"Neurodevelopmental effects of prenatal vitamin D in humans"

The results of the systematic review and meta-analysis published by Azahara García-Serna & Eva Morales [1] provide the blogging fodder today.

Their aim was to summarise the collected peer-reviewed research evidence pertinent to "the association between 25-hydroxyvitamin D [25(OH)D] levels in maternal blood in pregnancy or newborn blood at birth and neurodevelopmental outcomes, including cognition, psychomotor performance, language development, behavioral difficulties, attention deficit and hyperactivity disorder (ADHD), and autistic traits." This coming from authors who already have some research 'form' in this area (see here).

Twenty-five studies ("articles") were included in their boiling-down-of-the-relevant-research-literature published up to May 2018. From the combined data, a few *associations* were detected: "Comparing the highest vs. the lowest category of prenatal 25(OH)D levels, the pooled beta coefficients were 0.95... for cognition, and 0.88... for psychomotor development. The pooled relative risk for ADHD was 0.72..., and the pooled odds ratio for autism-related traits was 0.42." What this meant is that measured higher levels of vitamin D in pregnant mums-to-be or in offspring newborn blood correlated with "improved cognitive development and reduced risk of ADHD and autism-related traits later in life" for offspring.

Of course one has to be careful with such data whether it comes from a meta-analysis or not. We're still talking about observational studies where one variable (vitamin D) is being analysed in the context of one or a few others (related to offspring development). Yes, researchers can control for this potential confounder or that potential confounder, but there remains a 101 other variables that likely affect the likelihood of ADHD or 'autism-related traits' appearing, not least biology and genetics.

That being said, the García-Serna / Morales are potentially important. They point to the need for further research into various possibly interlinked areas when it comes to vitamin D levels and their intake. This follows Government guidance (at least here in Blighty) suggesting that many people should be taking a vitamin D supplement already (see here). I'm also minded to suggest that future investigations should also be looking at other related areas around vitamin D such as the various genetic processes that seem to be important to vitamin D levels and the metabolism of the sunshine vitamin (see here).

And if you're still not convinced by the potential effects of vitamin D and offspring outcomes, perhaps the findings - systematic review findings - published by Janet Janbek and colleagues [2] might help sway you a little...

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[1] García-Serna A. & Morales E. Neurodevelopmental effects of prenatal vitamin D in humans: systematic review and meta-analysis. Molecular Psychiatry. 2019. Jan 25.

[2] Janbek J. et al. Associations between vitamin D status in pregnancy and offspring neurodevelopment: a systematic literature review.  Nutr Rev. 2019 Feb 26. pii: nuy071.

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The DePaul Symptom Questionnaire for chronic fatigue syndrome (CFS) and myalgic encephalomyelitis (ME)

It's another short descriptive post today as I bring the paper by Len Jason & Madison Sunnquist [1] to your attention charting "the development of the DePaul Symptom Questionnaire (DSQ) to assess symptoms of the major chronic fatigue syndrome (CFS) and myalgic encephalomyelitis (ME) case definitions."

I say this is a descriptive post because the Jason/Sunnquist paper provides some important technical details about the DSQ and its evolution; all from a research group who seem to be pretty clued into ME/CFS and its very wide range of clinical presentation (see here).

There are some important aspects included in the paper; not least a focus on the issue of post-exertional malaise (PEM), something which has been a real focus to these researchers (see here). The other very welcomed side to the Jason/Sunnquist paper are the various links to the DSQ derivatives all provided free of charge.

'Nuff said.

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[1] Jason LA. & Sunnquist M. The Development of the DePaul Symptom Questionnaire: Original, Expanded, Brief, and Pediatric Versions. Front Pediatr. 2018;6:330.

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"Has Daniel always been autistic?"

"Has Daniel always been autistic?"

That was the question that led to Twitter uproar and newspaper headlines calling a TV presenter an 'idiot' and "embarrassing" and "ignorant" these past few days. Some have even called for veteran daytime TV presenter Richard Madeley to be sacked, as one of the premier national autism charities here in Blighty authoritatively announced "autism is a lifelong condition, people are born autistic, it’s not something a child grows out of" following the reporting of an interview between Madeley and Daniel Wakeford, one of the stars of the not particularly well titled TV series called The Undateables. Personally, I would have liked to have seen said charity comment on how the term 'undateable' really shouldn't be used in this day and age with any diagnosis/label in mind...

Emotions ran high following the interview, as many parents of children with autism and autistic people voiced their opinions about their own personal experiences of autism. These are all valid opinions. The problem however, is that within the wide - very wide - heterogeneity that is autism, some of the peer-reviewed science on the topic of autism actually supports the line of questioning from Madeley. Some of the peer-reviewed science highlights the sweeping error in saying that autism is (a) lifelong for everyone and (b) that everyone, past, present and future is 'born autistic'.

OK, first things first, autism is a label ripe for sweeping generalisations. We've seen it numerous times as psychological theories for example, have swept through proclaiming that everyone with autism is lacking a theory of mind or empathy or some other related construct. Likewise, I've seen people quite vehemently opine that autism is the product of this or that 'environmental factor' insinuating that simple changes to drink, food or medicines use for example, will 'stop autism'. The reality however is that autism is a label used to describe vast heterogeneity. It's also a label that says nothing about how a person came to be autistic and nothing about the prognosis of their presentation or their life in general.

So what is the cold, objective peer-reviewed scientific evidence to say that autism is not present from birth for everyone? Well, it's multi-fold. It comes from a number of studies that have followed children from early infancy into later childhood to see whether autism *always* manifest from the very earliest days. Take the recent findings from Sally Ozonoff and colleagues [1] (see here for my take) that concluded among late diagnosed children in their cohort: "Seven showed very little evidence of ASD [autism spectrum disorder] in preschool, whereas 7 demonstrated subtle, subthreshold symptomatology." Add it to other independent data [2] that "validate parents' reports that ASD may appear after a period of nonautistic development" (also that "such reports should not be attributed to recall bias") and then throw in the idea that 'regression', as in a regression of previously acquired skills, is perhaps no stranger to many instances of autism (see here). Then to top it all add in other data highlighting specific cases of 'acquired autism' following exposure to particular post-natal infections for example (see here), and the old 'autistic from birth' mantra does not universally hold for everyone diagnosed as being on the autism spectrum. The evidence against the sweeping 'autism is a lifelong condition' statement made following the interview? I'll direct you to some of the numerous occasions that I've talked about such an idea on this blog (see here and see here and see here) based again on the available peer-reviewed science. Cold. Objective. Science.

