Saturday, 18 February 2017

Social interaction and autism: it takes two to tango

Psychology experiments are not generally fodder for this blog when it comes to autism. The main reason being that quite a few appearing in the peer-reviewed literature tend to look at quite abstract features perhaps somewhat removed from the daily lives of autistic people and their significant others. A few also seem to struggle with the idea that grand over-arching psychological theories (that seem to inevitably follow psychological findings in particular) are not required when it comes to autism in these days of heterogeneity and plurality.

I am making an exception today however with the paper by Noah Sasson and colleagues [1] (open-access) and their findings suggesting advocating "for a broader perspective of social difficulties in ASD [autism spectrum disorder] that considers both the individual’s impairments and the biases of potential social partners." In other words, it takes two to [socially, interactively] tango. I might add that a doctoral thesis by one of the co-authors on the Sasson paper (Daniel Faso) is also available for further inspection too (see here).

Based on the idea that issues with social interaction "quantity and quality" might not be something exclusively under the control of those diagnosed with autism, Sasson et al devised a series of experiments to test their hypothesis: "three studies conceived and conducted independently by three research groups assessing observers’ first impressions of—and intentions to socially engage with— children and adults with ASD based upon “thin slices” of their real-world social behavior." I'm not going to go into too much detail about the experiments because the paper is open-access and you can read about them for yourselves. 'Thin slices' in the context of the experiments carried out referred to media that were rated pertinent to "observers’ first impressions of individuals with ASD engaging in real-world social behavior."

The results make for some important reading as across the different experiments undertaken the key messages were that: "first impressions of individuals with ASD are significantly less favorable than those of matched TD [typically developing] controls, and are associated with greater reluctance on the part of observers to pursue social engagement." Further: "social interaction difficulties in ASD are not solely an individual impairment but also a relational one, and consideration of both of these factors is necessary for a full understanding of social impairment in ASD." I relay all of that bearing in mind that these were experiments carried out under controlled conditions (I don't know about you, but I don't generally rate people at first contact using a "0-3Likert scale or a "non-graduated slider" on 'how approachable' they were or the likelihood of a friendship developing).

Although important, I don't think anyone should be too surprised by the results reported in the context of how first impressions count and how people are generally quick to judge from "personality and character traits" whether social engagement with a person or group of people is going to be a short or longer-term thing. I say this also bearing in mind that minus any psychobabble, people generally take into account things like context, familiarity and similarity when it comes to their social interaction decisions too [if for example, you happen to be a fan of Star Wars or a Shotokan karateka, I might be more inclined to chat with you than say if you talked about the goings-on on various reality TV shows]. Indeed, the authors note: "these studies present only group-wise comparisons and do not address individual differences among those with ASD, nor whether individual characteristics of the raters (e.g., gender, personality, etc.) affect the results reported here." I'd also forward the idea that they might also include important concepts such as self-monitoring for example when it comes to future studies in this area. Similarly, it would also be handy to see if 'comorbidity counts' when it comes to further investigations on this topic in light of expanding links between different labels and traits (see here).

The question of what to do about the Sasson findings similarly provide some food for thought. The authors suggest that: "intervention and education approaches that target both those with ASD as well as their TD [typically developing] peers may offer a more comprehensive approach for improving social and functional outcomes in autism." In the context of other studies looking at social interaction and autism particularly in the school setting (see here) I can see how this might work in terms of raising awareness of how people are not always the same when it comes to the presentation of their social persona. Intervening with a wider group (i.e. peers) and taking the onus off 'just the person with autism' is a win-win situation and will no doubt have other positive knock-on effects in terms of self-esteem and helping to remove barriers around the 'disability' framing of autism. I might add that in these days of the potential virality of personality traits, it makes sense to include everyone.

In a wider context - outside of school - and in the big, wide [adult] world however, I'm slightly less sure of how such intervention is going to be achieved. Yes, we would all love people to be more understanding and less 'judgemental' in their first (and subsequent) impressions, but when it comes to influencing aspects such as views on "awkwardness, attractiveness, [and] likability" I'm not so sure that this can be universally achieved. Indeed, facets such as attractiveness and likability are probably going to be influenced by lots of variables outside of those just linked to an autism diagnosis and its presentation (frank or not). By saying all that, I'm not suggesting that we shouldn't try to educate and perhaps even move people away from the whole 'first impressions last' [2] thing, but rather am looking at the realistic prospect of achieving such a societal goal, mindful that it takes two to tango...

