Neurodiversity 2.0: Judy Singer setting the record straight

I know I've kinda let this blog slip a little in recent months but work is work and blogging is blogging. Anyhow, I'm back with a short post to bring to your attention a rather important 'revision' presented by Judy Singer on her blog titled: NeuroDiversity 2.0 (see here).
I'm not going to rehash everything that Judy talks about in her post because it's all done exceptionally well in her blogpost. Neurodiversity is the term that has kinda turned into a movement (even a political movement) which has found something of a voice particularly on social media. As a critical voice to neurodiversity (see here) I would say that the concept of neurodiversity has been pushed way beyond it's original meaning and intention and well outside the scientific remit of the description (no, no-one is 'neurotypical' or NT). In her blogpost, Judy aims to clarify some important points about her description of neurodiversity and, as with all good ideas, adapts and modifies them as knowledge has increased. 

Some important things are mentioned by Judy which are worthy of note:

• "Neurodiversity is NOT a Psycho-Medical diagnosis for individuals." She goes on to say that "if Worker A has identified themselves with a specific syndrome, e.g. Autism, in which case call them "autistic". But they are no more neurodiverse than anyone else on the planet." In other words, neurodiverse or neurodivergent are not replacements for autism or autism spectrum disorder (ASD) and they don't magically bestow some differing neurological feature(s) or advantage(s). And just before you ask, "undiagnosed neurodiversity issues" (see here) is basically psychobabble BS and a good example of how neurodiversity has gone well beyond it's remit.
• "Neurodiversity is a term that refers to an obvious and indisputable feature of Earth's biosphere." Basically, everyone is neurodiverse. With all the millions of differing biological processes that everyone encounters and undergoes, every second of every day, neurodiversity is the property of populations not individuals.
• "It is not a synonym for "Neurological Disorder"." I might be repeating myself here but whether diagnosed or 'self-diagnosed' (another inherently problematic issue) with anything remotely related to behaviour and/or the brain, identifying as 'neurodiverse' says nothing about a person and their presentation. 
• "Neurodiversity is a positive principle, but it is NOT a moral principle." As the property of a population, neurodiversity says just that: everyone is different, and we should be proud of our individual differences. I know sometimes people don't like to be seen as different (group membership is a powerful thing), but everyone has strengths and everyone has weaknesses at an individual level. Yes, there are things that society can do to ensure that more strengths are seen as strengths, but that's a different topic altogether.

I'm not expecting Judy's revisions to be immediately and universally accepted by everyone. There are some really ingrained views and opinions about neurodiversity out there, and to some degree, people have already adapted the term to fit their experience and/or agenda. I am hopeful however that we can move on from identity politics (of which neurodiversity has certainly been a focal point) and start to move forward on this. Moving forward means reclaiming labels like autism and ADHD and various other labels that have often got missed from the whole neurodiversity thing (e.g. schizophrenia and psychosis) and moving away from the idea that there is something universally and inherently 'different' about the minds of those with such labels. Science has yet to pinpoint anything that universally distinguishes those diagnosed with autism from those not diagnosed with autism outside of the diagnostic features (similar to every other diagnostic label with a behavioural element to it). If and when it does, then we can start talking about possible neurodivergence, but until then it's all hot air and bluster. 

Bravo Judy for the revision and clarification.

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Maternal polycystic ovary syndrome (PCOS) and autism yet again

Another mash-up post for you today as I bring two papers to the blogging table discussing a topic which has already had quite a bit of airtime on this blog: maternal diagnosis of polycystic ovary syndrome (PCOS) and risk of offspring diagnosis of autism (see here and see here). The papers in question are from Maria Katsigianni and colleagues [1] and Carolyn Cesta and colleagues [2] and, via different experimental means, both papers suggest that women with PCOS have a significantly greater risk of having a child diagnosed with autism or autism spectrum disorder (ASD).

PCOS, in case you didn't know, is a fairly common condition according to the NHS entry. It's characterised by three main features: irregular periods, the presence of high levels of androgens (male hormones) and polycystic ovaries ("ovaries become enlarged and contain many fluid-filled sacs (follicles) that surround the eggs"). Mention of (male) sex hormones in relation to PCOS have led quite a few researchers to suspect a connection between PCOS and autism but another important angle to the diagnosis is a link between PCOS and insulin (the hormone involved in blood sugar control)...

Anyhow, the Katsigianni paper first. This was a systematic review and meta-analysis of the existing peer-reviewed science on the topic of "whether women with PCOS have increased odds of having a child with ASD, while, secondarily, if these women themselves are at high risk of having the disease." Now just before anyone gets shirty with the use of the word 'disease', those are the authors words not mine. I fully go with the idea that autism is not a disease. Their 'boiling down the research literature' efforts yielded 10 studies which included over 30,000 children with autism and some 320,000 "non-ASD children." The results: "Diagnosed PCOS was associated with a 1.66 times increase in the odds of ASD in the offspring" and: "Women with PCOS were 1.78 times more likely to be diagnosed with ASD." Most data on which those findings were based were deemed to be of 'good quality'.

Then to the Cesta study. The primary aim was to "measure, in the general population, the association between maternal PCOS and offspring neuropsychiatric disorders where prenatal androgen levels and/or altered androgen function have been implicated in their etiology." That population was the Sweden, and yet another example of those fantastic Scandinavian population registries being put to good research use. Autism, by the way, wasn't the only label looked at by Cesta et al: "offspring attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD), and Tourette's disorder and chronic tic disorders (TD/CTD)."

Results: based on detecting some 20,000 PCOS-exposed offspring and 200,000 "unrelated PCOS-unexposed offspring" authors concluded that: "PCOS-exposed offspring had increased risk of being diagnosed with ADHD, ASD, and TD/CTD compared with unrelated PCOS-unexposed offspring." Interestingly Cesta observed that the association between maternal PCOS and autism and ADHD was stronger in girl offspring than boy offspring. They then go on to talk about prenatal androgen exposure "leading to ‘hyper-masculine’ behavioral and cognitive traits" in offspring as being one potential biological mechanism.

What's more to say? Well, despite the whole 'male sex hormone' *link* to autism I'd like to see a lot more investigation looking at biological mechanisms. Going back to the insulin link with PCOS, there is a requirement for further study in light of other findings (see here and see here). Insofar as implications for policy, well, preferential screening for autism in offspring when mum has a diagnosis of PCOS could be indicated. This adds to the growing number of other circumstances where such preferential screening seems to be indicated.

Oh, and there could be other areas of potential investigation to consider too (see here)...

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[1] Katsigianni M. et al. Maternal polycystic ovarian syndrome in autism spectrum disorder: a systematic review and meta-analysis. Molecular Psychiatry. 2019. March 13.

[2] Cesta CE. et al. Maternal polycystic ovary syndrome and risk of neuropsychiatric disorders in offspring: prenatal androgen exposure or genetic confounding? Psychol Med. 2019 Mar 12:1-9.

