"Maternal infection during pregnancy may be responsible for some portion of autism..."

The quote heading this post - "Maternal infection during pregnancy may be responsible for some portion of autism..." - comes from the paper published by Benjamin al-Haddad and colleagues [1]. They continue a research theme observing that pregnancy infection may have some quite far-reaching effects on the unborn child and their subsequent risk for various conditions / labels / diagnoses (see here for example).

So: "A total of 1 791 520 Swedish children born between January 1, 1973, and December 31, 2014, were observed for up to 41 years using linked population-based registries." As per use of the term 'population-linked registries', this was another study originating in Scandinavia (this time in Sweden) and their important research registries (see here). The important variables being analysed were the presence of "fetal exposure to any maternal infection while hospitalized during pregnancy" and "diagnosis of autism, depression, bipolar disorder, or psychosis among offspring."

Results: "fetal exposure to any maternal infection increased the risk of an inpatient diagnosis in the child of autism... or depression" but not seemingly for bipolar disorder or psychosis. The magnitude of the risk could be described as 'notable' but perhaps not exceptional. 'Urinary tract infection' (UTI) is mentioned as one infection that seemed to increase the risk of offspring diagnosis; something that has been kinda hinted at in other research literature [2] outside of the classic 'acute psychosis and UTI' research that appears in the peer-reviewed literature (see here).

Mechanisms? Well, it doesn't take a genius to figure out that most infection has a bearing on immune system functions and onward concepts like inflammation. There's quite a long history of immune system 'issues' and inflammatory processes being potentially connected to labels like autism and depression (see here and see here respectively) that provide a template for further investigation. This, bearing in mind, that pregnancy is already a time of 'reprogrammed' immune function so that a mothers body can 'tolerate' the developing fetus. As good as any place to start for further investigations...

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[1] al-Haddad BJS. et al. Long-term Risk of Neuropsychiatric Disease After Exposure to Infection In Utero. JAMA Psychiatry. 2019. March 6.

[2] Hadjkacem I. et al. Prenatal, perinatal and postnatal factors associated with autism spectrum disorder. J Pediatr (Rio J). 2016 Nov - Dec;92(6):595-601.

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"...although their autistic traits were sometimes helpful, at other times they hindered their progress"

There's quite a lot of important information to be gleaned from the findings reported by Ginny Russell and colleagues [1] (open-access) following their questioning of autistic adults (or adults with autism if you prefer) about how they viewed themselves. How for example, said participants viewed their abilities and how "these abilities had helped them in their everyday lives: at work, in their relationships with other people, and at home" makes for interesting firsthand reading.

I have quite a lot of time for the primary author on this paper given other research she has produced (see here) and her recent involvement in an important paper that basically said what many people had been thinking for a while: autism research is typically biased against those who present with autism and intellectual (learning) disability [2]. That last research theme seems to have been something (partially) taken on board in this recent paper from Russell et al given their inclusion of voices from various 'parts' of the autism spectrum including those "receiving high-level support (living in full-time residential care)."

So: "All but one participant was able to describe their own traits and how these had benefited them, and the majority of participants could and did attribute these to autism." Various traits were discussed in the interviews (n=28) held with participants (n=24); key among them were "perceptual differences, memory, focus, and attention to detail, logic, and vivid imagination." Interview data / responses were also coded into various themes: "(1) experience of difference, (2) false dichotomies, and (3) moderating influences" which similarly provided further interesting data.

In relation to the 'experience of difference' we are told that this theme "encompassed how participants conceptualized the causes of their difference from “neurotypical” (NT) individuals." Although I am less than enamoured with the misnomer that is 'neurotypical' (see here for some discussions on how there is no single way for a brain to be 'normal') there is some important information contained in those accounts. Specifically how "most participants talked about autism as a set of qualities they possessed rather than an illness they had."

The theme of 'false dichotomies' was equally revealing as: "Participants gave accounts of traits as advantageous and simultaneously disadvantageous in the workplace, in relationships, and at home." The phrase 'double-edged sword' seems to be particularly apt when it came to the descriptions offered by participants in the Russell study; also denoting how: "There was no boundary between a strength and a weakness." This continues a theme from other research discussed recently (see here). Interestingly too under this category, some participants reported that: "there is no “autism—self” opposition... thus [they] saw their abilities and skills more holistically as generalized personality traits, which included autistic traits." Autistic traits as part of a wider picture eh?