Minus making any sweeping generalisations of my own, there is scientific evidence out there that 'born autistic' is not something that can be universally applied to everyone on the autism spectrum no matter how many people would like it to be so. In that respect, the question from Richard Madeley was not ignorant nor disrespectful but rather quite sensible and easily discernible from the available science. The fact also that Daniel's mother Carol talked about a 'loss of his language abilities' in her reply to the question (something I'm sure must have been mentioned before the interview took place and was aired) kinda adds to the sound reasoning for Madeley to ask. It also implies that science should keep studying such an important phenomenon.

It seems that when Carol Wakeford responded with the words 'yes, well there's controversy about that' as the first part of her answer to Madeley's question about Daniel, she certainly wasn't wrong...

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[1] Ozonoff S. et al. Diagnosis of Autism Spectrum Disorder After Age 5 in Children Evaluated Longitudinally Since Infancy. J Am Acad Child Adolesc Psychiatry. 2018 Nov;57(11):849-857.e2.

[2] Landa RJ. et al. Social and communication development in toddlers with early and later diagnosis of autism spectrum disorders. Arch Gen Psychiatry. 2007 Jul;64(7):853-64.

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"a neurodevelopmental abnormality possibly associated with congenital Zika virus infection"

I'm a little late getting to the findings reported by Marion Rice and colleagues [1] (open-access available here) but I did want to cover them because of their current importance and perhaps future implications. The topic in question was the Zika virus and specifically the research efforts of the U.S. Zika Pregnancy and Infant Registry (USZPIR) used to track those infants exposed to the virus during the important nine months than made them. Just in case you didn't follow the hows-and-whys of the Zika virus outbreak and its effects a while back, some background can be found here.

Rice et al report findings for nearly 1500 children "of mothers with laboratory evidence of confirmed or possible Zika virus infection during pregnancy" in terms of their level of care and clinical follow-up and also "to identify Zika-associated birth defects and neurodevelopmental abnormalities possibly associated with congenital Zika virus infection." Aside from reporting that the majority of their cohort had "some follow-up care reported" ('some' that included very basic "length/height, weight, or head circumference measurements and date of measurements" reported back to the USZPIR), a few other observations were also made. This included findings such as: "approximately one in seven (14%) were identified during infancy or early childhood as having either a Zika-associated birth defect, a neurodevelopmental abnormality possibly associated with congenital Zika virus infection, or both."

Although the talk about birth defects is important to Zika virus exposure (microcephaly being only one part of this), I was specifically interested in the 'neurodevelopmental' side of things reported in the Rice paper as affecting 9-10% of the cohort depending on what laboratory testing for Zika virus exposure was carried out. Bearing in mind the age group of the cohort (1 year old and above), and that such neurodevelopmental issues covered a lot of clinical ground (e.g. "hearing abnormalities; congenital contractures; seizures; body tone abnormalities; movement abnormalities; swallowing abnormalities; possible developmental delay; possible visual impairment; and/or postnatal-onset microcephaly") it's important to understand how infections such as Zika might have the ability to affect cognitive and/or neurodevelopmental outcomes. What's also important too is the realisation that given the young age of the cohort, "the full spectrum of adverse outcomes related to congenital Zika virus infection is not yet known." So developmental delay for example, *could* eventually develop into something else, and why appropriate monitoring will continue through initiatives like the USZPIR.

From a cold, objective science perspective and without wishing to diminish the very human effects associated with this event, the 2016 Zika outbreak that struck the Americas provides an ideal opportunity to study our important interaction with the environment around us. It emphasises how facets of our environment can very much influence both physical and psychological health, particularly at critical times of development. A lesson that perhaps is transferable to many different neurodevelopmental labels [2]...

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[1] Rice ME. et al. Vital Signs: Zika-Associated Birth Defects and Neurodevelopmental Abnormalities Possibly Associated with Congenital Zika Virus Infection - U.S. Territories and Freely Associated States, 2018. MMWR Morb Mortal Wkly Rep. 2018 Aug 10;67(31):858-867.

[2] Lydholm CN. et al. Parental infections before, during and after pregnancy as risk factors for mental disorders in childhood and adolescence – a nationwide Danish study. Biological Psychiatry. 2018. Oct 1.

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Pregnancy diet and offspring "hyperactivity-inattention symptoms"?

I appreciate that the findings reported by Cédric Galera and colleagues [1] are potentially a little uncomfortable. Their examination of over 1200 mother-child pairs looking at data from food frequency questionnaires during pregnancy and subsequent offspring 'externalising' behaviours into childhood, could be construed as evidence that poor eating habits during the nine months that made us have the ability to translate into childhood issues. Because food choices are seen as just that - 'choices' - the Galera results *could* potentially fall into the same category as other 'choices' that also seemingly affect offspring development in this area (see here for example). I make no value judgements.

Having also bumped into the Galera paper at the same time as seeing a BBC media report observing that "We learn nothing about nutrition, claim medical students", one might further make an argument for the need for much greater education, guidance, support and potentially 'nudging', when it comes to issues such as 'what to eat during pregnancy'. That however, is another discussion for another day.

Anyhow, the science...

Galera et al report findings based on the EDEN mother-child cohort [2], an initiative set up to examine "the relations and potential interactions between maternal exposures and health status during pregnancy, fetal development, health status of the infant at birth and the child’s health and development." It's interesting that the opening words to the Heude [2] description of the initiative mention the name 'Barker', as in the late David Barker, a man who helped popularise the idea that nutrition in the womb (through maternal diet) might have some important *consequences* for offspring in the short- and long-term. Looking at some of the other research produced by the EDEN mother-child cohort (see here), Barker and others may have indeed been on to something.