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Why the words "every one of us hovers somewhere along the autistic spectrum" are so dangerous

The Guardian, Friday 26th April 2019

Today I offer another post based on a newspaper report, as Greta Thunberg and her autism diagnosis continue to generate debate (see here).

This time around the report (letter) in question (see here) titled "Autism and Asperger’s are useless diagnostic labels" is the focus, and, in my opinion, quite a dangerous quote included in the text: "... every one of us hovers somewhere along the autistic spectrum."

Why is it so dangerous to imply that the general population is just a (hovering) footstep away from autism spectrum you might ask? Well, I don't think anyone would disagree with the idea that the behaviours noted in autism aren't something that's just magically present in those diagnosed. Such behaviours can be seen in various other states or conditions and/or across various different times of life and maturation. The thing that makes the presentation of such behaviours so distinct and worthy of a diagnosis of autism is the frequency and intensity of such behaviours and importantly, the way they significantly impinge on functioning and daily life. In that respect, yes, autistic behaviours are part of the complex and intricate tapestry of life. But the (sustained) frequency and impact of such behaviours distinguish autism from not-autism.

In such a context then, the idea that everyone hovers along the autism spectrum is a misnomer. It conflates the 'autistic behaviours are part of the complex and intricate tapestry of life' idea with the important reasons why an autism diagnosis is given. This is dangerous because it has the potential to belittle a diagnosis of autism and what it means to those in receipt of such a diagnosis; often a diagnosis that as taken months/years to finally receive. Indeed some people have suggested that the claim that 'everyone is on the autism spectrum' is an "absolute sin"...

It's also dangerous because such thinking opens the door to other things like the self-diagnosis of autism. I've talked about self-diagnosis quite a bit on this blog (see here and see here) and how, self-realisation is often an important (nay, crucial) step to getting an autism diagnosis for many. When however such self-realisation turns to self-identification and/or self-diagnosis on the basis of various 'are you autistic?' screens available on the Internet and beyond (see here), the side-stepping of formal assessments can lead to problems. Problems that can include potentially missing important conditions/states that seemingly overlap with autism or the presentation of autistic traits (see here and see here) as well as also skewing some important narratives from those who have been formally diagnosed with an autism spectrum disorder and their experiences.

I know some people disagree with such a position. Some people think that the diagnostic criteria for autism are too stringent, too medically focused, or access to formal assessment/diagnostic services is too restricted and costly. I don't disagree that we need to do more to 'fill a gap' and ensure that those who might fulfil the diagnostic criteria (including the "significantly impinge on functioning and daily life" bit) should have access to the relevant professional assessment services. But that doesn't mean that anyone and everyone can or should just publicly label themselves as autistic in the meantime.

And finally, as we're learning from the evolution of the neurodiversity movement, autism is still very much to be seen as a disability (see here). So another possible implication of the "every one of us hovers somewhere along the autistic spectrum" sentiment is that we are all somehow 'disabled' by our hovering along the autism spectrum. This is frankly a ridiculous suggestion and, continuing the theme of how dangerous such a sentiment is, could have some really serious consequences for the provision of resources and services for those who are genuinely disabled by facets of their autism. Words matter.

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"An estimated 7.7 million children in the United States (16.5 percent) have at least one mental health disorder"

The press release carrying the quote titling this post - "An estimated 7.7 million children in the United States (16.5 percent) have at least one mental health disorder" - concerns the findings reported by Daniel Whitney & Mark Peterson [1]. Their research letter discussed findings (from the United States) "providing recent national and state-level estimates of the prevalence of treatable mental health disorders and mental health care use in children."

Based on data derived from the 2016 National Survey of Children’s Health (NCSH), a "nationally representative, parent-proxy survey of US children younger than 18 years" that has been mentioned more than once on this blog (see here and see here), researchers present some important data. Including information from over 46 million children (now that's what I call a decent sample size) various trends were observed, notably that almost one in seven children and young adults were reported to have a mental health condition. Such conditions covered "depression, anxiety problems, or attention-deficit/hyperactivity disorder" and by present, I mean that parents responded in the positive to the question: "Has a doctor or other health care provider EVER told you that this child has” a mental health disorder?"

Another detail was also mentioned in the Whitney & Peterson paper: "half of the estimated 7.7 million US children with a treatable mental health disorder did not receive needed treatment from a mental health professional." This was based on responses to the question: "DURING THE PAST 12 MONTHS, has this child received any treatment or counseling from a mental health professional? Mental health professionals include psychiatrists, psychologists, psychiatric nurses, and clinical social workers." Other media on the Whitney / Peterson paper have picked up on this trend (see here) and the possible whys-and-wherefores.

The primary weakness of the NCSH - "parent-proxy survey" - is more than compensated for by the huge participant numbers included for study. The figures arrived at also follow a trend seemingly present across many nations (see here and see here and see here) suggesting that significant numbers of young people are experiencing mental health disorder. We can quibble about the reasons for the increase but there is no mistaking the fact that something is going on. And it's seemingly affecting millions of children and young people around the world...

And as if to prove the point further [2] the startling findings from Gräf et al: "School performance was available for 1462 children (51% boys, mean age 7.3 years). Of these, 41% had signs of at least one MHP [mental health problem]."

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[1] Whitney DG. & Peterson MD. US National and State-Level Prevalence of Mental Health Disorders and Disparities of Mental Health Care Use in Children. JAMA Pediatrics. 2019. Feb 11.

[2] Gräf C. et al. Mental health problems and school performance in first graders: results of the prospective cohort study ikidS. European Child & Adolescent Psychiatry. 2019. Feb 26.

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"The MMR Vaccine Is Not Associated With Risk for Autism"

The quote heading this rather long post - "The MMR [measles, mumps and rubella] Vaccine Is Not Associated With Risk for Autism" - comes from a patient summary covering the the findings reported by Anders Hviid and colleagues [1].

Hviid et al utilised some of those oh-so-useful Scandinavian population registries to provide support for the hypothesis that "MMR vaccination does not increase the risk for autism, does not trigger autism in susceptible children, and is not associated with clustering of autism cases after vaccination." As per some media reporting of the study (see here), such a finding comes at a time when cases of measles in particular, are on the rise (see here) in various parts of the developing and developed world (see here) as a possible/probable consequence of specific viewpoints around vaccination (see here).

The Hviid data, as important as it is, is nothing new in terms of research that has been done on the topic of childhood vaccination and autism risk (see here). Indeed, the author is no stranger to this area of the autism research 'scene' as per other population-based cohort studies looking at "whether vaccination with a thimerosal-containing vaccine is associated with development of autism" [2]. The answer on that peer-reviewed research occasion was probably not: "results do not support a causal relationship between childhood vaccination with thimerosal-containing vaccines and development of autistic-spectrum disorders." The authors have also previously looked specifically at the MMR vaccine and autism risk too [3] albeit with caveats, some of which they addressed in this more recent investigation...

