"maternal pre-pregnancy obesity is associated with autism-like behaviors in offspring"

The results reported by Kandice Varcin and colleagues [1] concluding that "maternal pre-pregnancy obesity is associated with autism-like behaviors in offspring" continue and extend a research theme (see here and see here). A research theme that highlights a potentially important relationship between maternal weight (and/or related parameters) and offspring development across various, potentially intertwined, variables (see here).

Including the notable name of Andrew Whitehouse on the authorship team (see here and see here for some examples of his other research), researchers set about to explore whether "pre-pregnancy weight was related to autistic-like traits among offspring not diagnosed with ASD [autism spectrum disorder]." I added the bold highlight to the word 'not' to emphasise how this work was set slightly apart from the other research that has observed an *association* between maternal weight before or during pregnancy and a risk of a formal diagnosis of autism in offspring. Pregnant women in their second trimester of pregnancy were recruited and "had their height measured." They also "reported their pre-pregnancy weight" which combined with the height measurements to give the measure known as the body mass index (BMI). And also: "At 19-20 years of age, 1238 offspring of these women completed a measure of autistic-like traits, the Autism-Spectrum Quotient (AQ)." Keep those issues in mind for now.

Results: "Regression analyses identified a positive association between increasing maternal pre-pregnancy BMI and increasing AQ Total Score amongst offspring; this association was maintained even after controlling for a range of variables including maternal/obstetric factors (age at conception, education, smoking, alcohol consumption, hypertensive diseases, diabetes, threatened abortion), paternal BMI at pregnancy, and child factors (parity, sex)." Sorry for the large quote, but the authors said it better than I ever could. Authors also reported that those women defined as being obese before pregnancy, according to their BMI measurement, were quite a bit more likely to "have offspring with high scores (≥26) on the AQ." This then lead them to conclude that "maternal pre-pregnancy obesity is associated with autism-like behaviors in offspring."

Caveats? Well, yes, a few. Height measured in the second trimester but participants "reported their pre-pregnancy weight"? I can see a few complications there in terms of accuracy of recall and perhaps the possibility of some bias creeping in. Having said that, many mums-to-be do have records of their weight during that 'special time' and some probably before as part of their regular clinical care or just as a result of how health conscious everyone is being these days. That and the fact that most people roughly know their typical weight (outside of pregnancy).

But also the AQ... the AQ. Regular readers probably already know that I have some qualms about the AQ and it's 'specificity' when it comes to autism and autistic traits (see here and see here). I know it's often seen as one of the internet's premier 'are you autistic?' instruments, but sometimes I think it's done more harm than good by way of it's probable link to the rise and rise of the 'self diagnosis' (see here) for example. I could go on about this, but I won't. Instead I'll just mention that 'autism-like' behaviours as judged by the AQ is probably the correct phrase to use in the context of the Varcin paper. Indeed, one might easily suggest that in a non-clinical population, AQ might also be tapping into other labels and traits [2]: "Higher AQ scores were associated with higher scores of loneliness, social anxiety, depression, and anxiety, as well as with lower scores of quality of life (QoL)." So unless one accepts that depression and/or anxiety might potentially be core features of autism (see here and see here), AQ might be picking up other things other than autism.

Still, I can't argue with the *association* talked about by Varcin et al, and what it might mean for the quite spectacular rise and rise in the numbers of people being diagnosed with an autism spectrum disorder (see here). No, not by any means the only factor to account for the increase in diagnoses, but potentially an important part of the story...

----------

[1] Varcin KJ. et al. Maternal pre-pregnancy weight and autistic-like traits among offspring in the general population. Autism Res. 2018 Sep 19.

[2] Reed P. et al. Loneliness and Social Anxiety Mediate the Relationship between Autism Quotient and Quality of Life in University Students. Journal of Developmental and Physical Disabilities. 2016; 28: 723-733.

----------

Polycystic ovary syndrome (PCOS) and autism continued

"These studies provide further evidence that women with PCOS [polycystic ovary syndrome] and their children have a greater risk of autism."

