"sufficient evidence supporting an association between developmental PBDE exposure and reduced IQ"

The results of the systematic review and meta-analysis published by Juleen Lam and colleagues [1] (open-access available here) make for interesting if rather worrying reading. Looking at the body of research examining whether developmental exposure to PBDEs - polybrominated diphenyl ethers - might have some effect on either developmental/behavioural outcomes of offspring or IQ (Intelligence Quotient), authors concluded that there was "sufficient evidence supporting an association between developmental PBDE exposure and reduced IQ." Such a specific conclusion was reached on the basis of four studies measuring something called BDE-47 in maternal serum during pregnancy or at birth that also looked at full scale intelligence quotient in offspring between 4 and 7 years of age and found a possible *association*.

When looking at the possibility that PBDE exposure might also be linked to "Attention Deficit/Hyperactivity Disorder (ADHD) and attention-related behavioral conditions in humans" the authors concluded that the available data was not up to the same standard as that connecting PBDE exposure and IQ.

"Preventing developmental exposure to PBDEs could help prevent loss of human intelligence." Such a conclusion might seem rather dramatic insofar as words such as a 'loss of human intelligence'. The implication being that like various other exposure events at critical times of development that can and do affect aspects of cognition - think lead for example - our environment seems to shape some important human functions. Despite the fact that PBDEs are apparently being phased out, there is still continuing cause for concern as a consequence of their quite excessive historic use, their ability to persist in the environment as well as their propensity to "bioaccumulate up the food chain."

And whilst we're on the topic of PBDEs and behavioural correlates, I might also draw your attention to other research that has been covered on this blog (see here) talking about the possible results of on-going PBDE exposure.

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[1] Lam J. et al. Developmental PBDE Exposure and IQ/ADHD in Childhood: A Systematic Review and Meta-analysis. Environ Health Perspect. 2017 Aug 3;125(8):086001.

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On preventing the deleterious effects of CMV: implications for some autism?

"Anxiety drug may prevent common virus that causes birth defects" went one of the headlines covering the study results published by Sara Ornaghi and colleagues [1].

Continuing a research theme from this group (see here) on how use of some mood stabilising medicines at critical periods might have some important impact on the deleterious effects of cytomegalovirus (CMV) infection, there is quiet optimism that this new research could have big implications for a range of different labels including some autism (see here).

So: "Valnoctamide (VCD), a neuroactive mood stabilizer with no known teratogenic activity, was recently demonstrated to have anti-CMV potential" was the starting premise for the Ornaghi study. Using mouse models - that's MOUSE models - of CMV infection and whether the anti-CMV potential of VCD could be "translated into an efficacious therapeutic effect to improve CMV-induced adverse neurological outcomes", researchers first looked at survival rates when injected 'low-dose' VCD was used. They reported that compared with those receiving a control substance (not VCD), the mice in receipt of VCD were more likely to survive. As per the media chatter about this study: "They lived longer, their body weight was greater – everything about them looked better" on the basis that congenital CMV infection can, in some cases, prove fatal.

Researchers also assessed whether various 'adverse neurological outcomes' associated with congenital CMV infection might be potentially offset by the use of VCD. They observed that: "VCD during the first 3 weeks of life restored timely acquisition of neurological milestones in neonatal male and female mice and rescued long-term motor and behavioral outcomes in juvenile male mice."

Then to the possible mechanism of effect, and based on the use of "CMV-infected human fetal astrocytes" they observed that "VCD reduced both viral infectivity and replication by blocking viral particle attachment to the cell." In other words, VCD, a medicine typically indicated as a sedative, seemed to possess some quite potent activity in relation to how CMV takes hold in important cells in the brain.

I've already mentioned about how at least some cases of autism might benefit from this work. I say this on the basis that there is a robust evidence base suggesting that congenital CMV infection could very well result in autism (see here). There is a need for quite a bit more investigation in this area in terms of translating mouse findings into human findings (see here) but the promises of this area of work are not to be under-estimated...

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[1] Ornaghi S. et al. Valnoctamide inhibits cytomegalovirus infection in developing brain and attenuates neurobehavioral dysfunctions and brain abnormalities. J Neurosci. 2017. June 19.

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Pendulum swings... prenatal antidepressant exposure not linked to autism or ADHD

"Multiple studies have examined the risk of prenatal antidepressant exposure and risk for autism spectrum disorder (ASD) or attention-deficit hyperactivity disorder (ADHD), with inconsistent results."

And...

"These results suggest that prior reports of association between prenatal antidepressant exposure and neurodevelopmental disease are likely to represent a false-positive finding, which may arise in part through confounding by indication."

'These results' refers to the findings reported by Castro and colleagues [1] (open-access available here) who looked at the records of over 1200 children diagnosed with ASD and ~1700 children diagnosed with ADHD compared with over 3400 and 3700 controls respectively with regards to antidepressant exposure during pregnancy and maternal antidepressant use before pregnancy. Based on exposures identified "using e-prescribing data in the EHR [electronic health records], both inpatient and outpatient, which record number of pills, frequency and refill number, allowing calculation of exposure period" researchers were, with reasonable confidence, able to test the idea that a diagnosis of ASD or ADHD might be elevated following prenatal exposure to said pharmaceutics.

The headline that most media discussing this study picked up on was the lack of any significant association between antidepressant use during pregnancy and risk of offspring autism or ADHD. This finding kinda contrasts with other recent independent reports that have been covered on this blog (see here). Indeed the authors - including one Isaac Kohane (see here) - suggest that their results, bearing in mind certain limitations, highlight how 'false-positive' might indeed be a good description of some of the previous data in this area.

But just before any sweeping generalisations are made about this class of pharmaceutic being 'off the hook' there were some other potentially important findings also reported by Castro et al. To quote once again: "For both ASD and ADHD, pre-pregnancy antidepressant use was associated with greater risk, even after adjustment for maternal major depression." The risk reported was significant insofar as what it might mean for offspring autism and/or ADHD and also how "the requirement for maternal antidepressant treatment, rather than the medication itself, may be associated with risk for neurodevelopmental disorders in offspring".