The basics this time around: look through the registry data of some 650,000 children "born in Denmark from 1999 through 31 December 2010, with follow-up from 1 year of age and through 31 August 2013." Collect and collate various information - use of "MMR and other childhood vaccinations, autism diagnoses, sibling history of autism" - and undertake some statistical analysis pertinent to the question of "whether autism developed in children who got the MMR vaccine compared with those who did not during the follow-up period." Researchers also included various potential confounders in their statistical analyses: "maternal age, paternal age, smoking during pregnancy, method of delivery, preterm birth, 5-minute Apgar score, low birthweight, and head circumference."

As per the opening paragraph, the results did not detect any link: "Comparing MMR-vaccinated with MMR-unvaccinated children yielded a fully adjusted autism hazard ratio of 0.93 (95% CI, 0.85 to 1.02)." This based on data where around 95% of the population received the vaccine (around 31,000 were classed as 'MMR-unvaccinated') and 1% (n=6,517) of the total population were diagnosed with autism. A few other observations were also noted by Hviid and colleagues: "The highest risk for autism was conferred by being a boy..., being born in a late birth cohort (2008-2010...), having no early childhood vaccinations..., and having siblings with autism at study entry." Such observations have some important links to other independent findings; for example, children with a sibling already diagnosed with autism are more likely to be diagnosed with autism (see here) and children who did not receive the MMR vaccine were actually slightly more likely to be diagnosed with autism than those who were vaccinated (a trend particularly noted in girls I believe). That last result might tie into other independent findings too (see here).

As with any research study, there were limitations attached to the Hviid investigation. So: "No individual medical chart review was performed" meaning that registry data, as strong as it is, is not the same as "medical records or direct examination of the children by research staff." The use of such population registries across a wide variety of different research topics (see here and see here for examples) carries the same limitation. I'm also minded to mention that population registry data is good for ascertaining population trends, but tends to say little about rare events. Individual issues can sometimes get lost in the statistical noise [4]. The focus of the Hviid study was also specifically on the MMR vaccine. Although not completely au-fait with the vaccination schedule in Denmark (see here) the data say little about the use of other vaccinations, their timing, and any connection (or not) to autism. And finally, I might quibble with the idea that Hviid et al looked at 'susceptible groups' on the basis of the variables they included in their 'autism risk score'. 'Smoking during pregnancy' for example has shown little to no association with autism (see here and see here) (something we can't say when it comes to offspring risk of ADHD for example). Other variables such a maternal metabolic syndrome signs and symptoms during pregnancy (see here) or maternal vitamin supplementation during pregnancy (see here) might have provided some stronger indications of autism risk/susceptibility. And then there's the recent results from Xie and colleagues [5] to also consider...

Still, the Hviid data provide further pretty powerful evidence disproving any population-wide link between MMR vaccine receipt and autism risk. The big question is whether such results, added to quite a lot of other science on this topic, are actually going to make any difference to something like vaccination rates against diseases like measles?

As per an editorial [6] accompanying the Hviid paper we live in an age where scientific data seems to have 'limited persuasive value' for some people and where the concept of 'risk' is often not well understood. The editorial authors also opine that "an alternative explanation of the perceived phenomenon should be provided" which is something else rather important. Not least because some parents, right or wrong, are still adamant that their child had a reaction to one or more of their childhood vaccinations (see here and see here). Autism research has tended to shy away from looking at this specific scenario (see here) thus leaving it unchallenged. Perhaps therefore the time is right for some brave researcher to study those children who were reported to have allegedly undergone a reaction to vaccination and see if anything is significantly 'different' about them on a behavioural and/or biological level? Whether indeed an alternative explanation could be provided for their clinical regression including the influence of variables immediately after the vaccination event [7]?

And as for the message about ensuring children (and adults, particularly vulnerable adults) are vaccinated and protected against diseases, I once again turn to the writings of Roald Dahl, and how measles devastated his family (see here) and what vaccination would have meant to his daughter. A powerful personal message that perhaps needs to be used a little more often alongside the dissemination (and translation) of scientific data to promote the benefits of vaccination to individuals and populations alike...

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[1] Hviid A. et al. Measles, Mumps, Rubella Vaccination and Autism: A Nationwide Cohort Study. Ann Intern Med. 2019 Mar 5.

[2] Hviid A. et al. Association between thimerosal-containing vaccine and autism. JAMA. 2003 Oct 1;290(13):1763-6.

[3] Madsen KM. et al. A population-based study of measles, mumps, and rubella vaccination and autism. N Engl J Med. 2002 Nov 7;347(19):1477-82.

[4] Poling JS. et al. Developmental regression and mitochondrial dysfunction in a child with autism. J Child Neurol. 2006 Feb;21(2):170-2.

[5] Xie S. et al. Family History of Mental and Neurological Disorders and Risk of Autism. JAMA Network Open. 2019; 2: e190154.

[6] Omer SB. & Yildirim I. Further Evidence of MMR Vaccine Safety: Scientific and Communications Considerations. Ann Intern Med. 2019 Mar 5.

[7] Schultz ST. et al. Acetaminophen (paracetamol) use, measles-mumps-rubella vaccination, and autistic disorder: the results of a parent survey. Autism. 2008 May;12(3):293-307.

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Suicide risk and autism: data from "Utah over a 20-year period"

The findings reported by Anne Kirby and colleagues [1] are not for the faint-hearted but continue a vitally important theme in autism research and practice circles looking at suicide risk and autism (see here and see here). The 'value-added' bit to the Kirby results to distinguish them from other study in this area was the reliance on data across a 20-year period from a place that has some important autism research history: Utah in the United States (see here).

So: "Four sources of existing data were utilized for this study: URADD statewide autism surveillance data, statewide suicide surveillance data collected by the Utah Office of the Medical Examiner (OME), the UPDB, and Utah's Indicator‐Based Information System for Public Health (IBIS‐PH)." From such data sources, researchers accessed information for nearly 17,000 people diagnosed with an autism spectrum disorder (ASD) "alive at the beginning of 1998 and at least 5 years of age in 2013." Most were male and most were white. They similarly determined that nearly 9,000 people in their total population - not just those diagnosed with ASD - died by suicide between 1998 and 2017. Again, most were male and most were white. The data were combined and interrogated "to calculate the incidence (in 5‐year intervals) of suicide deaths in people with ASD over a 20‐year period (1998 to 2017) in total, as well as by sex, and compared suicide risk in people with versus without ASD." Researchers also looked at other important variables such as "sex, race, death age, occupational status, marital status, and manner of death" across the groups.

Results: "In the first 15 years of the study (1998–2012), we did not observe differences in suicide cumulative incidences between the ASD and non‐ASD populations." This means that when the groups were compared as a function of death by suicide, the figures for those with autism were not significantly different from those without autism for this time period. By saying that I don't want to belittle the fact that between 1998 and 2012 for example, 2 people out of 5,202 autistic people died by suicide or that 1,671 out of 1,928,484 non-autistic people died. Each of these figures was a person with a life and with a family, and that's something that should never ever be forgotten.