As well as looking at offspring externalising symptoms such as conduct problems via use of "the Strength and Difficulties Questionnaire at ages 3, 5, and 8 years", authors also looked at "trajectories of hyperactivity-inattention symptoms." This, on the basis that the SDQ does pretty well at discriminating between ADHD and non-ADHD cases [3]. They concluded that, taking into account infant dietary patterns "at age 2 years" and various other potential influencing variables ("maternal stress and depression, gestational diabetes, and socioeconomic variables"), there was something to see with regards to use of a 'high Western diet' and 'low Healthy diet' during pregnancy in relation to offspring developmental outcome. Specifically: "Maternal diet during pregnancy was independently associated with children's hyperactivity-inattention symptoms."

Of course, one needs to be a little bit careful that *association* is not viewed as 'cause-and-effect' based on such observational studies. That also it is downright unethical to put mums-to-be on a 'healthy diet' vs. 'a non-healthy diet' is also a stumbling block to robust investigations in this area; similar to the fact that one wouldn't put mums-to-be on a tobacco smoking vs. a non-smoking intervention.

But the Galera results are not stand-alone in potentially implicating maternal diet as a factor in relation to offspring hyperactivity-inattention [4] and are therefore deserving of some further investigation. I've already mentioned that perhaps more guidance and 'nudges' need to be provided in the area of pregnancy nutrition, and that I assume, would include looking at the cost and convenience of a healthy diet vs. a not-so-healthy diet in the context of a possible *link* between diagnosed attention-deficit hyperactivity disorder (ADHD) and "socioeconomic deprivation" for example (see here). More than that however is the idea that David Barker and others who talked about 'foetal programming' during the pregnancy months as a result of what is in or perhaps not in a maternal diet may have been a lot more accurate than many people would have perhaps imagined...

And on the topic of 'foetal programming', diet might not be the only factor to consider [5]...

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[1] Galera C. et al. Prenatal diet and children's trajectories of hyperactivity-inattention and conduct problems from 3 to 8 years: the EDEN mother-child cohort. J Child Psychol Psychiatry. 2018 Mar 24.

[2] Heude B. et al. Cohort Profile: The EDEN mother-child cohort on the prenatal and early postnatal determinants of child health and development. Int J Epidemiol. 2016 Apr;45(2):353-63.

[3] Algorta GP. et al. Diagnostic efficiency of the SDQ for parents to identify ADHD in the UK: a ROC analysis. Eur Child Adolesc Psychiatry. 2016 Sep;25(9):949-57.

[4] Rijlaarsdam J. et al. Prenatal unhealthy diet, insulin-like growth factor 2 gene (IGF2) methylation, and attention deficit hyperactivity disorder symptoms in youth with early-onset conduct problems. J Child Psychol Psychiatry. 2017 Jan;58(1):19-27.

[5] Andersen SL. et al. Maternal Thyroid Function in Early Pregnancy and Child Neurodevelopmental Disorders: A Danish Nationwide Case-Cohort Study. Thyroid. 2018 Mar 27.

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ICF core sets for autism: "third in a series of four empirical studies"

Peer-reviewed discussions on the International Classification of Functioning, Disability and Health (ICF) core sets for autism have appeared a couple of times before on this blog (see here and see here). The idea behind developing the ICF core sets - a World Health Organisation (WHO) initiative - is to build up a kind of framework for describing and organising information on functioning and disability across various diagnoses.

Autism has been in the ICF sights for a few years now. The hope is that science and clinical practice can start to get closer to the many abilities and disabilities that seem to derive from a diagnosis and offer more evidence-based 'clues' of where and when support needs to be targeted. Also perhaps potentially providing some good evidence for just how heterogeneous the autism spectrum really is...

Bearing in mind the previous research occasions where the development of the ICF core sets for autism have been discussed from a systematic review and 'experts' perspective, the paper by Soheil Mahdi and colleagues [1] adds a third tier to proceedings: "to describe functioning in ASD (as operationalized by the ICF) derived from the perspectives of diagnosed individuals, family members, and professionals." This is an important part of the ICF development schedule, in that it gave an important voice to those people who are themselves autistic and their family members. All of this set in light of a growing 'debate' on who speaks for who(m) in the context of autism (see here) and how talking more to those on the autism spectrum about their experience of autism might be a rather good idea (see here) (bearing in mind that not everyone can or does make their voice heard in such conversations - see here).

So, drawing on discussions - "focus groups and semi-structured interviews" - with some 19 stakeholder groups, the authors report how 'meaningful concepts' talked about by stakeholders were linked to the draft ICF categories already present. Various talking points emerged; some mirroring what has been previously observed: "Positive aspects of ASD [autism spectrum disorder] included honesty, attention to detail, and memory". Others, not exactly aligning with other discussions by other groups: "Body structures were sparsely mentioned by the participants."

The outcome was however pretty much the same as the other ICF development occasions: "The experiences provided by international stakeholders support the need to understand individuals with ASD in a broader perspective, extending beyond diagnostic criteria into many areas of functioning and environmental domains." The core triad/dyad of symptoms it seems, is only the starting point when it comes to what autism looks like and means. A shocker indeed!

I await more on this topic, and perhaps, mentioning how the ICF core sets for autism might also *correlate* with other important research streams such as that related to quality of life [2].

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[1] Mahdi S. et al. An international qualitative study of functioning in autism spectrum disorder using the World Health Organization international classification of functioning, disability and health framework. Autism Res. 2017 Dec 11.

[2] Lin LY. & Huang PC. Quality of life and its related factors for adults with autism spectrum disorder. Disabil Rehabil. 2017 Dec 11:1-8.

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"Medical Conditions in the First Years of Life Associated with Future Diagnosis of ASD"

I rank the paper by Stacey Alexeeff and colleagues [1] (open-access available here) as being in the 'pretty important' category when it comes to hierarchy in autism research. Not only because of their use of data derived from Kaiser Permanente (KP) (quite a large US healthcare provider that has some autism research history) including some "3911 ASD [autism spectrum disorder] cases and 38,609 controls" but also because some of the findings reiterate what is already 'known' about in relation to autism and how various medical conditions might be quite important to at least some 'types' of autism. These results are also being presented at IMFAR 2017 (see here) which will be opening its doors very soon...