The final theme - "Moderating influences" - also included some interesting data. Authors defined this as: "Factors that might determine whether a participant experienced a trait as advantageous or disadvantageous were classified as moderating influences." Perhaps unsurprisingly, social context was something mentioned in this theme, with examples like serving in the army or being incarcerated in prison being places where "a lack of empathy" and "sticking to routines" respectively, were seen as the right places to present such behaviours. Personally I'd quibble that a lack of empathy is a good place for the armed forces given that serving in active theatre is only part of the job but ho-hum. Another important part of the 'moderating influences' theme was the issue of 'controllability and extent'. As per my musings on the issue of 'stimming' and autism (see here again) this is probably the best example of that 'double-edged sword'. How things like focus, attention to detail and logic whilst all very positive traits, can sometimes become 'out of control' and cause all-manner of issues to a person.

There are of course caveats to the Russell findings, not least that their study reflected "a lack of severely intellectually and language-impaired participants" and so results cannot be generalised to everyone on the autism spectrum. Indeed they offer a solution: "Eliciting the opinions of these groups would require a different approach, perhaps observational" which really should be a research priority (see here). I'd also have been interested to see data on the comorbidity profile of the participant group too, bearing in mind that autism rarely appears in some sort of diagnostic vacuum (see here). And I'm also minded to mention that similar to other discussions on the 'positives' of other diagnostic labels (see here) one has to remember that autistic traits are not just something noted alongside a diagnosis of autism, and what this means when using emotive terms like "autistic advantage". This, particularly in the context that autism is diagnosed on the basis of traits significantly impinging on functioning and daily life (see here).

I suppose the bottom line from the Russell findings is summed up pretty well in their conclusions: "The findings make us wary of describing autistic advantages as fixed traits, rather their expression (and development) is context dependent." In other words, things like 'situation' influence whether a trait is seen as a deficit or an advantage. And just because a trait might initially be start out as an advantage or a deficit does not mean that it will necessarily stay that way across many different situations and various different time periods...

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[1] Russell G. et al. Mapping the Autistic Advantage from the Accounts of Adults Diagnosed with Autism: A Qualitative Study. Autism in Adulthood. 2019. Apr 3.

[2] Russell G. et al. Selection bias on intellectual ability in autism research: a cross-sectional review and meta-analysis. Mol Autism. 2019 Mar 1;10:9.

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"In Utero Exposure to SSRIs and Development of Mental Disorders: A Systematic Review and Meta-analysis"

The title heading this post - "In Utero Exposure to SSRIs and Development of Mental Disorders: A Systematic Review and Meta-analysis" - comes from the findings published by Annemette Halvorsen and colleagues [1] on a topic that has been of some research interest for quite a few years (see here and see here for example).

SSRIs denote a class of medicines called the selective serotonin reuptake inhibitors, principally used to treat/manage various types of depression. Although in quite a few cases a lifesaver, such medicines also come with a risk-benefit profile (same as all medicines), a risk-benefit profile that also extends to their use during important times such as pregnancy. Minus any scaremongering sentiments, for quite a while now, there has been some interest in whether SSRI use during pregnancy *might* have some important implications for offspring health and development [2]. Such *associations* whilst potentially important, need of course to be balanced with the reasons why SSRIs are used, and how for example, depression is not typically something that magically disappears as and when a woman becomes pregnant...

The Halvorsen paper represents a "systematic review and meta-analysis" of the pertinent research literature examining whether "in utero exposure to selective serotonin reuptake inhibitors (SSRIs) is associated with increased risk of developing mental- or behavioral disorders." Such a 'boiling down'  of the research literature was, we are told, "conducted in adherence with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guideline" and specifically covered in connection to various childhood developmental labels such as attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD).

Based on their analysis of the available data - "20 studies were included in the review and results from 18 of these were meta-analyzed" - researchers observed "a statistically significant positive association between in utero exposure to SSRIs and mental- or behavioral disorders such as autism spectrum disorder..., attention-deficit/hyperactivity disorder... and mental retardation." I say that with the suggestion that intellectual (learning) disability might be a more appropriate description for that last label mentioned. The authors caution however that their results do not necessarily mean that prenatal SSRI exposure *causes* something like autism or ADHD: "these associations do not necessarily reflect a causal relationship since the results included in this meta-analysis are likely affected by residual confounding by indication, which is likely to account for some (or all) of the positive association."