The pattern however changed when researchers looked at the period between 2013 and 2017: "For the most recent time interval (2013–2017), the cumulative incidence of suicide death in the ASD population was 0.17%, which is significantly higher than the non‐ASD population cumulative incidence of 0.11%." This percentage (0.17%) represented 28 deaths from an autistic population of 16,907 and 2,791 deaths from a non-autistic population of 2,630,221. Although a sideline point, I'll also bring to your attention how the autistic population numbers changed over the 5-year blocks of study in the Kirby paper: 1998-2002: 5,202 people; 2003-2007: 8,722 people; 2008-2012: 13,890 people; 2013-2017: 16,907 people.

A few other details were observed by Kirby et al: "In comparison with non‐ASD + suicide cases, ASD + suicide cases had significantly younger average death ages (32.4 years vs. 41.8 years; t = −3.8, P < 0.001)." Also: "Combined, 73% of the ASD + suicide cases used methods for suicide considered to be violent; the remaining 26% used nonviolent methods." This again, is important information.

Researchers also mention how across the 2013-2017 period, another important trend was observed: "suicide risk in females with ASD was over three times higher than in females without ASD (relative risk (RR): 3.42; P < 0.01)." They contrast this with the finding that "there were no documented cases of suicide death among females with ASD during the first 15 years of the surveillance period" and what this could mean when it comes to possible explanations of suicide risk in relation to autism.

There's quite a bit to learn from the Kirby findings. Although there are limitations attached to the study design - "inadequate data on intellectual ability was available to examine the influence ID may have on suicide risk in individuals with ASD" - the study was a good one because of its population-wide focus and the pretty good autism-related resources that Utah has (and has had for many years). It demonstrates once again that the difficult topic of suicide and autism should remain a research priority in order to identify who might be most at risk and why, alongside the ways and means that such risk *might* be mitigated (see here for one example).

And for those who might need someone to text / email / talk to, there are always options (see here for services in the UK or see here for those elsewhere).

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[1] Kirby AV. et al. A 20-year study of suicide death in a statewide autism population. Autism Res. 2019 Jan 21.

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"Are women with autism at an increased risk of adverse pregnancy outcomes?"

The paper by Heléne Sundelin and colleagues [1] provides the blogging fodder today, and research pertinent to the question: "Are women with autism at an increased risk of adverse pregnancy outcomes?" The short answer to the question is yes: "Maternal autism is associated with preterm birth, likely due to an increased frequency of medically indicated preterm births, but also with other adverse pregnancy outcomes, suggesting a need for extra surveillance during prenatal care."

It was refreshing to read the results from Sundelin et al (a research group who are no strangers to autism research) because this was a study devoted to looking at women with autism / autistic women and their pregnancy outcomes. It was distinct from other research on maternal pregnancy outcomes and offspring autism more traditionally seen in the peer-reviewed research literature and covered on this blog (see here and see here for examples).

The source material for the Sundelin study was the Swedish Medical Birth Registry (yes, one of those fantastic Scandinavian population registries again) and records of "2,198 births to 1,382 women with autism and 877,742 births to 503,846 women never diagnosed with autism." When comparing the groups across various different measures including preterm delivery ("defined as <37 completed weeks of gestation"), tobacco smoking during pregnancy and the use of various prescription medicines during pregnancy, some interesting trends were observed.

"Women with autism were at an increased risk of preterm birth..., which after stratification, remained for moderately (32 to <37 weeks) preterm birth." Also: "Maternal autism was also linked with an increased risk of elective cesarean delivery in births to women with autism" and "Preeclampsia was more prevalent in mothers with autism."

Although not seemingly affecting many of the 'adverse' pregnancy outcomes examined, researchers also noted that rates of tobacco smoking (light and heavy use) during early pregnancy were elevated in mums with autism, alongside prescription medicine use (antiepileptics, antipsychotics, hypnotics/anxiolytics, antidepressants) being more frequently reported before and during pregnancy compared to non-autistic pregnant mums. Authors reported that "there was no increased risk of adverse pregnancy outcomes except for induction of delivery" but one has to remember that the focus was on pregnancy outcomes - "completed weeks of gestation, mode of delivery, 5-minute Apgar scores, intrauterine growth, stillbirth, and maternal complications (preeclampsia and gestational diabetes)" - and does not say anything about longer term post-pregnancy outcomes. I say this with a few potential 'issues' in mind (see here and see here and see here).

The Sundelin study is by no means perfect - a "limitation is the lack of information on life circumstances" - but does carry the research weight that comes from those extremely well-categorised Scandinavian population registries. The authors conclude that their: "results suggest a need for individual prenatal care for women with autism, weighing pros and cons for continuation of psychotropic medication, with a better understanding of the difficulties related to autism, especially regarding the communication with health care professionals." Who am I to argue with them?

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[1] Sundelin HE. et al. Pregnancy outcomes in women with autism: a nationwide population-based cohort study. Clin Epidemiol. 2018 Nov 30;10:1817-1826.

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Middle ear infection and autism (again)

"Autism was more common in children who had had an otitis media infection or who had been treated with antibiotics."

Minus any sweeping generalisations, that was the conclusion reached in the study by Theresa Wimberley and colleagues [1] continuing some important research themes (see here and see here) examining any "interplay among otitis media, antibiotics, and the subsequent risk of developing autism."

Just in case you don't already know, otitis media infection refers to an infection of the middle ear that "causes inflammation (redness and swelling) and a build-up of fluid behind the eardrum." Aside from the use of painkillers, the seriousness of certain otitis media infections can sometimes mean that antibiotics are prescribed to combat any underlying bacterial infection or even in some cases, grommets inserted as treatment.

Wimberley et al report results based on "the entire Danish population", well, over three-quarters of a million children "followed from birth (January 1, 1997 to December 31, 2008) until December 31, 2012." They calculated various 'risk of autism' statistics as a function of a previous medical diagnosis of otitis media and "antibiotic prescriptions redeemed at Danish pharmacies." Yes folks, yet again those big data Scandinavian population registries have been used to good research effect.

Results: "The absolute risk of autism before age 10 was increased among children with otitis media (1.2% for females and 3.3% for males) and in children who had redeemed an antibiotic prescription (0.6% and 2.7% for females and males) compared to children without a history of otitis media and antibiotics usage (0.4% for females and 1.9% for males)." Researchers also reported finding "little evidence of a synergistic effect between otitis media infections and treatment with antibiotics" despite them being over-represented in relation to autism. They also caution that cause-and-effect cannot be inferred from their observational results.

What more can one say about the Wimberley findings? Well, echoing the idea that correlation is not the same thing as causation, I'd say that there is quite a bit more research to do on this topic. Further investigations are required into the possible mechanisms through which autism may manifest at least partially as a result of a history of ear infection (or indeed vice-versa). Mention of antibiotics also brings in areas of additional research interest such as the gut microbiome and what antimicrobials might 'be doing' to the trillions of passengers that are carried in the deepest, darkest recesses of the human body. I'm also minded to suggest that alongside antibiotic use to potentially treat infections like otitis media, researchers might also want to focus in on other medicines that might be accessed in such case such as over-the-counter pain relief in light of other *associations* that have been made (see here).