And on the topic of first impressions, at least get the handshake right (i.e. let go)...

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[1] Sasson NJ. et al. Neurotypical Peers are Less Willing to Interact with Those with Autism based on Thin Slice Judgments. Sci Rep. 2017 Feb 1;7:40700.

[2] Gunaydin G. et al. Impressions Based on a Portrait Predict, 1-Month Later, Impressions Following a Live Interaction. Social Psychological and Personality Science. 2017. 8: 36-44.

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ResearchBlogging.org Sasson NJ, Faso DJ, Nugent J, Lovell S, Kennedy DP, & Grossman RB (2017). Neurotypical Peers are Less Willing to Interact with Those with Autism based on Thin Slice Judgments. Scientific reports, 7 PMID: 28145411

Friday, 17 February 2017

Vitamin D halting colds and flu?

"Overall, the study said one person would be spared infection for every 33 taking vitamin D supplements. That is more effective than flu vaccination, which needs to treat 40 to prevent one case, although flu is far more serious than the common cold."

That was some of the media interpretation of the paper - "systematic review and meta-analysis of individual participant data" - published by Adrian Martineau and colleagues [1] looking at the collected data on vitamin D supplementation "on risk of acute respiratory tract infection." Including data on approximately 11,000 'randomised' participants reported in 25 studies, authors assessed whether the quite messy data on vitamin d supplementation potentially decreasing the risk of acute respiratory tract infection showed any semi-definitive trends.

Results: "Vitamin D supplementation resulted in a statistically significant reduction in the proportion of participants experiencing at least one acute respiratory tract infection." Further: "Use of vitamin D did not influence risk of serious adverse events of any cause... or death due to any cause. Instances of potential adverse reactions to vitamin D were rare." And finally: "Subgroup analysis revealed that daily or weekly vitamin D supplementation without additional bolus doses protected against acute respiratory tract infection, whereas regimens containing large bolus doses did not."

I note that in the BBC news report on the Martineau paper we are told: "Public Health England (PHE) says the infections data is not conclusive, although it does recommend supplements." This slightly counter-intuitive position follows more general advice from the powers-that-be that perhaps we should all be taking a little more vitamin D (see here) given what is emerging when it comes to the varied functions of the sunshine vitamin/hormone. But bear in mind that supplementation comes with potential risks too (see here) particularly when people forget to treat their vitamins and minerals as what they are: biologically active pharmaceutics. Neither is everyone completely sold on the idea that vitamin D 'could stop colds or flu' as an accompanying editorial to the Martineau paper makes clear [2]: "The results are heterogeneous and not sufficiently applicable to the general population."

What such research does advance however, is that vitamin D is a potentially important nutrient (more so for some groups) and one that we should be [cautiously] dedicating a lot more investigation to for all-manner of possible reasons (see here and see here) outside of just bone health and the English disease. And within that scheme of research, don't forget a few things: (a) there's more to vitamin D metabolism than just 'getting enough' and (b) even today, science is still finding out new things about the chemistry of vitamin D [3]. In short, the scheme of science around vitamin D needs to be broad...

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[1] Martineau AR. et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ 2017; 356: i6583.

[2] Bolland MJ. & Avenell A. Do vitamin D supplements help prevent respiratory tract infections? BMJ 2017; 356: j456.

[3] Pauwels S. et al. 1β,25-Dihydroxyvitamin D3: A new vitamin D metabolite in human serum. J Steroid Biochem Mol Biol. 2017 Feb 10. pii: S0960-0760(17)30040-7.

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ResearchBlogging.org Adrian R Martineau, David A Jolliffe, Richard L Hooper, Lauren Greenberg, John F Aloia, Peter Bergman, Gal Dubnov-Raz, Susanna Esposito, & et al (2017). Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data BMJ : 10.1136/bmj.i6583

Thursday, 16 February 2017

"early medical events are associated with clinical ASD phenotypes"

The paper by Charlotte Willfors and colleagues [1] (open-access) provides some food for thought today and the observation that various individual and cumulative medical events - "early medical events likely to be caused by environmental factors" - may be important to at least some autism.

Researchers "scrutinized the early medical histories of a rare and informative sample of 13 MZ [monozygotic] twin pairs discordant for clinical ASD [autism spectrum disorder]" also including "13 MZ typically developing (TD) control pairs (n=52) matched for sex" as an 'exploratory step. Discordant for autism means that one twin had autism and the other did not.