As I've discussed before, the idea that antidepressant use during pregnancy might be linked to offspring developmental outcomes is a complicated area. That such medicines use is not generally entered into lightly is something to bear in mind given what depression can do to a person and those around them. I cannot readily account for the discrepancy between these and other reports on this topic outside of the idea that the question of a connection or not may not be as simple as 'yes' or 'no' but rather a slightly more convoluted story where genetics and other more 'environmental' factors might play some role. The idea that there may be specific phenotypes of autism associated with such medication use has received a boost in other independent studies [2] looking at other medicines. I suppose such confusion kinda sums up autism research when it comes to questions of such exposure and the range of pharmaceutics that have been correlated with offspring risk (see here and see here).

Music: Björk - It's Oh So Quiet. Shhh.

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[1] Castro VM. et al. Absence of evidence for increase in risk for autism or attention-deficit hyperactivity disorder following antidepressant exposure during pregnancy: a replication study. Transl Psychiatry. 2016 Jan 5;6:e708.

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Castro VM, Kong SW, Clements CC, Brady R, Kaimal AJ, Doyle AE, Robinson EB, Churchill SE, Kohane IS, & Perlis RH (2016). Absence of evidence for increase in risk for autism or attention-deficit hyperactivity disorder following antidepressant exposure during pregnancy: a replication study. Translational psychiatry, 6 PMID: 26731445

Prenatal hormone involvement in autism risk?

The findings reported by Gayle Windham and colleagues [1] caught my eye recently and their observations based on the examination of mid-pregnancy serum hormone and protein markers for some 2500 mothers of children diagnosed with an autism spectrum disorder (ASD) compared with 600,000 controls.

Detailing results based on: "Second trimester levels of unconjugated estriol (uE3), human chorionic gonadotropin (hCG), and maternal serum alpha-fetoprotein (MSAFP)", researchers reported that their results: "further support prenatal hormone involvement in ASD risk."

I perhaps need to do a little 'defining' before progressing any further with this post. Unconjugated estriol (uE3) refers to an estrogen. It becomes the dominant oestrogen during pregnancy; produced by the baby's liver and placenta. Measured levels of uE3 during the 2nd trimester of pregnancy have been linked to various 'outcomes' including the possibility of Down's syndrome and neural tube defects.

Human chorionic gonadotropin (hCG) is another hormone; one that is normally used to confirm pregnancy. During pregnancy, levels of hCG can also be used to determine Down's syndrome. Serum alpha-fetoprotein (MSAFP) is the most abundant plasma protein found in the developing foetus. During pregnancy, extremes in levels of MSAFP can indicate issues in pregnancy. Combined together, these various hormones/proteins make up the so-called triple test, that when added to information such as maternal age and stage of pregnancy, can classify a pregnancy as being high or low risk for chromosomal abnormalities. That being said, the test is by no means perfect.

Windham et al report some rather complicated results based on adjusted odds ratios (AOR) when it came to autism vs control samples. So: "Lower uE3 (AOR for < 10th percentile vs. 25th-74th percentiles = 1.21, 95 % CI 1.06-1.37), and higher MSAFP (AOR = 1.21, 95 % CI 1.07-1.37 for > 90th percentile) were significantly associated with ASD. A U-shaped relationship was seen for hCG (AOR = 1.16, 95 % CI 1.02-1.32 for < 10th percentile; AOR = 1.19, 95 % CI 1.05-1.36 for > 90th percentile)." Lower uE3 is a trend found in relation to Down's syndrome. Higher MSAFP however runs slightly counter to what has been discussed in relation to Down's syndrome. By contrast, elevations in MSAFP tend to be more readily linked to pregnancies where neural tube defects may be present. What this all means is that yes, these results could indicate the involvement of prenatal hormones and chromosomal issues in relation to 'some' autism, but science still needs to go a little way before anyone talks about a triple test being applied to autism (and the ethical issues that this might bring).

I think it's also worthwhile briefly bringing in a few caveats to such pregnancy testing that could be pertinent to other autism research findings. As per other information, a mother's weight during pregnancy can affect what results you get - "Serum marker levels tend to be decreased in heavier women, and increased in lighter women." If you map this on to the research talking about maternal obesity linked to some autism (being careful not to generalise here), you can see how adjustments might have been / have to be made. Ethnicity is another factor that needs to be kept in mind. Also: "AFP and uE3 levels tend to be low (about 8% and 6% respectively) in women with insulin dependent diabetes mellitus." This is particularly interesting in view of the quite consistent literature detailing how gestational diabetes seems to show a connection to risk of offspring autism (see here). Various other factors (vaginal bleeding) can similarly affect results.

The Windham results are nevertheless interesting and are strengthened somewhat by the large participant numbers included for study. That other groups have similarly talked about elevations in MSAFP in relation to autism [2] increases the confidence that there may something further to see in this area, at least for some autism.

Music: Al Green - Tired of Being Alone.

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[1] Windham GC. et al. Autism Spectrum Disorder Risk in Relation to Maternal Mid-Pregnancy Serum Hormone and Protein Markers from Prenatal Screening in California. J Autism Dev Disord. 2015 Sep 14.

[2] Abdallah MW. et al. Autism spectrum disorders and maternal serum α-fetoprotein levels during pregnancy. Can J Psychiatry. 2011 Dec;56(12):727-34.

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Windham GC, Lyall K, Anderson M, & Kharrazi M (2015). Autism Spectrum Disorder Risk in Relation to Maternal Mid-Pregnancy Serum Hormone and Protein Markers from Prenatal Screening in California. Journal of autism and developmental disorders PMID: 26370672

Prenatal air pollution and autistic traits NOT linked (in Europe)

"Prenatal exposure to NO2 [nitrogen oxide] and PM [particulate matter] was not associated with autistic traits in children from four to ten years of age in four European population-based birth/child cohort studies."

That was the conclusion reached in the study published by Mònica Guxens and colleagues [1] (open-access available here) crossing various European population-based cohorts as part of the "European Study of Cohorts for Air Pollution Effects (ESCAPE)" and looking at some 8,000 children in total. Outside of the grand study design and large participant number included in the Guxens study, I wanted to talk about this study to provide a little balance to the previous discussions on this blog about autism and air pollution which seemed to be coming to rather different conclusions (see here and see here for example).