The Alexeeff paper is open-access but a few choice details are worthwhile pulling out:

• As per those participant numbers, the authors confirmed that "ASD cases were defined as children with either (a) an ASD diagnosis from an ASD specialist or (b) two or more ASD diagnoses from non-specialists, separated in time." This contrasted with controls who "were required to never have had an ASD diagnosis as of June 2012" (the period of study covered those born between 2000 and 2009).
• The medical conditions screened for in participant records were quite wide-ranging: "Over 1000 ICD-9 codes were grouped into 79 medical conditions (e.g., constipation) within 19 domains (e.g., gastrointestinal)" and importantly, relied on physician/clinician input. Researchers ascertained how frequently said medical conditions occurred in each of the groups: "whether certain medical conditions occurring in early childhood were associated with a higher risk of future ASD diagnosis."
• Results: "38 of the 79 medical conditions had statistically significant associations with ASD risk after multiple testing adjustment." These conditions ranged from various types/forms of developmental delay (language, learning, motor) to more somatic conditions: "nutrition, genetic, ear nose and throat, and sleep conditions." It's also worth noting that some types of diagnosis/conditions displayed only a weak association with subsequent risk of ASD including that related to asthma (previously discussed quite a bit on this blog).
• Researchers also looked at what clusters of medical conditions might be associated with lower or higher likelihood of an ASD diagnosis being given. They concluded that: "Developmental delay and mental health condition clusters were associated with the highest relative risks of ASD." They further suggest that "combinations of medical comorbidities could aid in risk stratification for ASD prior to ASD diagnosis using a supervised clustering analysis based on machine-learning methods." Machine learning yet again, applied to autism research eh?

There's little more for me to discuss about this work other than to say that much more targeted research is needed to build on these latest findings from Alexeeff and colleagues. Coinciding with the ideas that (i) autism rarely exists in some sort of diagnostic vacuum (see here) and that (ii) autism genes are not necessarily just genes for autism (see here) (indeed a topic rising in research importance [2]) the lessons to be learned are becoming a little clearer. I might also focus a little more on those somatic diagnoses discussed in the Alexeeff paper as being quite important to the clinical picture when it comes to autism. Y'know how various medical comorbidities are indeed over-represented when it comes to autism and how appropriate screening and management/treatment [3] should be offered when and where they are identified (see here) save any further healthcare inequalities arising...

To close, I appreciate that there are quite a lot of opinions out there about a certain US autism organisation, but a recent document of theirs talking about the various conditions/comorbidities that can follow a diagnosis of autism (see here) deserves an airing. Not that they were however the first group to talk about this important part of the autism spectrum (see here) but better late than never...

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[1] Alexeeff SE. et al. Medical Conditions in the First Years of Life Associated with Future Diagnosis of ASD in Children. J Autism Dev Disord. 2017 Apr 22.

[2] Diaz-Beltran L. et al. Cross-disorder comparative analysis of comorbid conditions reveals novel autism candidate genes. BMC Genomics 2017. 18: 315.

[3] Flor J. et al. Developmental functioning and medical Co-morbidity profile of children with complex and essential autism. Autism Res. 2017 May 5.

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Alexeeff SE, Yau V, Qian Y, Davignon M, Lynch F, Crawford P, Davis R, & Croen LA (2017). Medical Conditions in the First Years of Life Associated with Future Diagnosis of ASD in Children. Journal of autism and developmental disorders PMID: 28434058

Autism, pregnancy maternal immune activation and vitamin D?

Today's post is a bit of a mash-up, drawing on two articles quite recently published in the peer-reviewed science domain.

The first is by Stephanie Vuillermot and colleagues [1] (open-access) suggesting that "early dietary supplementation with vitamin D may open new avenues for a successful attenuation or even prevention of neurodevelopmental disorders following maternal inflammation during pregnancy." These findings have also received some media attention (see here for example) and continues a research theme focused on vitamin D (the sunshine vitamin/hormone) and [some] autism (see here for example).

The second paper is by Michael Lombardo and colleagues [2] (open-access) and also covers the topic of maternal immune activation (MIA) and its potential effects on offspring outcomes, concluding that: "MIA may confer increased risk for ASD [autism spectrum disorder] by dysregulating key aspects of fetal brain gene expression that are highly relevant to pathophysiology affecting ASD."

What are the connections between these papers? Well, obviously both deal with the concept of maternal immune activation (MIA) where infection, or possibly/rather 'inflammatory' responses to infection, during critical periods of pregnancy seem to be able to affect offspring developmental and other outcomes. This bearing in mind that pregnancy represents a time of 'reprogrammed immune function' such that the maternal immune system does not mount a response to the genetically dissimilar organism growing inside the body. Both papers model MIA in rodents (mice and rats respectively) given the ethics of undertaking such experimental studies in humans. Both studies concluded that (a) there is evidence that MIA is a real phenomenon and (b) bearing in mind rodents are not necessarily the same as humans (see here) (a shocker I know), MIA seems to invoke specific biochemical changes pertinent to the expression of genes *linked* to autism that are also potentially amenable to intervention.

The Vuillermot findings in particular, offer some rather intriguing prospects for further study as a function of their conclusion that: "maternal VitD co-administration blocked the emergence of the ASD-relevant deficits in social interaction, stereotyped behavior, and emotional learning and memory." I appreciate that 'blocking the emergence' of autistic behaviours is not something that everyone is going to unanimously welcome (the implication being that every single autistic trait is somehow something to be eradicated). The idea however that aspects of even something like certain stereotyped behaviours under certain conditions and with certain intensity might 'set someone up' for the presentation of truly disabling conditions such as anxiety [3] (see here too) offers a degree of support for the idea of intervention targeting such behaviours in particular circumstances.

But there is a potential research spanner in the works when it comes the idea that vitamin D might 'offset' some of the changes associated with exposure to MIA. The authors note: "VitD does not alter maternal or fetal inflammatory cytokine production." This statement was made on the basis that "prenatal administration of vitamin D had no effect on pro-inflammatory cytokine levels in dams or in fetal brains." Cytokines are those chemical messengers of the immune system. How then, you might ask? Well, back to the Lombardo paper and the possibility that vitamin D is not necessarily an 'anti-inflammatory' of choice under such circumstances but might - MIGHT - act on some of the mechanisms related to those genes expressed under MIA conditions. It's pretty well-known for example, that vitamin D does influence gene expression (see here for example) as our knowledge of the biological duties of the sunshine vitamin/hormone expand (see here). It is logical to assume that the next research step would be to see whether vitamin D administration *might* at certain times and under certain circumstances, affect the expression of those genes 'highly relevant to pathophysiology affecting ASD' under MIA conditions. This, in the context that maternal vitamin D levels during pregnancy again *might* have an important impact on the presentation of offspring autistic traits (see here).