This research first step looked at medical events (likely to be caused by environmental factors!) included things like delivery and neonatal variables (e.g. foetal distress, hypoxia), minor and frequent infections (e.g. ear infections), allergy and epilepsy to name a few. Data was acquired from a few sources including medical records and medical history "assessed from a parent reported questionnaire." They examined exposure to the medical events "in relation to either quantitative or qualitative discordance for ASD." Qualitative discordance referred to when "only one twin within a pair meeting the diagnostic criteria of ASD." A 'confirmatory' study was also carried out whereby a larger, independent cohort of 100 twin pairs "quantitatively discordant for autistic traits" were also quizzed and findings cross-validated.

Results: a few non-shared environmental (NSE) events seemed to be important based on their analysis. So: "Single early medical factors, likely to be caused by NSE, that discriminated between twins in qualitative ASD discordant pairs were dysregulation during the first year of life (comprising feeding and sleeping problems, excessive crying and worrying) and birth weight." Authors also reported that cumulatively, the appearance of early medical events were significantly different in MZ twins with autism compared with their non-ASD co-twin. It's worth mentioning that some of those 'dysregulation' events have been talked about in the earliest descriptions of autism (see here). Birth weight too has something of a long-standing connection to [some] autism (see here). When it came to analysis based on autistic traits (the confirmatory study) it seemed that "early dysregulation and the cumulative load of a variety of early adverse medical events" continued to be important variables (although birth weight linked to ASD traits lost its significance).

These are important findings. The focus on MZ twins (who share a common structural genetic blueprint) means that the genetics side of things is to a large extent 'controlled for' and the results are more likely to reflect some environmental or, more accurately, non-genetic influence. There is a caveat to this though, as per the authors recognition: "with the exception of putative post-twinning de novo mutations." I might also add that MZ twins are also not necessarily epigenetically the same too so gene expression can (and does) differ. What causes these epigenetic differences is still the source of some debate but I might chime in with one idea (see here) out of many possibilities.

"Our data indicate that taking into account the cumulative load of early medical factors might strengthen or discourage a suspicion of ASD, at least in a minority of cases." This is an interesting thought provided by the authors based on their findings. It ties in well with the idea that although behavioural presentation is core to autism presentation and diagnosis, behaviour might not be the only important feature present in relation to autism. I do have to express a degree of caution however with such an approach based on the idea that various types of regression have been noted in the peer-reviewed literature to accompany some autism (see here) and with it, the concept of 'acquired autism' should really be properly recognised (see here for example) in these days of the plural 'autisms'. Indeed, there's a research study idea for anyone out there: looking at MZ twins discordant for autism with onset of said autism tied into a regression of skills?

Scientific replication is the name of the [future] game in this area of study, drawing on larger cohorts and perhaps based in other geographical areas outside of Sweden. We also need to find out what mechanisms might be potentially associating something like 'early dysregulation' with the onset of autism, taking into account how factors such as early feeding practices/issues for example, might provide at least one avenue for future study (see here).

To close, in light of some recent media headlines about the 'myth' that autism rates are on the up (and quite significantly so over past two decades), I offer some past posts suggesting that the word 'myth' should be reserved for other [non-peer-reviewed] matters (see here and see here and see here) and not this particular branch of epidemiological science. As to what may be 'causing' the upswing in numbers of diagnosed cases, well, it's likely to be very, very, very complicated (and without any need for sweeping generalisations please)...

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[1] Willfors C. et al. Medical history of discordant twins and environmental etiologies of autism. Transl Psychiatry. 2017 Jan 31;7(1):e1014.

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ResearchBlogging.org Willfors C, Carlsson T, Anderlid BM, Nordgren A, Kostrzewa E, Berggren S, Ronald A, Kuja-Halkola R, Tammimies K, & Bölte S (2017). Medical history of discordant twins and environmental etiologies of autism. Translational psychiatry, 7 (1) PMID: 28140403

Wednesday, 15 February 2017

"Androgens were not associated with autistic traits at 12 months of age"

EARLI - the Early Autism Risk Longitudinal Investigation study - has been mentioned on this blog before (see here) with the aim of the initiative to "examine possible environmental risk factors for autism and study whether there is any interplay between environmental factors and genetic susceptibility."