So what to make of this research? Well 'it's complicated' is the long-and-short of it. Minus any sweeping generalisations I'll take you back to some other research (see here) that did try and disentangle the 'causality' side of this area of study (whether underlying maternal depression or antidepressant use was the most important variable). The findings reported by Rai et al [3] did [cautiously] talk about how "children exposed to antidepressants during pregnancy seemed to be at a higher risk of autism, particularly autism without intellectual disability, than children of mothers with psychiatric disorders who were not treated with antidepressants during pregnancy." Other research however has observed something rather different (see here). Y'see, it's complicated.

So all I can really say is that more research is required, and if in doubt, talk to your prescribing physician.

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[1] Halvorsen A. et al. In Utero Exposure to SSRIs and Development of Mental Disorders: A Systematic Review and Meta-analysis. Acta Psychiatr Scand. 2019 Apr 2.

[2] Pedersen LH. et al. Selective serotonin reuptake inhibitors in pregnancy and congenital malformations: population based cohort study. BMJ. 2009;339:b3569.

[3] Rai D. et al. Antidepressants during pregnancy and autism in offspring: population based cohort study. BMJ. 2017;358:j2811.

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Rituximab for Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: a fail

"B-cell depletion using several infusions of rituximab over 12 months was not associated with clinical improvement in patients with ME/CFS [Myalgic Encephalomyelitis/Chronic Fatigue Syndrome]."

That was the conclusion reached in the paper by Øystein Fluge and colleagues [1]. Their findings based on the use of rituximab, "a drug that is often used to treat inflammatory diseases (for example, rheumatoid arthritis) and lymphoma" were not entirely unexpected (see here) as a familiar theme of small scale results [2] being 'positive' but not translating into gains during more methodologically-sound study was rehashed.

The Fluge paper also has an accompanying easy-read summary of the results [3] which really aids my job. The long-and-short of it was that over 150 patients diagnosed with ME/CFS were enrolled into the study. Most had been ill with ME/CFS for several years. They were randomly assigned to receive either rituximab or saline (control) over the course of 1 year. Said timing and dosage of rituximab started with "2 infusions of rituximab, 500 mg/m2 of body surface area, 2 weeks apart, followed by 4 maintenance infusions with a fixed dose of 500 mg at 3, 6, 9, and 12 months." Participants completed various 'self-reported' questionnaires about their fatigue and functioning over a 2-year period alongside some more objective measurement of physical activity. Results were collated, and well, there was very little difference between rituximab and saline use noted when comparisons were made. What was notable in the published findings were the quite high rates of side-effects observed: "Twenty patients (26.0%) in the rituximab group and 14 (18.9%) in the placebo group had serious adverse events" and over a third of those adverse events were considered 'possibly or probably related to' rituximab use.

What's more to say? Well, the discrepancy between these latest findings and other previous results suggests a couple of potentially important processes *might* be at work. First, the placebo response seems to be quite prominent in this patient group. I say that on the basis that the calculated placebo response among those receiving saline ranged between 25-50% across the various centres that recruited participants for this study. Other commentators (see here) have similarly mentioned how the placebo response seems to be typically quite high in ME/CFS, and how that might have also been on show in other studies too (see here). This could have lots and lots of implications for various intervention trials relevant to ME/CFS. Second, one has to consider that similar to various other labels that include some significant heterogeneity 'under them', there may be responders and non-responders [4] to consider in relation to the use of something like rituximab [5]. Third, and also quite important is to mention that although negative, these results don't invalidate the idea that immune function seems to have something of an important relationship with quite a few cases of ME/CFS (see here for example).

Having said all that, it is difficult to talk about further research on rituximab with ME/CFS in mind on the basis of the Fluge negative results. Not least because, like all medicines, there is a risk-benefit balance to be struck with such a preparation and failures using gold-standard experimental methodologies cannot be easily brushed under the scientific carpet...

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[1] Fluge Ø. et al. B-Lymphocyte Depletion in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial. Annals of Internal Medicine. 2019. April 2.

[2] Fluge Ø. & Mella O. Clinical impact of B-cell depletion with the anti-CD20 antibody rituximab in chronic fatigue syndrome: a preliminary case series. BMC Neurol. 2009 Jul 1;9:28.

[3] Patient Summary: Rituximab for Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Annals of Internal Medicine. 2019. April 2.