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[1] Wimberley T. et al. Otitis media, antibiotics, and risk of autism spectrum disorder. Autism Res. 2018 Oct 3.

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'Mucosal healing' in treated coeliac disease "may come at a cost of an increased risk of mood disorders"

I was really quite intrigued by the findings reported by Jonas Ludvigsson and colleagues [1] attempting to "examine the relationship between anxiety, depression and mucosal healing in coeliac disease." Intrigued because such findings tap into a couple of potentially important areas such as the whole gut-brain 'being linked' bit (see here and see here) and how gut permeability (a.k.a leaky gut) might be something quite important to quite a few different labels/diagnoses/states (see here).

I should perhaps briefly go through a few choice terms before starting. Coeliac disease (sometimes written as celiac disease) is the archetypal 'food affects physiology' condition as per it's description encompassing the words 'gluten', 'autoimmune disease' and 'gastrointestinal'. Part of the biological profile of coeliac disease (CD) is involvement of the gut mucosal membrane and the characteristic 'flattening' of the mucosal surface reducing the capability to properly absorb various nutrients. This is known as villous atrophy and is measured using the Marsh criteria. Luckily, for most people with CD, when a gluten-free diet is installed to treat/manage CD, the gastrointestinal (GI) pathology linked to villous atrophy abate and mucosal healing can take place as long as gluten remains excluded from the diet.

Ludvigsson - a name not unfamiliar to all-research-things coeliac disease - and colleagues sought to look at the presentation of certain extra-gastrointestinal symptoms as a function of mucosal healing (through use of a gluten-free diet) or persistent villous atrophy. They analysed data collected over nearly 40 years "on all small intestinal biopsies with villous atrophy from Sweden's 28 pathology departments." They also garnered data on the presence of a diagnosis of depression and/or anxiety, and married the two data sets together...

Results: "During follow-up, 123 (2.8/1000 person-years) individuals with mucosal healing had developed anxiety, compared to 94 (2.1/1000 person-years) with persistent villous atrophy." What this means is that whilst the presentation of anxiety was spread both across those who did and did not seemingly biologically benefit from the use of a gluten-free diet, those who showed gut healing were seemingly at "a higher risk of future anxiety." A similar trend was also noted when it came to a diagnosis of depression. This led researchers to highlight how "the goal of mucosal healing may come at a cost of an increased risk of mood disorders."

I was truly in head-scratching mode when it came to these findings. I don't know if it's just me, but I would have thought that persistent villous atrophy akin to not-quite-complete mucosal healing would have been more pertinent to the expression of anxiety and depression. I say that from the point of view that micro nutrients (and specifically, the lack of them) seem to have some important relationships with mood states and related conditions (see here and see here) under other circumstances. I'd also mention that a patient with CD knowing that the gluten-free diet wasn't 'doing what it's supposed to' in relation to managing CD at a biological level might also be a cause for concern for them and possibly lead to more complicated 'issues'?

So what could be the reason for the Ludvigsson findings? Well, subject to independent replication of the findings and perhaps also looking at other variables potentially pertinent to the presentation of anxiety and depression in CD (see here for example based on the 'birds of an autoimmune feather' hypothesis), one might surmise a few things. First, that the biological expression of CD 'hides' underlying issues such as anxiety and depression, and only through (successful) treatment do such mood disorders become 'unmasked'. Anecdotally and without any supporting evidence, I remember back to some of my research days looking at gluten- and casein-free diets being used in the context of [some] autism, and how some parents / autistic people reported that the diet seemed to 'reveal' anxiety issues for example, at the costs of helping to resolve certain behavioural and somatic (bowel) issues they faced. Could similar mechanisms apply to CD bearing in mind the effect that dietary gluten removal has on gut barrier function?

Next possibility: gluten peptides. It's pretty well known that the gluten peptides - the intermediate compounds that form during the digestion of the gluten - have some important biological action insofar as them possessing potential opioid activity. The gluteomorphins as they're known, share similar structural data to other well known opioid compounds such as morphine. It's probably one of the reasons that we've had such an enduring relationship with such foodstuffs. Could the rise of mood disorders be related to such biochemistry? Y'know, removal of gluten peptides and the mucosal healing affecting transport to the wider central nervous system meaning that patients aren't getting 'their fix'?

One other possibility is also worth mentioning and investigating: Eyes should also perhaps turn to what other effects a dietary change such as gluten removal might have on physiology; specifically on the trillions of wee beasties that call our GI tract home: the gut microbiota. Does a healed mucosa have implications for the gut microbiota?

Questions, questions, questions...

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[1] Ludvigsson JF. et al. Anxiety after coeliac disease diagnosis predicts mucosal healing: a population-based study. Aliment Pharmacol Ther. 2018 Oct 4.

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Long-term health conditions and autism: a Scottish perspective

There were a few things that raised my eyebrow (Roger Moore style) in the paper published by Ewelina Rydzewska and colleagues [1]. The primary finding that: "Comorbidity is substantially greater in adults with reported autism than in other people" was one of the eyebrow raisers. But also the observation that: "Scotland’s Census is one of the few country censuses that asks every person in the country whether or not they have autism, indeed it may be unique in this regard" was another. There were others too...

Back to the first point and the primary purpose of the Rydzewska study: "to investigate the prevalence and predictors of deafness or partial hearing loss, blindness or partial sight loss, intellectual disabilities, mental health conditions, physical disability and other condition, in a whole country population of adults with reported autism aged 25+ compared with their peers without autism." Said whole country was somewhere not a million miles away from where I write this post - Scotland - and results based on Scotland's Census 2011. The Census did what Census (I don't know what the plural should be!) are normally designed to do: to provide details on the population (N=5 295 403) covering everyone "whether living in communal establishments (such as care homes and student halls of residence) or private households." As mentioned, I wasn't aware that Scotland asked about whether someone has autism or not as part of the Census but I'm impressed that they do. As to the authors' testing the idea that autism is rarely a stand-along diagnosis, well let's just say that this has already been discussed a few times in the peer-reviewed science arena (see here for example) so we kinda had some clues as to what might have been observed.

Results: "There were 6649/3 746 584 (0.2%) adults aged 25+ recorded to have autism as defined here, 4610 (69.3%) of whom were men and 2039 (30.7%) women compared with 1 776 845 (47.5%) men and 1 963 090 (52.5%) women in the adult population without autism." Let me just say that again: in the Scottish 2011 Census, that covered both private households and 'communal establishments' only 0.2% of the respondents above 25 years of age were reported to have a diagnosis of a "developmental disorder (eg, autistic spectrum disorder or Asperger’s syndrome)." Interesting.

Continuing: "The rate of autism was lowest in the oldest age groups (autism may be associated with reduced life expectancy)." 'Autism may be associated with reduced life expectancy' is another important detail mentioned in the Rydzewska study and something that taps into a wealth of other science (see here for example) observing that the diagnosis of autism can, very much, be a life-limiting label for some.