In this post I'm bringing the paper by Bo Park and colleagues [1] (open-access) to your attention and the observation(s) that umbilical cord blood levels of testosterone and other related androgens were seemingly not associated with autistic traits at 12 and 36 months of age in their cohort. Such findings represent yet another biological research blow (see here) to facets of the Extreme Male Brain (EMB) theory of autism and the suggestion that "ASD [autism spectrum disorder] is an extreme presentation of a typical male cognitive profile where the drive to “systemize” is stronger than the drive to empathize."

So, looking at cord blood samples from 137 children recruited on to EARLI - "a high autism-risk cohort following pregnant mothers with an older child diagnosed with an ASD (autistic disorder, Asperger syndrome, or pervasive developmental disorder not otherwise specified)" - researchers looked at whether measures of various androgens might correlate with scores on the Autism Observation Scales for Infants (AOSI) and Social Responsiveness Scale (SRS). Said schedules were administered at 12 months and 36 months respectively and various potentially confounding variables were taken into account when it came to looking at any associations. It's also worth pointing out that the technology of choice when it came to those measures of cord blood levels of androgens was an old favourite of this blog: liquid chromatography-tandem mass spectrometry (LC-MS/MS).

Results: well as per the title of this post, and after adjustment for potentially confounding variables - "maternal age, gestational age, and cesarean delivery" - there wasn't a great deal to see in terms of levels of androgens and the presence of autistic traits. Indeed, the title of this post only tells half the story as testosterone was also found not to be associated with the SRS scores at 36 months too. The authors do note that: "Male infants (n=75) showed significantly higher umbilical cord testosterone levels and greater social deficits at 36 months of age" than females, but after adjustment for confounders this observation was left wanting. They also talk about some interesting observations about when a child had an older female sibling diagnosed with autism - "androgen levels and autistic traits may depend on sex of the older affected sibling" - but I'm not so sure about the strength of such findings and whether other mechanisms might also be at work. I might reiterate that autistic traits were the name of the research game in this study not a diagnosis of autism.

As mentioned, the Park findings represent another setback for the generalisability of the role of androgens (prenatal and beyond) in relation to autism and/or autistic traits. I guess that in these days of the plural 'autisms' (see here) it's perhaps not entirely unexpected that grand theories of autism seem doomed to fail when put up to scientific scrutiny. Indeed someone recently has talked about this [2]. I still however remain interested in the discussions around the EMB theory of autism, and although this and other research has not been entirely kind to the hypothesis, it is still perhaps deserving of further study in order to see who it may be most relevant to in these days of plural autisms and subgroupings...

To close, isn't this why Twitter was invented?

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[1] Park BY. et al. Umbilical cord blood androgen levels and ASD-related phenotypes at 12 and 36 months in an enriched risk cohort study. Molecular Autism. 2017; 8: 3.

[2] Müller R-A. & Amaral DG. Editorial: Time to give up on Autism Spectrum Disorder? Autism Res. 2017. Jan 27.

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ResearchBlogging.org Park, B., Lee, B., Burstyn, I., Tabb, L., Keelan, J., Whitehouse, A., Croen, L., Fallin, M., Hertz-Picciotto, I., Montgomery, O., & Newschaffer, C. (2017). Umbilical cord blood androgen levels and ASD-related phenotypes at 12 and 36 months in an enriched risk cohort study Molecular Autism, 8 (1) DOI: 10.1186/s13229-017-0118-z

Tuesday, 14 February 2017

Relative age and ADHD medication

"Youngest children in class 'more likely to be given ADHD drugs'" went the NHS Choices headline that led me to the short report produced by Martin Whitely and colleagues [1] (open-access).

ADHD - attention-deficit hyperactivity disorder - is something of interest to this blog; not least the idea that relative age (age relative to peers in the same school year group) might be an important variable when it comes to at least some diagnoses of the condition (see here).

The Whitely paper draws on data from a research favourite place - Western Australia (WA) - and focused on "the proportions of WA children born in the early and late months of a recommended school-year intake who received at least one Pharmaceutical Benefits Scheme [PBS] prescription for an ADHD medication in 2013."

The results: from a starting population of some 300,000 children, about 6,000 of them (~2%) were in receipt of a state-recognised prescription of an ADHD medication. The article does not actually mention which ADHD medication was given but methylphenidate (a.k.a Ritalin) is listed in the PBS directory and is the typically indicated medication used for ADHD (see here). Boys, we are told, were more likely to be prescribed ADHD medication than girls (2.9% vs. 0.8% respectively).