And since we're on the topic of vitamin D and autism (yet again), how about reading a new hypothesis paper on some potentially important connections [4]?

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[1] Vuillermot S. et al. Vitamin D treatment during pregnancy prevents autism-related phenotypes in a mouse model of maternal immune activation. Molecular Autism. 2017; 8: 9.

[2] Lombardo MV. et al. Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder. Mol Psychiatr. 2017. Mar 21.

[3] Bitsika V. & Sharpley CF. The association between parents' ratings of ASD symptoms and anxiety in a sample of high-functioning boys and adolescents with Autism Spectrum Disorder. Res Dev Disabil. 2017 Mar 1;63:38-45.

[4] Gillberg C. et al. The role of cholesterol metabolism and various steroid abnormalities in autism spectrum disorders: A hypothesis paper. Autism Res. 2017. April 12.

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Vuillermot, S., Luan, W., Meyer, U., & Eyles, D. (2017). Vitamin D treatment during pregnancy prevents autism-related phenotypes in a mouse model of maternal immune activation Molecular Autism, 8 (1) DOI: 10.1186/s13229-017-0125-0




Lombardo, M., Moon, H., Su, J., Palmer, T., Courchesne, E., & Pramparo, T. (2017). Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder Molecular Psychiatry DOI: 10.1038/mp.2017.15

Maternal immune activation (MIA) and Old World monkeys

Old World monkeys detailed in the title of this post, specifically refers to a type of animal called a rhesus macaque who were the 'participants' of choice as detailed in a recent study by Destanie Rose and colleagues [1] looking at a concept called maternal immune activation (MIA).

Those who followed this blog down the years will no doubt have seen me discuss MIA before in the context of autism and/or schizophrenia (see here for example). The basic theory is that whilst in-utero and enjoying approximately nine months in a warm and comfortable environment with a reprogrammed maternal immune system to stop a mother's body from 'rejecting' a developing foetus, infections encountered by the mother at critical periods of pregnancy might themselves or through their effects on the maternal immune system, have the ability to 'affect' offspring outcomes in a variety of ways. The majority of work on the concept of MIA has been in smaller animals such as rodents, so the inclusion of rhesus macaques is an important step as it was in other work with the immune system and autism in mind (see here).

So, take 21 pregnancy rhesus macaques and give them either "three injections over 72 hours of poly I:C-LC [an immune stimulant], a double stranded RNA analog (viral mimic), or saline as a control." Said injections were given either "near the end of the first trimester or near the end of the second trimester" to see whether timing of immune stimulation might be important. Macaque offspring were subsequently born and followed for about 4 years. Blood samples were collected from offspring "at the end of their first (year 1) and fourth (year 4) years to assess dynamic cellular immune function." At the same time, the behaviours of monkey offspring were also analysed to see if there were any effects from MIA exposure.

Results: behaviour did seem to be affected by MIA exposure, particularly stereotyped behaviours, noted to be a core feature of autism. Similarly, researchers reported some important immune system 'changes' associated with MIA exposure: "elevated production of innate inflammatory cytokines including: interleukin (IL)-1β, IL-6, IL-12p40, and tumor necrosis factor (TNF)α" at 1 year of age. Immune system changes were also noted longer-term at 4-years: "the MIA exposed offspring continued to display elevated IL-1β, and there was also a pattern of an increased production of T-cell helper type (TH)-2 cytokines, IL-4 and IL-13." Although being careful not to generalise too much when it comes to immune system markers and what they mean for pro- or anti-inflammatory signals, the leaning towards the production of Th-2 cytokines is typically linked to atopy and 'the promotion of IgE and eosinophilic responses in atopy.' The authors - including some notable names from the MIND Institute - conclude by suggesting that: "Data from this study suggests long-term behavioral and immune activation was present in offspring following MIA."

Accepting that animal models of something like MIA are not necessarily the same as human MIA and its responses, this is interesting work. If one however accepts the data on something like vaccine function being modelled in animals (see here for example) is akin to what happens in people, real people, there is some added strength to the information published by Rose and other groups on how MIA may indeed be a relevant factor when it comes to immune function potentially affecting offspring behaviour and development.

This research also intersects with quite a lot of other peer-reviewed science talking about how (human) pregnancy infection does seem to be related to offspring risk for conditions such as autism (see here). That various immune-related conditions such as asthma in mothers might also 'prime' for offspring neurodevelopmental issues is another important strand of research potentially pertinent to this area (see here). And then also there is the idea of an 'inflammatory autism subtype' (see here) also previously suggested continuing the important theme of immune function and behaviour/development being linked. There are, as you can see, quite a few potentially important connections that can be made between the Rose results and other data on MIA and offspring development.

Oh, and I'll be coming to the recent paper by Zerbo and colleagues all in good time...

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[1] Rose DR. et al. Long-term altered immune responses following fetal priming in a non-human primate model of maternal immune activation. Brain Behav Immun. 2016 Nov 19. pii: S0889-1591(16)30522-0.

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Rose, D., Careaga, M., Van de Water, J., McAllister, K., Bauman, M., & Ashwood, P. (2016). Long-term altered immune responses following fetal priming in a non-human primate model of maternal immune activation Brain, Behavior, and Immunity DOI: 10.1016/j.bbi.2016.11.020

Antibiotic brain part 3

"This study demonstrates an association between antibiotic use in the first year of life and subsequent neurocognitive outcomes in childhood."

So said the findings reported by Slykerman and colleagues [1] who relied on data from the Auckland Birthweight Collaborative Study (an initiative set up to determine whether "internationally recognized risk factors for small-for-gestational-age (SGA) term babies were applicable in New Zealand") to examine the suggestion that early life antibiotic use might be associated with a "detrimental effect on later neurocognitive outcomes."