The Guxens paper is open-access but here are a few pointers:

• First, take three population-based birth cohorts (GENERATION R, GASPII & INMA) and one "European longitudinal child and adolescent twin study: CATSS". 
• Follow a well-trodden path of estimating air pollution exposure based on birth home addresses and looking at air pollution levels "in the study areas" and "estimate annual average air pollution concentration at the participants’ birth home addresses."
• Next, assess your cohort(s) for the presence of autistic traits (not actual diagnoses) using various instruments (though not necessarily the same instrument for every country included for study). Control for possible confounders including urbanicity and various maternal characteristics including those during birth and apply statistics.
• Results: anywhere between 3-12% of children studied showed "autistic traits within the borderline/clinical range." Further: "between 0.7% and 3.6% were classified as having autistic traits within the clinical range." These were mostly boys and "had a higher proportion of mothers with low educational level and mothers who smoked during pregnancy compared to children without autistic traits."
• "We found no evidence for an association between prenatal air pollution exposure and autistic traits in children aged 4 to 10 years." Further: "These results were consistent for all air pollutants assessed, across countries, using different cut-offs of autistic traits, examining autistic traits as continuous variables, and after adjusting for several socioeconomic status variables and urbanicity."

Guxens et al note how their results are in direct contrast to the some of the previous and emerging research [2] in this area, citing some important references along the way. They explain this in a few ways including noting how: "previous case-control studies selected children with a diagnosis of ASD [autism spectrum disorder] whereas in our study we studied children with autistic traits from population-based birth/child cohorts." Further: "We hypothesize that prenatal exposure to air pollution could be related to ASD but not with broad autistic traits in children" but based on their data "found no indication of an association between prenatal air pollution exposure and autistic traits within the clinical range."

The idea that: "Further research including trace metal content of the PM such as lead or manganese is warranted to better understand the discrepant findings" is also banded about and I'm in agreement with them on this matter [3] given some of the previous findings on the metallome and autism (see here). Lead (Pb) and its health effects by the way, is also something that I've been interested in down the years of blogging (see here).

Without trying to turn null findings into positive findings, I'm also minded to bring another variable to the table that might be worth re-analysing for based on the findings from Heather Volk and colleagues [3] (one of the co-authors on the Guxens paper) who talked about gene x environment interactions when it comes to the possibility of a link between risk of autism and prenatal air pollution exposure (covered in a previous blog post). I say this bearing in mind that studying MET genotype on its own and without reference to the multitude of genetic and epigenetic factors that may also be involved, is but a drop in the scientific ocean; but at least it would be a start.

I end however with the statement that: "this study showed a null association between prenatal exposure to several air pollutants, including NO2 and PM, and autistic traits in children aged 4 to 10 years in four European population-based birth/child cohorts." Once again, autism research comes up with conflicting findings...

Music: AC/DC - Highway to Hell.

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[1] Guxens M. et al. Air Pollution Exposure during Pregnancy and Childhood Autistic Traits in Four European Population-Based Cohort Studies: The ESCAPE Project. Environ Health Perspect. 2015 Jun 12.

[2] Talbott EO. et al. Fine particulate matter and the risk of autism spectrum disorder. Environmental Research. 2015; 140: 414-420.

[3] Sanders AP. et al. Perinatal and Childhood Exposure to Cadmium, Manganese, and Metal Mixtures and Effects on Cognition and Behavior: A Review of Recent Literature. Current Environmental Health Reports. 2015. July 5.

[4] Volk HE. et al. Autism spectrum disorder: interaction of air pollution with the MET receptor tyrosine kinase gene. Epidemiology. 2014 Jan;25(1):44-7.

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Guxens M, Ghassabian A, Gong T, Garcia-Esteban R, Porta D, Giorgis-Allemand L, Almqvist C, Aranbarri A, Beelen R, Badaloni C, Cesaroni G, de Nazelle A, Estarlich M, Forastiere F, Forns J, Gehring U, Ibarluzea J, Jaddoe VW, Korek M, Lichtenstein P, Nieuwenhuijsen MJ, Rebagliato M, Slama R, Tiemeier H, Verhulst FC, Volk HE, Pershagen G, Brunekreef B, & Sunyer J (2015). Air Pollution Exposure during Pregnancy and Childhood Autistic Traits in Four European Population-Based Cohort Studies: The ESCAPE Project. Environmental health perspectives PMID: 26068947

Effects of prenatal organophosphate pesticide exposure on a mouse model of autism

Pesticides and autism is a topic previously covered on this blog (see here for example). The idea that some of the various preparations that we use to control the pests which have an ability to blight our crops or cause serious health issues could be linked to an increased risk of autism is an area likely to invoke some divisions within elements of the autism and wider scientific community.


Part of the problem with the available evidence suggesting a link between autism and pesticide exposure is that it is, to a large extent, observational and correlational. As per the paper from Janie Shelton and colleagues [1], results are based on variables such as looking at what types and amounts of pesticides are used in a specific area and correlating proximity to that area as a function of a diagnosis of autism or not. Similar to the work looking at other environmental factors linked (or not) to autism such as air pollution (see here), it's all about where and when you were, followed by calculations on your probable exposure being tied into risk.

The paper from Alessia De Felice and colleagues [2] (open-access) approaches the research area of pesticide exposure and autism (a model of autism) from a slightly different angle. Their findings were based on the use of a mouse model of autism and what happened to mouse offspring when mother mice were exposed to a particular pesticide "at doses devoid of maternal or systemic toxicity."

The mouse model in question was a favourite in autism research circles, the BTBR T+tf/J strain (see here). The pesticide used was "the organophosphate insecticide chlorpyrifos (CPF)." Organophosphate (OP) by the way, refers to the chemical make-up of the compound and its particular effects on the enzyme acetylcholinesterase working in a similar fashion to certain warfare agents.

