing headline...

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[1] Lee B. et al. Nanoparticle delivery of CRISPR into the brain rescues a mouse model of fragile X syndrome from exaggerated repetitive behaviours. Nature Biomedical Engineering. 2018. June 25.

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