Then to the main event: lots of different diagnoses/labels were seemingly over-represented alongside a diagnosis of autism. Indeed, pretty much all of the ones enquired about by researchers fell into that category. A third of participants for example, reported experiencing 'something' under the heading of "a mental health condition"; a finding also fairly consistently stretching across individual analyses based on different age bandings. When it came also to the category titled 'intellectual disabilities' (also known as learning disability here in Blighty) the figures stood out: "A high rate of intellectual disabilities in children with autism has been described previously; we have now quantified the extent of this—29% (25%–32% depending on age group; 22%–35% for men and 31%–42% for women)—in a much larger study of adults." This [roughly] accords with other independent data too (see here).

What's more to say? Well yet again, it's all about not looking at autism as some sort of 'stand alone' label given the over-representation of some pretty significant categories of health issues, covering both the somatic (physical) and the psychological. I don't think anyone would disagree with such an observation in this day and age as the words 'Autism Plus' are also mentioned in the Rydzewska paper. Once again, this also has implications for preferential screening when a diagnosis of autism is received and also the treatment/management of any issues that are detected (see here and see here for examples).

As for that 0.2% adult (over 25 years old) prevalence figure noted by the authors, I'm not going to say too much more about that for now. Aside that is, from dropping in some discussions about another adult autism prevalence study (see here) which reported that figures were potentially climbing in line with the childhood autism prevalence figures (see here). I'm sure that there are multiple discussions that could be generated around such figures but not here, not now, and not to distract from the important observation that autism rarely appears in a diagnostic vacuum...

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[1] Rydzewska E. et al. Prevalence of long-term health conditions in adults with autism: observational study of a whole country population. BMJ Open. 2018;8:e023945.

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The headline: "One in nine young people in Scotland have attempted suicide"

I have to say that I drew a sharp intake of breath when I read the media headline titling this post - "One in nine young people in Scotland have attempted suicide" - based on the findings reported by Rory O'Connor and colleagues [1]. The idea that, from a sample of some 3500 young people in Scotland, some 10% and 15% of respondents to the questions: "Have you ever made an attempt to take your life, by taking an overdose of tablets or in some other way?’ and ‘Have you ever deliberately harmed yourself in any way but not with the intention of killing yourself? (i.e. self-harm)" answered in the affirmative, seemed pretty important. Not least with the question 'why?' in mind.

OK, media headlines aside, the O'Connor findings require some dissection. The reasoning behind studying this issue was not only to look at the very complicated topic of suicide in a part of the UK (Scotland) that authors write "has a higher suicide rate than England", but also to try and understand how non-suicidal self-injury (NSSI) or non-suicidal self-harm (NSSH) presents in young adults and whether there is something important linking NSSH and suicidal thoughts and/or attempts.

The participant group was drawn from "a representative sample of young people aged 18–34 years from across Scotland" who were recruited to the Scottish Wellbeing Study. Lots of measures were completed by participants as part of the wider study initiative but we are told that "only the prevalence of NSSH and suicide attempts information is reported" in the O'Connor article on this occasion. I might also add that participants were compensated to the tune of £25 (pounds sterling) for their time and participation.

Alongside those headline findings on self-reported attempted suicide and self-harm, a few other important trends were observed. So: "More than 20% reported lifetime suicidal thoughts, 2.4% reported that they last thought about suicide in the past week and 10.4% reported they last thought about suicide in the past 12 months." Around 6% of respondents reported that they had both attempted suicide and also engaged in self-injury suggesting that professionals should "routinely enquire about history of self-injurious behaviour, especially as past behaviour is such a strong predictor of suicide." Also: "Earlier age at NSSH or suicide attempt onset was associated with more frequent lifetime NSSH and suicide attempts." And finally: "The prevalence of NSSH and suicide attempts was significantly higher among those classified as unemployed... and economically inactive... compared with those who were employed." Age, societal and environmental factors seem to play some roles too.

Then to another important set of questions: (a) why? and (b) what can be done to reduce these headline-grabbing statistics? Well, there are no easy answers to such questions I'm afraid. The authors do note that: "From a public health perspective, the unemployment and economic inactivity findings are noteworthy" and perhaps suggest that there are some modifiable variables that could influence suicidal thoughts and/or actions focused on getting people into employment and the benefits that this brings (wide-ranging benefits by all accounts). But this probably only covers one side of the issue, as discussions inevitably turn to what role psychiatric and/or behavioural comorbidity might play in such reporting (see here and see here and see here) and whether there may be a need for (a) something like enhanced screening for suicidal thoughts or other 'risks' among selected populations and/or (b) the [careful] use of 'preventative' strategies in such cases (see here and see here). I say all that accepting that diagnoses around mental health probably play an important role in suicide-related behaviours but are not necessarily a pre-requisite...

As always, there is always someone to talk to if needed...

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[1] O'Connor RC. et al. Suicide attempts and non-suicidal self-harm: national prevalence study of young adults. BJPsych Open. 2018; 4: 142-148.

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Has the ADHD 'phenotype' become more common over the past decade?

It's a question that continues to prominently figure in ADHD (attention-deficit hyperactivity disorder) circles: Are there more people out there 'developing' ADHD, or is the quite rapid increase in cases being diagnosed due to various other 'artificial' factors?

Far be it from me to come down on either side with any great certainty - as per a similar question being asked with autism in mind - but the findings reported by Mina Rydell and colleagues [1] do provide some important discussion on this question. Authors concluded that: "the increased rates of clinically diagnosed ADHD might reflect changes in diagnostic and treatment practices of ADHD, administrative changes in reporting diagnoses, greater awareness of ADHD, better access to healthcare, or current overdiagnosis, rather than an increase in the ADHD phenotype." But...

The evidence for their conclusion came from their use of an instrument called the A-TAC (Autism-Tics, ADHD and other Comorbidities inventory) and its application to a study initiative called the
Child and Adolescent Twin Study in Sweden (CATSS). Indeed mentioning about a similar question being posed in autism research circles, I'll direct you to a recent blog post where A-TAC and CATSS led researchers - some of the same researchers as on the Rydell paper - to conclude that the autism of today might not necessarily be the same as autism of yesteryear (see here).

As well as assessing ADHD symptoms with the A-TAC (not to be confused with the ATEC) for some 20,000 twins between 2004 and 2014, researchers also "modeled the lifetime prevalence of diagnostic-level and subthreshold ADHD with logistic regression" using data from the National Patient Register (NPR) in Sweden.

Results: well, as I've already indicated, there seemed to be quite an influence of those other 'artificial' factors noted from the Rydell paper. So: "The prevalence of diagnostic-level ADHD based on parent ratings did not differ significantly over time from 2004 to 2014." This refers to data garnered through the CATSS using the A-TAC. By contrast: "Clinically diagnosed ADHD increased more than fivefold from 2004 to 2014" based on data from the NPR. You can perhaps see the difference between the two databases.