'These studies' refers to the studies conducted and reported on by Adriana Cherskov and colleagues [1] drawing on previous peer-reviewed research literature suggesting that there may be a *connection* between exposure to PCOS and autism or autistic traits (see here).

PCOS is a condition that affects how a woman's ovaries function. Although linked to an imbalance in certain sex hormones (specifically testosterone), one of the proposed starting points for PCOS is an elevation of insulin (a hormone that controls the amount of sugar in the blood). I'll return to this point shortly...

Cherskov et al report results from 3 studies included in their research strategy: study 1 "examined the risk of PCOS in women with autism compared to those without autism"; study 2 "examined the risk of autism in women with PCOS compared to those without PCOS"; and study 3 "examined the risk of autism in first-born children of mothers with PCOS compared to first-born children of mothers without PCOS." The autism *connection* is integrated into the idea that sex hormone exposure in-utero might play some role in the risk of autism to offspring. Bearing in mind that the participant numbers were not to be sniffed at, a few interesting results emerged from the collected studies.

So: "A significantly higher percentage of women with autism were diagnosed with PCOS than controls" (study 1). Looking at the percentages of PCOS among the groups, the results weren't exactly startling: 2.3-7.8% autism vs. 1.1-3.5% controls (depending on the PCOS criteria used) but a difference was noticed.

Then: "Autism was almost two times more prevalent in PCOS cases (n = 26,263) than in controls (n = 130,717)" (study 2). But... when authors took into account various 'psychiatric conditions' also present in mums, the results went from significant to non-significant ("p-value = 0.084"). And please, don't use the term 'approaching significance'...

Finally: "In Study 3 we found the odds of having a child with autism were significantly increased, even after adjustment for maternal psychiatric diagnoses, obstetric complications, and maternal metabolic conditions."

What's to make of this collected data? Well, the use of anonymous electronic records derived from the Clinical Practice Research Datalink (CPRD) electronic health record database here in Blighty is a strength both in record number and quality. The associated feature that other clinical findings and diagnoses outside of PCOS were also included for study is very positive too. But one has to be slightly careful about making too many sweeping generalisations from the results of such studies. I can't disagree with the sentiments expressed by the authors that: "These studies provide further evidence that women with PCOS and their children have a greater risk of autism" but we can say that the picture is complicated and not straight-forward.

Then back to the questions of 'how and why'? Thankfully, the authors don't just focus on the 'sex steroids' viewpoint but do also talk about how insulin - hyperinsulinemia - might also play a role. My gut feeling is that this is of central importance, particularly in light of observations about a diabetes connection to autism (see here for a 'meta-analysis' example) and similar observation in other studies on PCOS and autism too (see here). Add in the findings on pregnancy metabolic syndrome and autism (see here and see here), featuring an 'inability to control blood sugar levels' and things get even more interesting in this area.

Oh, and there could be other [speculative] factors to consider too (see here)...

----------

[1] Cherskov A. et al. Polycystic ovary syndrome and autism: A test of the prenatal sex steroid theory. Transl Psychiatry. 2018 Aug 1;8(1):136.

----------

An exercise intervention for autism

"Our results provide support for exercise and physical activity, including basic coordination and strength exercises, as important therapeutic interventions for children with ASD [autism spectrum disorder]."

So said the results published by Chrystiane Toscano and colleagues [1] looking at an important, and sometimes easily overlooked, avenue of intervention with autism in mind: physical activity. I say 'intervention' but as with quite a few other programs/activities described in such terms, it's often more about offering equal access to things that most children (and adults) take for granted. Indeed, to 'intervention-ise' something like exercise in the context of autism kinda follows a pattern where even playing with some well-known connecting blocks is sometimes talked about in 'therapeutic' terms when mentioned alongside autism rather than just being play (see here). One has to be quite careful about the language used...

Anyhow, various parameters were monitored and measured as "a 48-week exercise-based intervention" was put into place looking at the presentation of autism as well as various physical-metabolic variables: "high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and total cholesterol."