Relying on maternal report of antibiotic use among offspring "between 12 months and 3.5 years of age" researchers compared data with that derived from "Intelligence test scores and measures of behavioural difficulties" when children were 3.5, 7 and 11 years of age. They found that antibiotic use during the first 12 months of life was high in their cohort (70%) and that: "Those who had received antibiotics had more behavioural difficulties and more symptoms of depression at follow up." I've highlighted the 'relying on maternal report' bit because although parents are typically the experts on their own children (yes, they are), the reliance on parental report is not the same as reliance on objective medical or prescribing records for antibiotic use and important information on antibiotic type, dose and reason for such use that they typically contain. Indeed, I might also stress that correlating antibiotic use and developmental outcome whilst interesting should also be mindful of the myriad of other variables that might play a role, including the idea that 'behavioural difficulties' often don't present until later infancy for whatever reason. Be careful with single associations.

But... I've labelled this post 'Antibiotic brain part 3' because I feel that the Slykerman findings are another important piece of evidence potentially pertinent to the idea that antibiotics may be pretty good at tackling bacterial infection but that also that they may have some quite potent effects on behaviour and development as well as physiology (see here for antibiotic brain part 1 and antibiotic brain part 2).

What's the possible mode of action linking [early] antibiotic use and behaviour and development? Well, far be it from me to speculate too much but I'm minded to bring in the idea that those trillions of wee beasties that inhabit our deepest, darkest recesses (the gut microbiome) might play some role in any process. Minus hype [2] we're for example, already finding out how gut bacteria 'might' show some important behavioural connections (see here for example) and specifically how certain strains of bacteria might link to important states such as depression (see here and see here). It's not outside the realms of possibility that 'swallowing a grenade' (although not literally) designed to kill bacteria rather willy-nilly, might influencing either bacterial diversity in the gut or impact on specific strains that could be consider more rather than less beneficial.

One more idea for science to perhaps consider relates to why antibiotics were given in the first place. If for example we assume that ear infection might be a common reason, could it not be that the actual symptoms over and above the [antibiotic] treatment might be the more important variable in relation to 'behavioural difficulties'? [3]

There is much more to do in this area, but alongside the dangers of antibiotic resistance perhaps science might also be more open to the idea that antibiotics might do so much more than just impact on physiology?

To close, for those in Blighty who might remember Hastings, 1066 and a certain Tapestry, things were a whole lot more complicated/gory that you might have expected...

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[1] Slykerman RF. et al. Antibiotics in the first year of life and subsequent neurocognitive outcomes. Acta Paediatr. 2016 Oct 4.

[2] Bik EM. The Hoops, Hopes, and Hypes of Human Microbiome Research. Yale J Biol Med. 2016 Sep 30;89(3):363-373.

[3] Niclasen J. et al. Associations between otitis media and child behavioural and learning difficulties: Results from a Danish cohort. Int J Pediatr Otorhinolaryngol. 2016 May;84:12-20.

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Slykerman RF, Thompson J, Waldie KE, Murphy R, Wall C, & Mitchell EA (2016). Antibiotics in the first year of life and subsequent neurocognitive outcomes. Acta paediatrica (Oslo, Norway : 1992) PMID: 27701771

Fatty acids and reading ability replicated

I'm a fan of scientific replication on this blog. Y'know, when one group comes out with some new marvellous research findings and another [independent] group says 'yep, we found that too'.

It is with that sentiment in mind that I'm talking about the results published by Mats Johnson and colleagues [1] who suggested that "3 months of Omega 3/6 treatment improved reading ability" following a "3-month parallel, randomized, double-blind, placebo-controlled trial" with schoolchildren aged 9-10 years old. The trial was actually a little longer than 3 months given that it also included a 3-month active treatment period for all subjects. The replication angle harks back to another study [2] that has been mentioned on this blog (see here) and that concluded: "DHA [docosahexaenoic acid] supplementation appears to offer a safe and effective way to improve reading and behavior in healthy but underperforming children from mainstream schools."

The Johnson paper, whose ClinicalTrials.gov records can be found here, utilised a gold-standard methodology when it came to testing whether a particular fatty acid formulation - "a daily dose of 558 mg EPA [eicosapentaenoic acid], 174 mg DHA, and 60 mg gamma-linolenic acid" - could improve the reading ability of mainstream schooled children. The primary outcome being measured were any changes to the LOGOS test as well as whether fatty acid intervention also impacted on attention-deficit hyperactivity disorder (ADHD) symptoms, bearing in mind those formally diagnosed with ADHD were supposed to have been excluded from the study. The behavioural side of things also coming from some history with fatty acids there too (see here).

Results: "Compared with placebo, 3 months of Omega 3/6 treatment improved reading ability – specifically the clinically relevant ‘phonologic decoding time’ and ‘visual analysis time’ – in mainstream schoolchildren. In particular, children with attention problems showed treatment benefits." The placebo by the way, was palm oil. Importantly too, side-effects described during the study were fairly rare and mild: "mainly stomach pain/diarrhea (active n = 9, placebo n = 2)." I should also mention that the participant size was over a hundred when it came to those who completed the study so these results are not to be sniffed at.

I'd like to think that these and the various other results out there on this topic will start to be taken seriously some time soon. I know that there has been a lot of hype associated with fatty acids down the years, but the science is growing ever stronger to suggest that such preparations probably do more good than harm. Health promotion messages to eat more oily fish (a good source of fatty acids) for example, are important but unfortunately as per other occasions, are unlikely to provide the same levels of such nutrients as artificial supplementation delivers. That and the fact that oily fish is probably not going to be to everyone's taste.

Insofar as the 'where next?' of this area of research, well, longer-term follow-up is perhaps an important goal to see whether positive changes to reading ability and/or potential amelioration of behavioural issues translates into more favourable academic and other outcomes as a function of fatty acid intake. Accepting that for example, ADHD and/or ADHD-type behaviours might place someone at varying degrees of disadvantage (see here for example), the onus is also on providing the best chances for a person and if that includes a daily fatty acid supplement to help in some way, I don't see too many people quibbling about it [3].