The De Felice paper is open-access but as ever, a few details are provided:

• Recognising that pesticide exposure already has quite a long history in terms of adverse health effects (pesticide applicators of the world take note), the authors set about looking to "evaluate in the offspring of both sexes the effect of the gestational CPF exposure on spontaneous locomotion, ultrasonic vocalization and neurodevelopment during the first two weeks of postnatal life, to evidence early changes in behavioral profile." Further they decided to "evaluate the long-term effects of CPF on selected markers of the peculiar behavioral repertoire of this mouse strain." You'll note that the word autism does not appear in either of those aims.
• Male and female BTBR mice were allowed to 'get it on' in breeding cages. Females mice were regularly inspected for evidence of carrying a baby mouse and 14 days into the pregnancy were either given peanut oil (vehicle) or CPF dissolved in peanut oil by oral gavage for 4 days. This was given as a single dose.
• Baby mice were born ("Twenty-four litters (13 Vehicle-treated and 11 CPF-treated"). Various behavioural assessments were conducted including an analysis of ultrasonic vocalisations and spontaneous movements. Various other behavioural measures were also made when the baby mice grew into adult mice.
• Results: "prenatal CPF exposure significantly modifies spontaneous motor activity in BTBR pups, delaying their motor development and further enhancing the abnormally high vocalization rates." The authors also reported reduced weight gain in CPF exposed offspring during the early days. 
• Looking into adulthood, CPF exposure seemed to show more pronounced effects for males over females with an "altered pattern of investigation of a sexual partner." This finding has however been downplayed by the authors to a certain extent. They conclude with the need for further research in this area "to evaluate the role of environmental chemicals in the etiology of neurodevelopment disorders."

Taking a few steps back, one has to remember that this was a study of mouse exposure to pesticides not humans. Indeed, other similar work from some of the authors has also recently seen the light of day [3]. As per other discussions, mice might be good 'models' of something like autism but they are never ever going to reflect autism (and its important comorbidities) in their entirety. Given also that the BTBR mouse "exhibit a 100% absence of the corpus callosum and a severely reduced hippocampal commissure" according to suppliers, one has to be careful about any sweeping generalisations to all autism. The timing and route of CPF exposure described by De Felice et al might also be seen as potentially important variables insofar as their focus some time into pregnancy and sole reliance on the oral route of exposure. 

That all being said, these are potentially important results not least because of their focus on how both genes and environment might be implicated in [models of] cases of autism. As I've mentioned, this was a study of offspring BTBR mice thus implying that there may be some familial predisposition to mimicking the effects of autism anyway. The idea that in predisposed individuals there may be additional effects from an environmental factor is an important one and perhaps complements the whole 'air pollution effects modified by genotype' suggestion (see here) with autism in mind. Certainly, I think there is quite a bit more research to see and do in this area.

Music: Buddy Holly - Rave on!

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[1] Shelton JF. et al. Neurodevelopmental disorders and prenatal residential proximity to agricultural pesticides: The CHARGE study. Environ Health Perspect. 2014: June 23.

[2] De Felice A. et al. Prenatal Exposure to a Common Organophosphate Insecticide Delays Motor Development in a Mouse Model of Idiopathic Autism. PLoS One. 2015 Mar 24;10(3):e0121663.

[3] Venerosi A. et al. Effects of maternal chlorpyrifos diet on social investigation and brain neuroendocrine markers in the offspring – a mouse study. Environmental Health 2015, 14:32.

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De Felice, A., Scattoni, M., Ricceri, L., & Calamandrei, G. (2015). Prenatal Exposure to a Common Organophosphate Insecticide Delays Motor Development in a Mouse Model of Idiopathic Autism PLOS ONE, 10 (3) DOI: 10.1371/journal.pone.0121663

Prenatal genetic testing and autism: a delicate subject

I realise that the paper by Lei-Shih Chen and colleagues [1] covers a most sensitive topic when it comes to the autism spectrum, exploring: "the attitudes toward PGT [prenatal genetic testing] and termination decisions of 42 parents of children with ASD [autism spectrum disorder]". Indeed, this is not the first time that this research group has looked at this area of autism research [2] and it seems like they will be talking about it further too (see here).

I chose to discuss the most recent paper on this blog because (a) the Chen paper is peer-reviewed science, (b) the likelihood of PGT being 'applied to autism' at some point in the future is growing (if not here in some parts of the world?), and (c) similar to the screening tests available for conditions like Down's syndrome (see here), there are going to be conversations to be had about the decisions and choices potentially offered to parents on the basis of any screening results. Charities here in the UK such as Antenatal Results and Choices (ARC) are probably going to figure in those conversations which, in some quarters, have already begun to happen (see here). I write this blog from a cold, scientific perspective so please don't get offended by some of the discussions.

The Chen paper describes the results of a qualitative study where parents of children with ASD were given "a hypothetical scenario" regarding PGT and asked their hypothetical response to using PGT and their hypothetical response to a positive test response. "Of the 31 parents who were either willing or unsure about undergoing the PGT, approximately three-fourths would continue their hypothetical affected pregnancies".

A few things struck me about the Chen paper. First is a line introducing the abstract which reads: "In the United States, prenatal genetic testing (PGT) for Autism Spectrum Disorders (ASD) is currently available via clinical genetic services". I was quite taken aback by this sentence. As far as I was aware science was still feeling around as to the underlying genetics of autism (that is, if you consider autism to be a unitary concept rather than a more plural condition and to be solely driven by structural genetics over and above environmental factors or epigenetic changes). If someone is suggesting otherwise, please do point me towards the peer-reviewed science for that prenatal genetic test outside of something like just screening for Fragile X syndrome [3] or the preliminary results reported by Wapner and colleagues [4] mentioned with autism in mind...

The next thing that caught my eye was the high number of parents who, if faced with the hypothetical PGT situation, said they would continue with their pregnancy. I'm not so surprised at this, given that researchers were asking parents who already had a child with autism and so perhaps knew a little bit about both the good and not-so-good times which go with raising a child with a developmental disability. I also emphasise the word 'child' there before their condition/label. If the questions were put to parents with no personal experience of autism, one wonders whether similar outcomes would have been reported. Likewise if parents were for example, offered differing scenarios under such experimental conditions with other conditions outside of autism, such as Down's syndrome, the question remains about what results might have shown also bearing in mind the literature in this area [5].

Finally, and I again tread very carefully with this, was the observation that: "Parents who reported they would terminate the affected pregnancy in this hypothetical situation were primarily Asians". I go to great lengths on this blog not to over-generalise autism research such that not every finding has to apply to every single person with autism. In this instance I'd also point out that the sample size for the Chen results was very small and outside of cultural differences and representations [6], one similarly cannot assume that every person/parent of Asian origin is going to report like this. Neither however should judgement be passed on those parents who did choose this hypothetical option and the road(s) which might have led them to this hypothetical decision. This might however suggest that as per other examples, autism is looked at in very different ways according to factors such geography and culture.