Then to the headline: when splitting the children into two age groups - 6-10 year olds and 11-15 year olds - researchers noted that those born in June (the last birth month influencing year of school intake) were more likely to be prescribed ADHD medication than those born in July. This trend was noted in both age groups. The conclusion being that the youngest children in a year group at school were more likely to be in receipt of prescribed medication for ADHD compared to older children in the year group.

Alongside the caveats linked to the Whitely report made by NHS Choices, there is a need for further investigation in this area and in particular, whether the results generalise to places outside of just WA. I've already linked to my previous discussion about relative age and ADHD diagnosis/medication (see here again) and from comparisons with the Taiwanese data [2] on this topic, including the fact that Taiwan have a different cut-off month for school entry (August 31). On that basis, yes the trend appears to generalise across geographies...

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[1] Whitely M. et al. Influence of birth month on the probability of Western Australian children being treated for ADHD. MJA. 2017; 206: Feb 6.

[2] Chen MH. et al. Influence of Relative Age on Diagnosis and Treatment of Attention-Deficit Hyperactivity Disorder in Taiwanese Children. J Pediatr. 2016 May;172:162-167.e1.

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ResearchBlogging.org Martin Whitely, Leanne Lester, John Phillimore, & Suzanne Robinson (2017). Influence of birth month on the probability of Western Australian children being treated for ADHD The Medical Journal of Australia

Monday, 13 February 2017

Depression, SMILES and Modified Mediterranean diet (advice)

SMILES in the title of this post refers to the SMILES trial - Supporting the Modification of lifestyle In Lowered Emotional States - and results recently published by Felice Jacka and colleagues [1] (open-access) pertinent to the idea that "dietary improvement" might be something to consider when a diagnosis of major depressive episode (MDE) is received.

Having previously published their study protocol [2], researchers set about looking at whether under "single blind, randomised controlled" conditions, the application of advice pertinent to a diet - the 'ModiMedDiet' - focused on increasing diet quality along Mediterranean diet lines, might be useful for those diagnosed with MDE. The results (which had already been revealed before peer-reviewed publication) said 'yes', such an intervention might be something to consider based on scoring of the Montgomery–Åsberg Depression Rating Scale (MADRS) after 3 months of "individual nutritional consulting sessions delivered by a clinical dietician."

Looking at two groups, those randomly allocated to dietary advice/intervention (n=31 completing) and those allocated to a control condition (social support) (n=25 completing), researchers noted improvements in the MADRS scores more frequently in the diet intervention group. To quote: "At 12 weeks, 32.3% (n = 10) of the dietary support group and 8.0% (n = 2) of the social support control group achieved remission criteria of a score less than 10 on the MADRS." Similar differences were also noted on other study schedules: the Hospital Anxiety and Depression Scale (HADS)-depression subscale.

Caveats? Well as a seasoned veteran of research looking at how dietary intervention for labels generally thought to be outside of the somatic domain can go, I can testify to the limitations attached to this kind of work associated with a lack of double-blindedness and issues associated with dietary compliance. This was also a study providing dietary support and so was not necessarily making study controlled meals for each participant over the course of the study (lessons from other recent research show that advice and prompts can only go so far in dietary studies). The authors also note that they "recruited participants on the basis of existing ‘poor’ quality diet" and how "this may limit the generalisability of our findings to the wider population of individuals with depression." An important point indeed.

But this study represents important work and provides yet more evidence that 'nutritional medicine' should perhaps be part of mainstream psychiatry (see here). You can um-and-ah about whether 'food is medicine' and all that jazz (have you never heard of pharmacognosy?) but I'm firmly with the idea that what we eat might, on occasion and for some people, have some pretty profound implications for things other than our physical health and that includes depression (included in several forms)...

To close, a note to any would-be ageing karateka, middle-aged hips tend to take a little more time to get used to perfecting yoko geri kekomi (pass the ibuprofen please). But practice does (eventually) make perfect...

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[1] Jacka F. et al. A randomised controlled trial of dietary improvement for adults with major depression (the ‘SMILES’ trial). BMC Medicine. 2017; 15: 23.

[2] O'Neil A. et al. A randomised, controlled trial of a dietary intervention for adults with major depression (the “SMILES” trial): study protocol. BMC Psychiatry. 2013; 13: 114.