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[1] Johnson M. et al. Omega 3/6 fatty acids for reading in children: a randomized, double-blind, placebo-controlled trial in 9-year-old mainstream schoolchildren in Sweden. J Child Psychol Psychiatry. 2016 Aug 22.

[2] Richardson AJ. et al. Docosahexaenoic Acid for Reading, Cognition and Behavior in Children Aged 7–9 Years: A Randomized, Controlled Trial (The DOLAB Study). PLoS ONE. 2013; 7(9): e43909.

[3] Königs A. & Kiliaan AJ. Critical appraisal of omega-3 fatty acids in attention-deficit/hyperactivity disorder treatment. Neuropsychiatr Dis Treat. 2016 Jul 26;12:1869-82.

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Johnson M, Fransson G, Östlund S, Areskoug B, & Gillberg C (2016). Omega 3/6 fatty acids for reading in children: a randomized, double-blind, placebo-controlled trial in 9-year-old mainstream schoolchildren in Sweden. Journal of child psychology and psychiatry, and allied disciplines PMID: 27545509

Parental concerns about offspring autism: listen up!

"The developmental concerns expressed by parents of undiagnosed toddlers were highly consistent with the diagnosis the child later received."

So said the findings reported by Megan Richards and colleagues [1] who continue a research theme suggesting that when it comes to 'developmental concerns' about offspring behaviour, parents are generally pretty good at spotting potential red flags and professionals should perhaps take further note.

Based on data derived from "a toddler screening study" some 270 parents of autism positive screened infants and 250 autism negative screened infants were asked via a questionnaire about "their child's development, therapy received, and specialists consulted." The kinds of details collected included what sort of developmental concerns parents had about their children before any diagnostic evaluation was eventually completed.

The results suggested a few things not least that the vast majority of parents "reported concerns about their child's development." Parents, as we know from various other research sources, are generally experts in their own children. This concern also seemed to be reflected in the type(s) of intervention/therapy selected being pertinent to the types of concern parents had: "Parent concerns were associated with therapies received and specialists consulted."

Finally: "The number of concern categories was positively associated with several ASD [autism spectrum disorder] scores." This harks back to the opening sentence of this post and the idea that beyond just having concerns, quite a few parents might also have some thoughts/feelings on how 'severe' the behavioural issues displayed by their child might be.

This is important stuff. What it tells us yet again is that parents are active agents when it comes to screening their child's behaviour and clinicians and other expert groups should be further encouraged to listen to them and their concerns. I also feel it is important that such groups listen to other issues that parents might have about their child outside of just behaviour. At this point I might also introduce the findings by Little and colleagues [2] suggesting that sex/gender should also be taken into account when discussing parental concerns of offspring behaviour. The data does not however say that diagnosis should be totally removed from those in the know (similar to the problems that can arise when 'self-diagnosis' is applied at the expense of a full professional diagnostic assessment).

"Results emphasize the need for providers to elicit and take seriously parent concerns during the referral and diagnostic processes." Indeed, and one wonders whether this might extend to other symptoms/labels that seem to cluster around the diagnosis of autism?

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[1] Richards M. et al. Parents' Concerns as They Relate to Their Child's Development and Later Diagnosis of Autism Spectrum Disorder. J Dev Behav Pediatr. 2016 Aug 18.

[2] Little LM. et al. Do early caregiver concerns differ for girls with autism spectrum disorders? Autism. 2016 Aug 18. pii: 1362361316664188.

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Richards M, Mossey J, & Robins DL (2016). Parents' Concerns as They Relate to Their Child's Development and Later Diagnosis of Autism Spectrum Disorder. Journal of developmental and behavioral pediatrics : JDBP PMID: 27541581

ALSPAC says maybe to link between prenatal paracetamol exposure and childhood behavioural difficulties

ALSPAC - the Avon Longitudinal Study of Parents and Children - continues to give in research terms as today I approach the findings reported by Evie Stergiakouli and colleagues [1]. They observed that: "Children exposed to acetaminophen [paracetamol] prenatally are at increased risk of multiple behavioral difficulties, and the associations do not appear to be explained by unmeasured behavioral or social factors linked to acetaminophen use insofar as they are not observed for postnatal or partner’s acetaminophen use." Some media attention for the study can be found here.

Continuing the research journey on a topic not unfamiliar to this blog (see here and see here for example) that exposure to paracetamol during the nine months that made us might not be a totally benign affair, Stergiakouli et al analysed data for some 7,700 mothers included in the initiative between 1991 and 1992. Questions about paracetamol use at 18 and 32 weeks of pregnancy were asked of mothers and maternal reports of child behaviour problems at 7 years using the Strengths and Difficulties Questionnaire (SDQ) were thrown into the research mix.

Results: those behavioural difficulties potentially associated with maternal paracetamol use at both 18 and 32 weeks of pregnancy included both conduct problems and hyperactivity symptoms. Researchers were also able to record no (significant) connection between post-natal paracetamol use nor partner paracetamol use and childhood behavioural problems. They concluded that "the timing of acetaminophen use might be important" and that "the association between prenatal acetaminophen exposure and childhood behavioral problems is not explained by unmeasured familial factors linked to both acetaminophen use and childhood behavioral problems and that the findings are consistent with an intrauterine effect."

Combined with the various other studies suggesting an association between prenatal exposure to paracetamol and offspring behavioural 'issues' the case for a possible link is growing. ALSPAC has a number of methodological strengths to its design, not least "the availability of prospective information on acetaminophen use during the second and third trimesters of pregnancy and postnatally by the mother and by her partner." The fact that numerous potentially confounding variables were also controlled for is another bonus for the study results: "maternal age at birth, parity, socioeconomic status, smoking and alcohol consumption during pregnancy, prepregnancy body mass index (BMI), maternal self-reported psychiatric illness, and possible indications for acetaminophen use." This is pretty strong data (or at least as strong as the other data published on this topic).

Mechanism(s) of effect? Still something that needs a little more work I'm afraid, before any precise information is revealed. The authors go with some ideas based on the "endocrine-disrupting properties of acetaminophen" for example, but let's wait and see before anyone makes too many sweeping generalisations. I might however suggest that the possibility of a link between paracetamol exposure and asthma (see here) could be important in light of what asthma might mean for the risk of presentation of ADHD (attention-deficit hyperactivity disorder) for example (see here). Just a thought and bearing in mind the evidence linking paracetamol use and asthma is not always all on-way.