As I mentioned at the top of this post, prenatal testing (genetic or otherwise) is always going to be a sensitive subject when applied to autism and will inevitably stir up considerable emotions for many people, not least those who are themselves on the autism spectrum. I'm going to leave you with some more discussion about this area from Prof. Andrew Whitehouse - he of the 'Is autism one or multiple disorders?' paper - and a very sensible post he wrote (see here) which covers most of the important issues well.

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[1] Chen LS. et al. Autism Spectrum Disorders: A Qualitative Study of Attitudes toward Prenatal Genetic Testing and Termination Decisions of Affected Pregnancies. Clin Genet. 2014 Sep 24.

[2] Chen LS. et al. Autism genetic testing: a qualitative study of awareness, attitudes, and experiences among parents of children with autism spectrum disorders. Genet Med. 2013 Apr;15(4):274-81.

[3] Gutiérrez JF. et al. Prenatal screening for fragile x: carriers, controversies, and counseling. Rev Obstet Gynecol. 2013;6(1):e1-7.

[4] Wapner RJ. et al. Chromosomal Microarray versus Karyotyping for Prenatal Diagnosis. NEJM. 2012; 367: 2175-2184.

[5] Scott CJ. et al. Prenatal diagnosis and termination of pregnancy: perspectives of South African parents of children with Down syndrome. J Community Genet. 2013 Jan;4(1):87-97.

[6] Bie B. & Tang L. Representation of Autism in Leading Newspapers in China: A Content Analysis. Health Commun. 2014 Jul 29:1-10.

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Chen LS, Xu L, Dhar SU, Li M, Talwar D, & Jung E (2014). Autism Spectrum Disorders: A Qualitative Study of Attitudes toward Prenatal Genetic Testing and Termination Decisions of Affected Pregnancies. Clinical genetics PMID: 25251361

Yet more air pollution and autism risk research

Air pollution and autism risk. It's a topic which has cropped up a few times on this blog (see here and see here and see here) with the majority of the research (but not all) suggesting that there may be something to see when it comes to such a correlation.

Enter then the paper by Amy Kalkbrenner and colleagues [1] to proceedings, and their conclusion: "Our study adds to previous work in California showing a relation between traffic-related air pollution and autism, and adds similar findings in an eastern US state, with results consistent with increased susceptibility in the third-trimester". I might add that Dr Kalkbrenner has some research form when it comes to looking at environment and autism and has appeared on this blog before (see here).

Based on two datasets covering the east and west coasts of the United States (North Carolina and "the San Francisco Bay Area in California") including nearly 1000 children diagnosed with an autism spectrum disorder (ASD) and some 14,000 asymptomatic controls, researchers compared estimated exposure patterns based on birth addresses. Specifically, they looked at exposure to particulates "less than 10 μm (PM10)" within a period starting from preconception through to the child's first birthday. They also took into account a whole slew of geographic and demographic variables which potentially may have influenced results. They reported odds ratios (ORs) - adjusted ORs - which seemed to indicate that exposure, "a 10 μg/m increase in PM10", particularly during the third trimester of pregnancy was associated with increased susceptibility to autism. Ergo, more evidence for a potential link between prenatal air pollution exposure and offspring autism risk.

If I'm reading the Kalkbrenner paper correctly however, PM10 exposure during the first and second trimesters of pregnancy was not associated with autism. Indeed for the first trimester at least (bearing in mind the confidence intervals) the adjusted OR was "0.86 (95% CI = 0.74-0.99)" which I'll leave to readers to decide whether it was important or not.

There's little more for me to say about this area of autism research aside from the usual caveats applying regarding the use of estimated exposure patterns over and above actual individual exposure levels and the further requirement to elaborate on any mechanism potentially pertinent aside from any general description such as a role for oxidative stress or inflammatory markers [2]. I say this acknowledging the preliminary observations made about genotype, air pollution and autism risk [3] which still require independent follow-up.

In light of the my recent discussions on asthma being a potential risk factor for autism (see here) and further research on atopy and autism [4] which I'll be blogging about soon, one wonders whether other manifestations of air pollution exposure might also play some role in such findings. That combined with the more general developmental effects thought to be had as a result of air pollution exposure [5], and the whole thing starts to get rather complicated and in need of much greater scrutiny...

Music then and at the risk of [musically] repeating myself: Alice Cooper and No More Mr Nice Guy...

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[1] Kalkbrenner AE. et al. Particulate Matter Exposure, Prenatal and Postnatal Windows of Susceptibility, and Autism Spectrum Disorders. Epidemiology. 2014 Oct 3.

[2] Volk HE. et al. Residential proximity to freeways and autism in the CHARGE study. Environ Health Perspect. 2011 Jun;119(6):873-7.

[3] Volk HE. et al. Autism spectrum disorder: interaction of air pollution with the MET receptor tyrosine kinase gene. Epidemiology. 2014 Jan;25(1):44-7.

[4] Chen MH. et al. Is atopy in early childhood a risk factor for ADHD and ASD? A longitudinal study. J Psychosom Res. 2014 Oct;77(4):316-21.

[5] Calderón-Garcidueñas L. et al. Air pollution and detrimental effects on children's brain. The need for a multidisciplinary approach to the issue complexity and challenges. Front Hum Neurosci. 2014 Aug 12;8:613.

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Kalkbrenner AE, Windham GC, Serre ML, Akita Y, Wang X, Hoffman K, Thayer BP, & Daniels JL (2014). Particulate Matter Exposure, Prenatal and Postnatal Windows of Susceptibility, and Autism Spectrum Disorders. Epidemiology (Cambridge, Mass.) PMID: 25286049

Maternal iron intake and offspring autism risk

Much like the discussions around the paper by Rogers and colleagues (see here) on treating autism in the first year of life, the media scrum around the findings from Rebecca Schmidt and colleagues [1] talking about maternal iron supplements and offspring autism spectrum disorder (ASD) risk preceded the publication of the paper by a few days. It's getting to be a pet-hate of mine that big headlines are being generated sometimes days before your average Jane or Joe can see the data upon which they're based...