[4] Rekeland IG. et al. Rituximab Serum Concentrations and Anti-Rituximab Antibodies During B-Cell Depletion Therapy for Myalgic Encephalopathy/Chronic Fatigue Syndrome. Clin Ther. 2018 Nov 28. pii: S0149-2918(18)30514-9.

[5] Morris MC. et al. Leveraging Prior Knowledge of Endocrine Immune Regulation in the Therapeutically Relevant Phenotyping of Women With Chronic Fatigue Syndrome. Clin Ther. 2019 Mar 28. pii: S0149-2918(19)30112-2.

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a "family history of mental and neurological disorders is associated with autism risk"

There's a couple of ways that one could interpret the findings reported by Sherlly Xie and colleagues [1] who concluded that: "family history of mental and neurological disorders is associated with autism risk, and the familial component of autism etiology may differ by presence or absence of co-occurring intellectual disability."

You could 'use' such findings to imply that autism is much more likely expected as and when one or other parent presents with something like "ADHD [attention-deficit hyperactivity disorder], ID [intellectual disability], other childhood disorders, alcohol misuse, drug misuse, NAPD [non-affective psychotic disorder], bipolar disorder, depression, anxiety disorders, OCD [obsessive-compulsive disorder], stress-related disorders, other neurotic disorders, eating disorder, or personality disorder." Indeed, when I tweeted the Xie paper out, I got one (joking) reply saying something along the lines of 'my kids didn't stand a chance' in light of the familial connection being made.

The other way that one could approach the Xie findings is to look at them as part of a bigger picture, where familial genetic, epigenetic and perhaps even non-genetic influences might overlap across an array of different labels. Further, the possibility that if one was able to get to the source(s) of such shared 'risk', one might potentially be able to positively affect a whole range of labels and diagnoses and perhaps mitigate some of their more quality-of-life sapping characteristics associated with them.

I'm an optimist and take the Xie findings with option number 2 in mind. I say that on the basis that whilst some people talk about the 'positives' of something like ADHD or bipolar disorder (perhaps in the context of the movement known as 'neurodiversity') I'm very much more influenced by the peer-reviewed research talking about the heightened risks that come with such diagnoses. Risks that can very much influence important facets of quality of life and sometimes in some pretty extreme ways (see here and see here for examples).

Anyhow, back to the Xie findings and yet another population-based cohort study with participant numbers totalling about half a million. With those sorts of numbers, you probably won't be surprised to hear that this was a study yet again (see here) utilising some of those marvellous Scandinavian registries; this time in Sweden. 'Index people' comprised births where among other things, their medical and other records could be "linked to both biological parents" and beyond (i.e. "Through the eligible index persons, we ascertained their first- to fourth-degree relatives who had resided in Sweden for at least 2 years"). Researchers trawled the records looking for one or more of those psychiatric and/or neurological diagnoses and looked to see if there was an connection to the index cases where autism was diagnosed.

Results: "Having a first-degree relative with ASD [autism spectrum disorder] without ID was associated with a 9-fold increase in odds of ASD without ID in index persons compared with those with unaffected first-degree relatives." Nothing particularly novel about those findings in light of other independent studies reaching similar conclusions (see here and see here).

Then: "Having a first-degree relative with ADHD, ID, other childhood disorders, alcohol misuse, drug misuse, NAPD, bipolar disorder, depression, anxiety disorders, OCD, stress-related disorders, other neurotic disorders, eating disorder, or personality disorder was associated with 1.5- to 4.7-fold increases in odds of the index person having ASD without ID compared with those with first-degree relatives without each of these conditions." Again, alongside other independent results, we are told that: "These associations diminished for more distant family relations."

When it came to autism with intellectual (learning) disability, authors reported some equally important connections: "Having a first-degree relative with ASD with ID was associated with a 14.2-fold increase in odds of the same outcome in index persons compared with those with unaffected first-degree relatives." They also observed some similar connections with regards to first degree relatives (defined as fathers, mothers, and full siblings) with one or more of those psychiatric disorder and the risk of autism and ID as that seen in the risk of autism without ID. In short, the familial presence of various psychiatric and/or neurological diagnoses seemed to up the risk of autism (with or without learning disability).

Oh, and lest I forget, another important detail was mentioned in the Xie paper: "The prevalence of ASD with and without ID was 0.4% and 1.5%, respectively."