Of course the debate is not entirely closed as to what might be going on with the ADHD phenotype and the rise in cases being diagnosed. The authors for example, do report that they found "small increases in normal and subthreshold variations of ADHD-like traits" which could indicate that more children are starting to show more ADHD-related traits as time passed. Harking also back to other previous research by some of the authors [2], I wonder if further investigations into this area might take into account variables such as physical activity / inactivity as being something to consider, in light of other evidence (see here)? I don 't doubt there will be other considerations too (see here and see here and see here)...

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[1] Rydell M. et al. Has the attention deficit hyperactivity disorder phenotype become more common in children between 2004 and 2014? Trends over 10 years from a Swedish general population sample. J Child Psychol Psychiatry. 2018 Feb 27.

[2] Rommel AS. et al. Is Physical Activity Causally Associated With Symptoms of Attention-Deficit/Hyperactivity Disorder? J Am Acad Child Adolesc Psychiatry. 2015 Jul;54(7):565-70.

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On hormonal contraception and suicide risk

I'll freely admit that the material covered in the paper by Charlotte Wessel Skovlund and colleagues [1] suggesting that: "Use of hormonal contraception was positively associated with subsequent suicide attempt and suicide" is (a) slightly outside of the typical remit of this blog and (b) not something that I'm particularly qualified to talk about. I was however minded to discuss this paper in the context that previous work from this research group has *linked* hormonal contraception use with depression [2] (see here for some of the media on this past paper) and in the more general context of blogging occasions where depression and risk of suicide have been discussed here (see here).

Similar to their last research outing where hormonal contraception - 'birth control methods that act on the endocrine system' - was analysed, some of those rather important Scandinavian population registries were the source study material. Denmark was the country of choice and "a nationwide prospective cohort study of all women in Denmark who had no psychiatric diagnoses, antidepressant use, or hormonal contraceptive use before age 15 and who turned 15 during the study period, which extended from 1996 through 2013." You'll note the words 'no psychiatric diagnoses, antidepressant use' were included, illustrating how researchers were already mindful of the role that depression has in such extreme behaviour(s). Researchers collected information "about use of hormonal contraception" and also suicide attempts and completions. This, based on resources such as the Danish National Prescription Register, illustrating once again the long Scandinavian tradition of "creating nationwide administrative and health registries" [3].

Results: "Compared with women who never used hormonal contraceptives, the relative risk among current and recent users was 1.97 (95% CI=1.85–2.10) for suicide attempt and 3.08 (95% CI=1.34–7.08) for suicide." I should put that in some context in terms of hundreds of thousands of women - "nearly half a million women" - who were tracked over the course of the study, and how nearly 7000 first suicide attempts were recorded and 71 [completed] suicides registered. The numbers were comparatively small; bearing in mind that behind each figure is a person, a life and a family.

Taking into account the tenet 'correlation is not the same as causation' and indeed, appreciating how complex and individual suicidal thoughts and behaviour can be, these are potentially important data minus any scaremongering. Certainly these are findings worthy of quite a lot more study, particularly in light of the large population included for study mimicking the authors' previous chosen study design, alongside the prospective nature of their investigation.

Mechanisms of effect? I don't think anyone is quite there yet with regards to definitive hows-and-whys. I note that others have talked about a possible *correlation* between elevations in progesterone and suicide attempts [4] but such observations need to be treated cautiously at this point, again reiterating how complex and individual the processes leading someone to suicidal thoughts and behaviours are. Skovlund and colleagues did talk about suicide risk potentially differing according to different contraceptive formulations used: "Risk estimates for suicide attempt were 1.91... for oral combined products, 2.29... for oral progestin-only products, 2.58... for vaginal ring, and 3.28... for patch" potentially suggesting that specific products might have differing risk profiles. This is something else that could perhaps help isolate any pertinent mechanisms.

Questions remain, not least: Are there particular groups of women, based on genetics or other biology, that may be at increased risk of depression and/or suicide when taking such contraception? The answer: we don't yet know. Bearing in mind that in this, and their other work on hormonal contraception and depression, age seemed to be an important variable as per the observation: "Adolescent women experienced the highest relative risk" thus representing a good place to start. And on the topic of adolescent women perhaps having an elevated risk, I might also draw your attention to the findings reported by Jean Twenge and colleagues [5] who discussed another potentially important variable to consider: "Since 2010, adolescents spent more time on social media and electronic devices, activities positively correlated with depressive symptoms and suicide-related outcomes." I wonder if this is something that perhaps needs to be controlled for in future studies?

To close, there's always someone to talk to (see here) if needs be, and please, talk to your medical professional (not Dr Google) if you're at all concerned by these latest findings.

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[1] Skovlund CW. et al. Association of Hormonal Contraception With Suicide Attempts and Suicides. Am J Psychiatry. 2017 Nov 17:appiajp201717060616.

[2] Skovlund CW. et al. Association of Hormonal Contraception With Depression. JAMA Psychiatry. 2016 Nov 1;73(11):1154-1162.

[3] Pottegård A. et al. Data Resource Profile: The Danish National Prescription Registry. Int J Epidemiol. 2017 Jun 1;46(3):798-798f.

[4] Mousavi SG. et al. Recurrent suicide attempt and female hormones. Advanced Biomedical Research. 2014;3:201. doi:10.4103/2277-9175.142046

[5] Twenge J. et al. Increases in Depressive Symptoms, Suicide-Related Outcomes, and Suicide Rates Among U.S. Adolescents After 2010 and Links to Increased New Media Screen Time. Clinical Psychological Science. 2017. Nov 14.

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Tobacco smoking and psychiatric illness

"The prevalence of smoking has remained alarmingly high among individuals with schizophrenia and bipolar disorder, and the disparity with those without psychiatric disorders and with the general population is increasing."

So said the findings reported by Faith Dickerson and colleagues [1] who surveyed nearly 2000 people "about their cigarette smoking at enrollment into a research study for which they were selected without regard to their smoking status." Their findings make for important reading in the context that tobacco smoking is not exactly a healthy activity (see here) and could potentially contribute to some of the health inequalities already recognised when it comes to serious mental illness (SMI) (see here).

The sorts of figures of smoking prevalence observed by Dickerson et al are not to be ignored: "62% of individuals with schizophrenia, 37% with bipolar disorder, and 17% of participants without a psychiatric disorder (control group) reported that they were current smokers." This set in the context of falls in the rates of smoking in the general population. It's also worthwhile noting that being a 'current smoker' with reference to a diagnosis of schizophrenia or bipolar disorder typically meant smoking "more cigarettes per day" than the control cohort.

There are other implications from this work. Without generalising (or stigmatising) if one draws on other work talking about a possible connection between prenatal nicotine exposure and offspring [heightened] risk of schizophrenia for example (see here), a complex pattern of *association* seems to emerge. No, I'm not saying that every woman with schizophrenia who is pregnant will smoke through their pregnancy (despite evidence of some increased risk [2]) but greater focus and education on the need to restrict tobacco smoking during that critical period is perhaps warranted. Such discussions may also have implications for the whole nature-nurture debate with regards to such psychiatric diagnoses too.