Grumbling aside, here are a few factoids from the now published Schmidt paper:

• CHARGE was the source initiative for participants, as it has been for various studies, and following on from other research on nutrition during pregnancy potentially affecting offspring autism risk from this group (see here), the idea was to look at pre- and pregnancy maternal iron intake in relation to autism risk.
• Data for mothers of children with autism (n=520) were compared against mothers with children who did not have autism (n=346) and "maternal daily iron intake was quantified on the basis of frequency, dose, and brands of supplements and cereals consumed each month from 3 months before pregnancy through the end of pregnancy and during breastfeeding (the index period), as reported in parental interviews". You'll note the words 'parental interviews' there.
• Results: well, the mothers of children with autism were less likely to report taking 'iron-specific supplements' than control mothers and overall, a "lower mean daily iron intake" in the order of 5-6 mg/day less than controls was observed.
• "Low iron intake significantly interacted with advanced maternal age and metabolic conditions; combined exposures were associated with a 5-fold increased ASD risk". Advanced maternal age by the way, refers to women who were 35 or older at the time of their child's birth, and metabolic conditions means obesity, diabetes or hypertension (in line with other evidence).

These are interesting findings which add to the growing literature on how maternal nutrition before and during the nine months that made us potentially impacts on offspring development and outcome. Certainly, there are hints of the foetal programming hypothesis in there, for which the late David Barker receives quite a bit of credit. I was also wondering whether other issues potentially affecting foetal nutrition such as the inter-pregnancy interval (see here) might also tie into these findings too?

But there are some obvious cautions to take on board when it comes to these findings. First is the continued reliance on self-report, which even under the most controlled of situations, is always going to be an estimate at best. Next, and I might be completely wrong about this, but even with the report of a mean daily intake of ~51 mg/day, the mothers with children with autism group were still quite a bit above the daily recommendations in the United States (see here) for pregnant or lactating women. Finally, I'm wondering whether the idea of "combined exposures" when it comes to maternal age and the presence of metabolic syndrome might actually be the more important issue raised in this paper...

Iron and autism is a topic which has been discussed a few times on this blog (see here). The data is slightly mixed when it comes to looking at iron levels in children with autism as per my discussions on the Reynolds paper [2] versus the Hergüner findings [3]. Dr Schmidt and colleagues did not directly assay for iron or ferritin levels in their current paper so we can't really say much more at this point on how actual maternal iron levels translated into offspring iron levels and what effect(s) this may have had on offspring autism or other risks. That and whether other factors might also have played some role as per the rodent findings from Harvey & Boksa [4] talking about an additive effect from iron deficiency and prenatal immune activation (a topic that has cropped up a few times with autism in mind). These are perhaps the next studies that need to be done alongside what biological effects supplementation may have [5].

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[1] Schmidt RJ. et al. Maternal Intake of Supplemental Iron and Risk of Autism Spectrum Disorder. Am J Epidemiol. 2014. 22 September.

[2] Reynolds A. et al. Iron status in children with autism spectrum disorder. Pediatrics. 2012; 130 Suppl 2:S154-S159.

[3] Hergüner S. et al. Ferritin and iron levels in children with autistic disorder. Eur J Pediatr. 2012; 171: 143-146.

[4] Harvey L. & Boksa P. Additive effects of maternal iron deficiency and prenatal immune activation on adult behaviors in rat offspring. Brain Behav Immun. 2014 Aug;40:27-37.

[5] Dosman CF. et al. Children with autism: effect of iron supplementation on sleep and ferritin. Pediatr Neurol. 2007 Mar;36(3):152-8.

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Rebecca J. Schmidt, Daniel J. Tancredi, Paula Krakowiak, Robin L. Hansen, & Sally Ozonoff (2014). Maternal Intake of Supplemental Iron and Risk of Autism Spectrum Disorder American Journal of Epidemiology : doi: 10.1093/aje/kwu208

Prenatal SSRI exposure and autistic traits

A quote to start today's post: "Our results suggest an association between prenatal SSRI exposure and autistic traits in children". That was a primary finding reported by Hanan El Marroun and colleagues [1] who looked at whether maternal depressive symptoms or a class of quite commonly used pharmaceutics - the selective serotonin reuptake inhibitors (SSRIs) - used to manage depressive symptoms, during pregnancy might impact on offspring development.

"Everything the light touches is our kingdom" 

Before progressing through some of the details around this area, I'm going to also direct your attention to a couple of important accompanying commentaries on the Marroun findings from Jones & McDonald [2] and Petersen and colleagues [3] (open-access). Both caution about reading too much too soon into the reported association between SSRIs and offspring outcomes, and the very real outcomes that can come about if psychiatric issues such as depression are not properly managed. Something I think most people might have heard about recently.

A few details about the Marroun paper might be useful:

• Following some previous discussions correlating maternal SSRI use during pregnancy and offspring outcome with autism in mind (see here) including the quite recent papers by Harrington and colleagues [4] and Rai and colleagues [5], the authors looked to "prospectively determine whether intra-uterine SSRI exposure is associated with childhood autistic symptoms in a population-based study". 
• "A total of 376 children prenatally exposed to maternal depressive symptoms (no SSRI exposure), 69 children prenatally exposed to SSRIs and 5531 unexposed children were included" for study. The commentary from Petersen et al notes how small a group were actually exposed to SSRIs and how "these numbers rapidly dwindled when it came to the measurement of the outcome".
• The Child Behavior Checklist and Social Responsiveness Scale (SRS) were used to assess "pervasive developmental and affective problems" and "autistic traits" respectively. 
• Results: aside from an association between prenatal selective serotonin reuptake inhibitor (SSRI) exposure and autistic traits in children, researchers also reported that: "Prenatal exposure to maternal depressive symptoms without SSRIs was related to both pervasive developmental (odds ratio (OR) = 1.44, 95% CI 1.07-1.93) and affective problems (OR = 1.44, 95% CI 1.15-1.81)". The suggested link between maternal depressive symptoms and autistic traits was to some degree weaker than the SSRI exposure correlation.
• The authors conclude that: "Long-term drug safety trials are needed before evidence-based recommendations are possible" as once again I'll direct you to the Jones and Petersen commentaries.

In the same way that the emerging data on prenatal valproate exposure *might* link into offspring outcome including the presence of autism (see here), so the Marroun paper potentially adds another medicine to the list. I would perhaps temper that last sentence by adding that the valproate story is perhaps a little further along in terms of rodent models of prenatal valproate exposure mimicking some features of autism (see here) and the data providing something like mechanisms to be looked at with further investigations in mind [6]. Still, the CDC Treating for Two initiative might be once again relevant.