I don't think anyone should be particularly surprised by the Xie findings, but that doesn't mean that they aren't important. They're important for the implementation of screening programmes for potentially 'at-risk' populations when it comes to the early diagnosis of autism, bearing in mind that autism can seemingly come about for lots and lots of different reasons (see here and see here) and early diagnosis might not necessarily be relevant to everyone (see here). The findings are also important for future research looking at what 'common mechanisms' might be at work. And, as I've said, they're important because of what it might eventually mean when it comes to intervening in various diagnoses with some potentially shared biology.

Just before I go, there is another angle to mention as a consequence of the Xie results. An angle that I've talked about quite a bit on this blog in two parts: (i) 'autism genes are probably not just genes for autism' (see here) and (ii) 'autistic traits are not just confined to a diagnosis of autism' (see here and see here). It strikes me that the Xie findings provide some quite strong support for both these points...

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[1] Xie S. et al. Family History of Mental and Neurological Disorders and Risk of Autism. JAMA Netw Open. 2019;2(3):e190154.

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"support the hypothesis that early life gut microbiota are associated with neurodevelopmental outcomes in childhood"

Question: "Is the gut microbiome in infancy associated with neurodevelopment in children at preschool age?" Answer: "findings appear to support the hypothesis that early life gut microbiota are associated with neurodevelopmental outcomes in childhood."

That was the about the sum of the findings reported by Joanne Sordillo and colleagues [1] and their analyses of "Ages and Stages Questionnaire, third edition (ASQ-3)" data and "microbiome analysis using 16S rRNA gene sequencing" of stool samples from over 300 infants who were taking part in something called the "Vitamin D Antenatal Asthma Reduction Trial (VDAART)."

The Sordillo paper is open-access so doesn't require any rehashing from me. A few details do however stick out. So: "findings suggest that the infant gut microbiome may be associated with subsequent development of communication, personal and social, and fine motor skills in typical developing 3-year-old children and with odds of possible developmental delays." The authors were specifically drawn to "Clostridiales (Lachnospiraceae genera and other, unclassified Clostridiales taxa)" as being important when it came to their stool analyses. Said bacteria seemed to be *associated* with various ASQ-3 data covering "poorer ASQ-3 communication... and personal and social... scores and with increased odds of potential delay for communication... and personal and social skills."

The word 'autism' is also mentioned in the Sordillo paper, alongside the idea that (1) "poor performance of children on the ASQ-3 (particularly on communication skills) at 16 to 30 months of age has been shown to be sensitive (but not specific) for diagnosis of ASDs [autism spectrum disorders]", and (2) "A number of cross-sectional studies comparing the gut microbiome of neurotypical children with that in children with ASDs have reported increased levels of Clostridiales in the gut microbiome of individuals with ASDs, including higher levels of Clostridium,... Clostridium histolyticum,... and Ruminococcus." Indeed, there's also mention of the Luna study [2] covered on this blog previously (see here).

Obviously there are caveats to the Sordillo findings; not least that this all about looking at two variables (ASQ-3 scores and stool bacterial content) and marrying them together at some quite specific time points. I'd for example, be interested to see whether further follow-up studies saw a continuation of the trends described in this paper perhaps covering examination of multiple stool samples taken over different testing occasions. Also going back to the 'autism' suggestion, the authors note that they "did not have data on clinical diagnoses of ASDs for our analysis" so one has to be a little bit careful with any suggestions there too.

Still, such work is important and further contributes to the idea that the brain probably isn't the only place to look when considering things like cognitive and behavioural development (see here). Indeed, as mentioned previously on this blog (see here), a possible role for inflammation 'impairing' social cognitive processes might not be a million miles away from the Sordillo findings on the basis that the new triad - gut bacteria, intestinal permeability, gut immune function - might be really quite important for lots of processes. And then there is another question to consider: if one is able to 'alter' the gut bacterial make-up at an early age, can one potentially affect behavioural and/or developmental outcomes? I say that in the context that something similar has been talked about before (see here).

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[1] Sordillo JE. et al. Association of the Infant Gut Microbiome With Early Childhood Neurodevelopmental Outcomes. JAMA Netw Open. 2019; 2: e190905.

[2] Luna RA. et al. Distinct Microbiome-Neuroimmune Signatures Correlate With Functional Abdominal Pain in Children With Autism Spectrum Disorder. Cellular and Molecular Gastroenterology and Hepatology. 2017; 3: 218-230.

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