Although there are many (many!) good reasons for encouraging those with a SMI to quit smoking, I do feel it is important also to understand why so many are smokers. The findings reported by Li and colleagues [3] offer something of a perspective on this issue where for example: "Smokers had a higher mental QOL [quality of life] than non-smokers... in MDD [major depressive disorder]." Similarly, Mallet and colleagues [4] discussed results that suggested that "some therapeutics may improve daily smoking behavior in smokers" in the context of schizophrenia (as others seemed to be associated with 'not improving' smoking behaviours). In short, the roads that lead to, and perpetuate tobacco smoking in the context of SMI are likely as complex as the ones needed to lead people away from such habits...

And aside from the health reasons to quit smoking particularly among those diagnosed with a SMI, the grand review, meta-analysis and meta-regression paper by Cassidy and colleagues [5] lists tobacco smoking as one potentially important (and modifiable) correlate when it comes to risk factors for suicidality in schizophrenia...

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[1] Dickerson F. et al. Cigarette Smoking by Patients With Serious Mental Illness, 1999-2016: An Increasing Disparity. Psychiatr Serv. 2017 Sep 15:appips201700118.

[2] Nilsson E. et al. Women with schizophrenia: pregnancy outcome and infant death among their offspring. Schizophr Res. 2002 Dec 1;58(2-3):221-9.

[3] Li XH. et al. Prevalence of smoking in patients with bipolar disorder, major depressive disorder and schizophrenia and their relationships with quality of life. Sci Rep. 2017 Aug 16;7(1):8430.

[4] Mallet J. et al. Cigarette smoking and schizophrenia: a specific clinical and therapeutic profile? Results from the FACE-Schizophrenia cohort. Prog Neuropsychopharmacol Biol Psychiatry. 2017 Oct 3;79(Pt B):332-339.

[5] Cassidy RM. et al. Risk Factors for Suicidality in Patients With Schizophrenia: A Systematic Review, Meta-analysis, and Meta-regression of 96 Studies. Schizophr Bull. 2017 Sep 23.

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Pregnancy antidepressant use and offspring outcomes beyond autism?

I'll say one thing for the British Medical Journal (BMJ), they don't seem to be afraid to cover important issues relating to the *possible* "reproductive safety of drugs" [1] as per their publication of yet another paper looking at antidepressant use during pregnancy and offspring outcomes published by Xiaoqin Liu and colleagues [2]. This follows another paper published in the BMJ and covered on this blog a few weeks back (see here).

The specific class of drugs being examined again are, as I mentioned, the antidepressants and based, yet again, on data from one or more of those wonderful Scandinavian population registries in relation to how pregnancy use of antidepressants *might* impact on risk of risk of various psychiatric disorders in offspring. A diagnosis of autism spectrum disorder (AD) has been a primary focus of previous research in this area; particularly the question of whether the medicines themselves or the condition(s) that the medicines are used for (i.e. maternal psychopathology) might be the more important variables related to enhanced offspring risk of autism. The last paper covered on this blog by Rai and colleagues [3] very cautiously suggested that: "The results of all these analyses, which used different assumptions, seemed to be consistent with each other, suggesting that the association between in utero exposure to antidepressants and autism might not be fully explained by confounding." Cautiously...

This time around the net was widened from just looking at autism as an offspring outcome to "overall risk of psychiatric disorders" including: "autism spectrum disorder... mood disorder... neurotic, stress related, and somatoform disorder... behavioural and emotional disorder... and mental retardation." I might add that these are the authors words not mine and diagnoses were based on ICD-10 criteria and codings.

Looking and following some 900,000 children born between 1998 and 2012 in Denmark until 2014, researchers categorised participants according to their pregnancy antidepressant exposure(s): "unexposed, antidepressant discontinuation (use before but not during pregnancy), antidepressant continuation (use both before and during pregnancy), and new user (use only during pregnancy)" and looked at the frequency of those conditions included for study.

Results: some 2% of children were born to mums who used an antidepressant during pregnancy (n=21,063). Various types of antidepressants were used but the majority were prescribed SSRIs (Selective Serotonin Reuptake Inhibitors) either alone (monotherapy) or in conjunction with other non-SSRI medication.

"We observed increased risks of psychiatric disorders in all three groups of antidepressant users (discontinuation, continuation, and new user groups), compared with the unexposed group." This itself is an important finding but does not yet disentangle whether medicine use or the reason(s) for medicine use might be the more important variable. Then: "we observed an increased risk of psychiatric disorders in children whose mothers continued antidepressant use during pregnancy, compared with mothers who discontinued." Such a statement potentially edges a little closer to some influence of pregnancy antidepressant use on offspring outcomes but, and it is an important but: "These associations could be attributable to the severity of the underlying maternal disorders in combination with in utero antidepressant exposure." In other words, those mums who needed to continue antidepressant use throughout pregnancy probably had to do so because their symptoms either returned or were not controlled properly when medication is not in place. This might imply that more serious maternal psychiatric disorder could be a variable in any enhanced risk of offspring psychiatric disorder.

When it came to looking at specific diagnostic labels for offspring, all but "mental retardation" (I prefer the term learning disability) seemed to be elevated alongside "in utero exposure to antidepressants." The conditions with the highest risk were the mood disorders including diagnoses such as clinical depression and bipolar disorder. Given that antidepressants are typically (but not exclusively) used to treat/manage mood disorders, such a finding of maternal mood disorder potentially transmitting down into offspring mood disorder receives further credence from such results.

The Liu paper and accompanying editorial grapple with the question of whether the *possible* risks from pregnancy use of antidepressants on offspring merit a change to guidance on their use at such a critical time. As I've mentioned on other occasions discussing this topic, antidepressants are not typically just dispensed willy-nilly without appropriate clinical indication. They provide an important service in controlling various types of symptoms; pertinent to the idea that uncontrolled depression during pregnancy for example, can have all-manner of negative outcomes. As all medicines do, yes they may have side-effects but these need to be weighed up against perceived benefits, taking into account any important influence on the developing child. Indeed, the authors note: "any final decision on antidepressant continuation should be individualised and made jointly by health professionals and patients."

And whilst I've mentioned pregnancy antidepressant use and offspring autism risk, yet another review paper enters the scientific fray [4]...

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[1] Nordeng H. et al. Prenatal exposure to antidepressants and increased risk of psychiatric disorders. BMJ. 2017; 358: j3950.

[2] Liu X. et al. Antidepressant use during pregnancy and psychiatric disorders in offspring: Danish nationwide register based cohort study. BMJ. 2017; 358: j3668.

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

[4] Andalib S. et al. Maternal SSRI exposure increases the risk of autistic offspring: A meta-analysis and systematic review. Eur Psychiatry. 2017 Jun 20;45:161-166.

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