The added complication with the SSRI-autism correlation is the discussion about maternal depressive symptoms also potentially mediating any link with offspring autism or autistic traits. The paper by Sørensen and colleagues [7] (open-access here) kinda hinted that this and other important confounding factors might impact on any studies of association, including details like: "paternal antidepressant use during the time of pregnancy was not associated with an increased risk of autism spectrum disorders, except for a 30% increase when the fathers took SSRI". Even more recently Clements and colleagues [8] talked about how maternal "major depression" confounded any medication relationship with offspring presentation. They also talked about a link with ADHD which brings me back to yesterday's post on comorbidity (see here)...

One would do well not to discount such confounding factors at this stage. Indeed, if one assumes that depression might have a physiological link to something like inflammation for example [9] we then start to arrive at the increasingly important research looking at maternal inflammation as being a risk factor for offspring autism (see here). And before you ask, yes, C-reactive protein (CRP) has been linked to depressive symptoms as per the meta-analysis by Valkanova and colleagues [10].

The Marroun results are interesting and add something to an increasing bank of peer-reviewed literature [11] suggestive of a possible link between SSRI use during pregnancy and offspring outcomes. On the basis of the current existing literature and with my blogging caveat of no medical advice given or intended, I would be minded to conclude that there is quite a bit more experimental investigation to be done on this category of medicines. But I don't yet think there is enough clear evidence to conclusively put an elevated risk of offspring autism on the list of potential side-effects of these medicines.

Music then. Scissor Sisters and Laura.

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[1] Marroun HE. et al. Prenatal exposure to selective serotonin reuptake inhibitors and social responsiveness symptoms of autism: population-based study of young children. The British Journal of Psychiatry. 2014; 205: 95-102.

[2] Jones I. & McDonald L. Living with uncertainty: antidepressants and pregnancy. The British Journal of Psychiatry. 2014; 205: 103-104.

[3] Petersen I. et al. Prenatal exposure to selective serotonin reuptake inhibitors and autistic symptoms in young children: another red herring? The British Journal of Psychiatry. 2014; 205: 105-106.

[4] Harrington RA. et al. Prenatal SSRI Use and Offspring With Autism Spectrum Disorder or Developmental Delay. Pediatrics. 2014 Apr 14.

[5] Rai D. et al. Parental depression, maternal antidepressant use during pregnancy, and risk of autism spectrum disorders: population based case-control study. BMJ. 2013 Apr 19;346:f2059.

[6] Bambini-Junior V. et al. Prenatal Exposure to Valproate in Animals and Autism. Comprehensive Guide to Autism. 2014: 1779-1793.

[7] Sørensen MJ. et al. Antidepressant exposure in pregnancy and risk of autism spectrum disorders. Clin Epidemiol. 2013 Nov 15;5:449-59.

[8] Clements CC. et al. Prenatal antidepressant exposure is associated with risk for attention-deficit hyperactivity disorder but not autism spectrum disorder in a large health system. Molecular Psychiatry. 2014. August 26.

[9] Berk M. et al. So depression is an inflammatory disease, but where does the inflammation come from? BMC Med. 2013 Sep 12;11:200.

[10] Valkanova V. et al. CRP, IL-6 and depression: a systematic review and meta-analysis of longitudinal studies. J Affect Disord. 2013 Sep 25;150(3):736-44.

[11] Rais TB. & Rais A. Association Between Antidepressants Use During Pregnancy and Autistic Spectrum Disorders: A Meta-analysis. Innov Clin Neurosci. 2014 May;11(5-6):18-22.

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Marroun, H., White, T., van der Knaap, N., Homberg, J., Fernandez, G., Schoemaker, N., Jaddoe, V., Hofman, A., Verhulst, F., Hudziak, J., Stricker, B., & Tiemeier, H. (2014). Prenatal exposure to selective serotonin reuptake inhibitors and social responsiveness symptoms of autism: population-based study of young children The British Journal of Psychiatry, 205 (2), 95-102 DOI: 10.1192/bjp.bp.113.127746

Prenatal valproate exposure and brains

The paper by Amanda Wood and colleagues [1] (open-access) makes a potentially very important contribution to the growing literature looking at how prenatal exposure to sodium valproate (VPA) may affect some children. Authors reported on: "regional structural cortical brain changes in humans exposed to VPA in utero" and specifically, increased cortical thickness in the left inferior frontal gyrus.

Lightning and lava @ Oliver Spalt @ Wikipedia 

In case you need any background on the story behind pregnancy exposure to VPA, I would direct you to a few previous posts where the topic has been covered on this blog (see here and see here) with an autism slant. You might also read my small contribution to a more formal article on this topic here.

Outside of any reported elevated risk of offspring autism or autistic traits associated with prenatal VPA exposure, I'm also minded to bring in some interesting work on intestinal inflammation being reported in a VPA mouse model (see here) to further highlight that important gut-brain axis which I seem to be a little obsessed with.

The Wood paper is open-access and has some accompanying media coverage but a few pointers might be useful...

• Following other work by the authors on this topic [2] the idea behind this latest research was to apply the science of neuroimaging to a participant group comprising 16 children exposed to VPA in-utero compared with age- and sex-matched children not exposed to such pharmaceutics prenatally.
• MRI scans were taken and analysed and "whole brain group differences" assessed. 
• Results: well, as discussed, there were some findings in terms of cortical thickness but also specifically with language skills in mind. To quote again: "Asymmetry of cortical thickness in the inferior frontal lobes was seen in controls but not cases". I understand that this finding might have some relevance to language processing [3] although set my non-expert stall out on such matters. As per that previous link [2] and other evidence [4], language functions in VPA exposed children tend to poorer compared to controls and to those exposed to other anti-convulsant medication during the nine months that made us. This last point on different medications potentially carrying different risk profiles [5] is something equally interesting.

Allowing for the relatively small participant groups studied and the lack of any other research parameter such as looking at accompanying brain chemistry which may be important [6], the Wood paper offers some intriguing insights into how pregnancy VPA use might affect infant brain development. The very important detail of analysis being based on real human children and not rat offspring also invites some further examination of previous results based on rodents [7]. Rats are rats, children are children.