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ResearchBlogging.org Jacka, F., O’Neil, A., Opie, R., Itsiopoulos, C., Cotton, S., Mohebbi, M., Castle, D., Dash, S., Mihalopoulos, C., Chatterton, M., Brazionis, L., Dean, O., Hodge, A., & Berk, M. (2017). A randomised controlled trial of dietary improvement for adults with major depression (the ‘SMILES’ trial) BMC Medicine, 15 (1) DOI: 10.1186/s12916-017-0791-y

Saturday, 11 February 2017

Pregnancy exposure to SSRIs and offspring autism risk: debate continues

"It remains unclear whether the association between first trimester SSRI [selective serotonin reuptake inhibitorexposure and child autism that was present in the case-control studies even after adjustment for MMI [maternal mental illness] is a true association or a product of residual confounding."

So said the results of the systematic review and meta-analysis undertaken by Hilary Brown and colleagues [1] looking at a potentially important association between pregnancy use of a class of medicines typically used as antidepressants (albeit with some caveats [2]) and risk of offspring autism. This topic has previously received some airtime on this blog (see here and see here) and specifically, how maternal mental health - as per the question 'why were mothers taking SSRIs during pregancy?' - might be a rather large confounding variable affecting any possible correlation.

Unfortunately even with the Brown paper, the debates will continue as to whether the SSRI-offspring autism correlation is a 'true' correlation or not. Based on the results of 6 studies - "4 case-control studies and 2 cohort studies" - where MMI was adjusted for/restricted to, authors reported some interesting trends. So in their meta-analysis of the data where results from case-control studies were adjusted for a potential impact from MMI, researchers observed that "first trimester exposure remained statistically significant." In "MMI-restricted analyses" covering the same study type, the collected studies did not show any connection between pregnancy SSRI use and offspring autism during either the first trimester or 'any time during pregnancy'. Similar results were found in the cohort studies included in the Brown paper (although both first trimester and 'any point during pregnancy' SSRI use both showed significant correlations to offspring autism in adjusted studies). I might also add that the Brown meta-analysis on this topic is not the only recent addition to the peer-reviewed literature [3]; indeed, there are several [4] others.

"Future studies require robust measurement of MMI prior to and during pregnancy" said Brown et al. I would agree with this sentiment added to the caveat that we may never truly know whether there is a definitive connection between pregnancy SSRI use and offspring autism risk on the basis of observational studies alone. Yes, I know it is unethical to withhold treatment such as SSRIs when clinically indicated even during pregnancy and so investigations utilising this kind of 'interventionist' study design are not likely to be undertaken anytime soon. But it does strike me that we could do quite a bit more modelling any potential effects (or not) in animal studies for example, as per some investigations with fish a while back (see here) as a start.

And finally, although it is not my place to give clinical or medical advice on this blog, I should point out that much like investigations on another medicine prescribed during pregnancy potentially linked to offspring outcomes (see here), SSRIs are not generally given willy-nilly to pregnant women; there are very valid reasons for managing mum's psychiatric health particularly during pregnancy. If anyone is in doubt, please consult your doctor (and not just Dr Google).

To close, before 'fake news' there was The Day Today (and they did it oh so well)...

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[1] Brown HK. et al. The Association Between Antenatal Exposure to Selective Serotonin Reuptake Inhibitors and Autism: A Systematic Review and Meta-Analysis. J Clin Psychiatry. 2017 Jan;78(1):e48-e58.

[2] Jakobsen JC. et al. Selective serotonin reuptake inhibitors versus placebo in patients with major depressive disorder. A systematic review with meta-analysis and Trial Sequential Analysis. BMC Psychiatry. 2017; 17: 58.

[3] Kaplan YC. et al. Prenatal selective serotonin reuptake inhibitor use and the risk of autism spectrum disorder in children: A systematic review and meta-analysis. Reprod Toxicol. 2016 Dec;66:31-43.

[4] Kobayashi T. et al. Autism spectrum disorder and prenatal exposure to selective serotonin reuptake inhibitors: A systematic review and meta-analysis. Reprod Toxicol. 2016 Oct;65:170-178.

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ResearchBlogging.org Brown HK, Hussain-Shamsy N, Lunsky Y, Dennis CE, & Vigod SN (2017). The Association Between Antenatal Exposure to Selective Serotonin Reuptake Inhibitors and Autism: A Systematic Review and Meta-Analysis. The Journal of clinical psychiatry, 78 (1) PMID: 28129495