Further studies are required on this increasingly important topic. Please also bear in mind no medical or clinical advice is given or intended on this blog. Speak to your physician if you need more information about pain relief during pregnancy.

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[1] Stergiakouli E. et al. Association of Acetaminophen Use During Pregnancy With Behavioral Problems in Childhood. JAMA Pediatrics. 2016. Aug 15.

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Stergiakouli, E., Thapar, A., & Davey Smith, G. (2016). Association of Acetaminophen Use During Pregnancy With Behavioral Problems in Childhood JAMA Pediatrics DOI: 10.1001/jamapediatrics.2016.1775

On the question of valproate use and pregnancy

I very much want to stress the point that 'no medical or clinical advice is given or intended' on this blog before proceeding further with discussions based on the commentary paper by Richard Balon & Michelle Riba titled: 'Should Women of Childbearing Potential Be Prescribed Valproate?' [1].

Valproate, as in preparations like sodium valproate, has been a particular talking point in recent years as a consequence of something of an emerging body of peer-reviewed science suggesting that its use during pregnancy may place offspring at some elevated risk for various neurodevelopmental outcomes (see here). The Medicines and Healthcare Products Regulatory Agency (MHRA) here in Blighty issued some revised guidance last year (2015) 'strengthening' warnings about the use of valproate under certain circumstances. This follows some research history on how for example, a valproic acid mouse model of autism has been used as "environmentally induced ASD [autism spectrum disorder] models in rodents" [2] for quite a few years.

Balon & Riba cover various points in the debate about valproate use during pregnancy specifically focused on the known "teratogenic outcome[s]" that have been reported down the years bearing in mind that valproate serves an important (sometimes life-saving) use. I was particularly struck by the 'interference' with folic acid metabolism discussed in their commentary on the basis of some science in this area [3]. With that pinch of salt at the ready, some readers might already know that folate metabolism has some research history in autism circles (albeit not necessarily settled science) and indeed, continues to make scientific waves. Accepting that valproate might have more than one action when potential offspring outcomes are concerned (see here), I do wonder if further research focus could be directed on the folate aspect of the drug when it comes to risk of various neurodevelopmental diagnoses for example?

The question of valproate use outside of the management of epilepsy is a focus of the Balon/Riba article; specifically "used in acute mania or in prophylaxis of bipolar disorder." Bearing in mind that various other medicines are available to manage these conditions and that "unplanned pregnancies are common in this population" [4] I don't think it's out of place for the authors to "recommend that the FDA and valproate manufacturers declare valproate contraindicated in women of childbearing age and issue guidelines for counseling women of childbearing potential with bipolar disorder." Indeed, NICE here in England, seem to have taken a lead on this...

If in doubt, please consult with your medical physician.

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[1] Balon R. & Riba M. Should Women of Childbearing Potential Be Prescribed Valproate? J Clin Psychiatry. 2016; 77: 525–526.

[2] Ergaz Z. et al. Genetic and non-genetic animal models for Autism Spectrum Disorders (ASD). Reprod Toxicol. 2016 Apr 30. pii: S0890-6238(16)30077-6.

[3] Fathe K. et al. Brief report novel mechanism for valproate-induced teratogenicity. Birth Defects Res A Clin Mol Teratol. 2014 Aug;100(8):592-7.

[4] Marengo E. et al. Unplanned pregnancies and reproductive health among women with bipolar disorder. J Affect Disord. 2015 Jun 1;178:201-5.

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Balon R, & Riba M (2016). Should women of childbearing potential be prescribed valproate? a call to action. The Journal of clinical psychiatry, 77 (4), 525-6 PMID: 27137420

Developmental regression in autism affects screening results

In today's short post I'd like to bring the findings reported by Lotta Höglund Carlsson and colleagues [1] to your attention and a reminder that developmental regression accompanying autism onset is an important feature for quite a few people.

With the aim of looking at the "national, routine 18-month developmental surveillance at Child Healthcare Centres (CHC) on children later diagnosed with autism spectrum disorder (ASD)" in Stockholm County, Sweden, authors reported on the results of said surveillance for those (N=175) diagnosed with autism in terms of those who initially passed this screen and what might be done to increase it's diagnostic utility. Some interesting data emerged.

We are told that over a third of the autism group "did not pass the required number of items" included in the screen and this was particularly prominent in those later diagnosed with autism and learning (intellectual) disability. We are also told that adding in additional variables linked to "regulatory problems - crying, feeding and sleeping" (the sorts of things that Kanner himself talked about) might increase the diagnostic yield of the 18 month surveillance by about 10%. But also... "Of those with ASD and ID who had passed, more than one-third experienced developmental regression after 18 months of age."

There you have it. Regression is very much part and parcel of quite a few cases of autism and all the chatter about autism being [universally] present during the earliest points of infancy is not necessarily accurate and applicable to all cases. Of course this probably won't be a surprise to many as previous examples of later onset or 'acquired autism' litter the peer-reviewed literature (see here and see here for example). Appreciating that many factors might influence the age at which an autism diagnosis is given (see here) and how the Swedish findings might be important for future work coming out of the UK for example (see here), I'd like to think there is more to do in this area. Y'know everyone keeps talking about the more plural 'autisms' for example (see here), well I'd be minded to suggest that those who passed vs. those that didn't pass early developmental screens might be another comparison to throw into the autism research mix with a focus on phenotypes. And given the previous research conducted by some of the authors on the Höglund Carlsson paper (see here and see here), there may be quite a few other variables that could also be included in future work in this area...

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[1] Höglund Carlsson L. et al. Autism spectrum disorders before diagnosis: results from routine developmental surveillance at 18 months. Acta Paediatrica. 2016. April 8.

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Höglund Carlsson, L., Westerlund, J., Barnevik Olsson, M., Eriksson, M., Hedvall, �., Gillberg, C., & Fernell, E. (2016). Autism spectrum disorders before diagnosis: results from routine developmental surveillance at 18 months Acta Paediatrica DOI: 10.1111/apa.13418