I'm going to leave you with a quote from the authors about their study: "VPA remains an important medication for people with epilepsy. What this study really tells us is that further research is required so that all women with epilepsy can make informed decisions about their medication use during pregnancy". I couldn't agree more, and as per the Treating for Two initiative, I'm not the only one.

Music then... HRH Gaga and Just Dance.

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[1] Wood AG. et al. Altered cortical thickness following prenatal sodium valproate exposure. Annals of Clinical and Translational Neurology. 2014. July 3. doi: 10.1002/acn3.74

[2] Nadebaum C. et al. Language skills of school-aged children prenatally exposed to antiepileptic drugs. Neurology. 2011 Feb 22;76(8):719-26.

[3] Powell HWR. et al. Hemispheric asymmetries in language-related pathways: A combined functional MRI and tractography study. NeuroImage. 2006; 32: 388-399.

[4] Shallcross R. et al. In utero exposure to levetiracetam vs valproate: development and language at 3 years of age. Neurology. 2014 Jan 21;82(3):213-21.

[5] Vajda FJE. et al. The teratogenicity of the newer antiepileptic drugs – an update. Acta Neurol Scand. 2014. July 18

[6] Almeida LE. et al. Increased BDNF expression in fetal brain in the valproic acid model of autism. Mol Cell Neurosci. 2014 Mar;59:57-62.

[7] Mychasiuk R. et al. Effects of rat prenatal exposure to valproic acid on behaviour and neuro-anatomy. Dev Neurosci. 2012;34(2-3):268-76.

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Wood, A., Chen, J., Barton, S., Nadebaum, C., Anderson, V., Catroppa, C., Reutens, D., O'Brien, T., & Vajda, F. (2014). Altered cortical thickness following prenatal sodium valproate exposure Annals of Clinical and Translational Neurology DOI: 10.1002/acn3.74

Elevated amniotic fluid steroid hormones and autism risk

"These results provide the first direct evidence of elevated fetal steroidogenic activity in autism". Such were the sentiments of the paper by Simon Baron-Cohen and colleagues [1] (open-access) looking at amniotic fluid samples for the presence of various sex steroid levels: Progesterone, 17α-Hydroxy-progesterone, Androstenedione, Testosterone and Cortisol. Most compounds are found in the Δ4 pathway. Suffice to say that the media kinda liked the press release for this study (see here) and the study findings have been reported by quite a few outlets (see here and see here).

The paper is open-access but as always, I'd like to give a brief overview:

• Based on amniotic samples collected in Denmark (yet again those Scandinavian registries are proving their scientific worth), "all amniotic fluid samples of males born between 1993 and 1999 who later received ICD-10 (International Classification of Diseases, 10th Revision) diagnoses of autism, Asperger syndrome or PDD-NOS (pervasive developmental disorder not otherwise specified) (n=128)" were compared with 217 asymptomatic controls. Note the focus on males only.
• Samples were in storage for quite a few years (average of 14 years) but were eventually thawed and prepared for analysis by a favourite technique of mine: liquid chromatography tandem mass spectrometry. If you're really interested, the mass spec used was a triple quadrupole system operated in positive ion mode relying on chemical ionisation.
• Results: rather than any one of the sex steroids being singled out as a biomarker for the autism samples, "a latent steroidogenic factor is elevated, which includes all hormones in the Δ4 pathway, as well as cortisol". Further: "This observation suggests dysregulation of pathways mediated by cytochrome P450-containing enzymes that catalyze the conversion of hormones along the Δ4 and glucocorticoid pathways". One of the figures included in the paper provides a good overview on the extent of the group elevations noted in the study (see here).
• "The source of elevated steroidogenic activity in the fetal development of autism was not tested in the current study, and more research will be needed to understand how different sources such as the fetus, mother, placenta or other environmental factors might contribute to such elevations". In other words, researchers were only recording sex steroid values in samples not looking at the hows and whys of such elevations.

Those who are familiar with the autism research scene will probably know about Prof SBC and his work going back some years (see here). In more recent times, I note that quite a bit more of his work is focusing on the sex hormones and how they may relate to cognitive phenotypes such as systemisers and empathisers (see here and see here) potentially overlapping with facets of the autism and other spectrums. Perhaps more interesting to me has been some shift away from grand sweeping psychological theories of autism to other disciplines pertinent to autism research such as those similar to his analytical chemistry work shown in this post [2]. 

I note in the current paper mention of the words "epigenetic fetal programming" as being one suggestion for how being 'bathed' in elevated levels of these 'male' hormones might potentially explain why a child goes on to develop autism. I know this is a trendy area to talk about these days; David Barker (RIP) must be casting a smile over how far and wide his writings are now seemingly reaching. That being said, I'd be interested to see how subsequent research fares in this area particularly when taking into account other placental-related autism findings and the rise and rise of epigenetics in autism research (see here). The authors also for example write: "The current results may also be relevant to the literature on prenatal stress and autism. We found that cortisol, a biomarker typically associated with stress, is elevated early in the fetal development of autism". Knowing what we think we know about cortisol and autism (see here) again, it will be interesting to see where this research leads. Interestingly too, the authors also talk about GABA and cytokines in their discussion of results hinting at the multitude of possible effects that may stem from their findings.

Finally, I note the authors do add quite a big caveat to their findings: "From a clinical standpoint, the current results say nothing about the potential for such data as a prospective prenatal test of autism risk". This based on an issue that Prof SBC has talked about before in the lay arena (see here) which heads down a potentially quite uncomfortable path. Treading carefully, I await replication of these results and that all-important focus on the hows and whys of elevated foetal steroidogenic activity potentially associated with elevated autism risk.

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[1] Baron-Cohen S. et al. Elevated fetal steroidogenic activity in autism.  Molecular Psychiatry. 2014. June 3.

[2] Steeb H. et al. Serum proteomic analysis identifies sex-specific differences in lipid metabolism and inflammation profiles in adults diagnosed with Asperger syndrome. Mol Autism. 2014 Jan 27;5(1):4.

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Baron-Cohen, S., Auyeung, B., Nørgaard-Pedersen, B., Hougaard, D., Abdallah, M., Melgaard, L., Cohen, A., Chakrabarti, B., Ruta, L., & Lombardo, M. (2014). Elevated fetal steroidogenic activity in autism Molecular Psychiatry DOI: 10.1038/mp.2014.48