Bearing in mind potentially problematic issues such as a lack of blinding - double-blinding - and of course the idea that exercise really needs to make you feel happy in order to keep doing it, researchers reported that many aspects seemed to improve over the quite long study period, more so for the group in receipt of exercise intervention. Not only did physical indicators show improvements, so did autistic features and also "parent-perceived quality of life" too.

Allowing for the fact that there could be 101 different variables impacting on the Toscano results outside of the increase in physical activity, I am happy to see that exercise is a continued focus when it comes to the autism spectrum [2]. There is literally oodles and oodles of research out there talking about how sedentary behaviour(s) do seem to be over-represented in relation to autism (see here for example) and where they could (in part) lead (see here); bearing in mind the sentiment: you can't outrun a bad diet. Anything that gets kids (and adults) up and active has to be a good thing.

Once again, I'm going to draw your attention to one potential exercise option that ticks many boxes when it comes to the autism spectrum and beyond: the martial arts (see here and see here). Physical activity... check. Focus on "basic coordination and strength"... check. Focus on predefined and (sometimes very) repetitive patterns of movement... check. Focus on individual performance set within a social context... check. Regular accomplishment levels - gradings - to boost confidence, pride and self-esteem... check. Something that will make any would-be bullies perhaps think twice or thrice... check.

And of additional importance to any discussions on exercise and physical activity, the data from Flygare Wallén and colleagues [3] highlight the important physiological reason(s) why getting those on the autism spectrum moving more is so damn important...

----------

[1] Toscano CVA. et al. Exercise Effects for Children With Autism Spectrum Disorder: Metabolic Health, Autistic Traits, and Quality of Life. Percept Mot Skills. 2017 Jan 1:31512517743823.

[2] Najafabadi MG. et al. The Effect of SPARK on Social and Motor Skills of Children with Autism. Pediatrics & Neonatology. 2018. Jan 6.

[3] Flygare Wallén E. et al. High prevalence of diabetes mellitus, hypertension and obesity among persons with a recorded diagnosis of intellectual disability or autism spectrum disorder. J Intellect Disabil Res. 2017 Dec 26.

----------

I would walk 500 miles... or maybe just 8 miles (a day).

"Desk-bound workers should ‘walk EIGHT miles a day’ to slash risk of heart attacks or stroke" went one headline talking about the findings reported by William Tigbe and colleagues [1]. Drawing on data from over 110 postal workers - "(55 office-workers, 5 women, and 56 walking/delivery-workers, 10 women)" - who wore "activPAL physical activity monitors for seven days", researchers observed some potentially important trends.

Alongside wearing their activity monitors, participants were also assessed on the basis of weight, height, and blood pressure; also providing blood samples pertinent to analyses for cholesterol and triglycerides. Such collected data were used to assess cardiovascular risk based on the PROCAM risk calculator.

Results: those who were described as office workers and had a 'desk job' were generally larger at the waist and showed a slightly larger body mass index (BMI) score. They were also deemed to have an elevated risk of cardiovascular disease (over 10 years) compared with the walking/delivery workers. These observations were discussed in terms of the sedentary behaviours associated with their desk job. By contrast, those who delivered post (i.e. were active for large parts of the day) fared quite a bit better than their desk-bound colleagues, bearing in mind that all study participants were fairly healthy to begin with in terms of being non-smokers for example and not being in current receipt of blood pressure or glucose lowering medicines at time of study.

The 'walk 8 miles a day' headline that followed the Tigbe study was derived from the observation(s) that: "Those with no metabolic syndrome features walked >15 000 steps/day, or spent >7 h/day upright." Metabolic syndrome refers to a collection of symptoms - "a combination of diabetes, high blood pressure and obesity" - that increases the risk of adverse events associated with cardiovascular (dys)function. It seems that being active, or at least not being sedentary, is important for our health - a shocker indeed!

I've covered some of the other research in this area before (see here and see here for examples) and so the Tigbe results really don't come as a surprise. The strengths of the study are multiple in terms of objective measuring of activity (not reliant on the 'how much activity/exercise did you do today' type questionnaires) and all those biochemical measurements taken for participants to complement such findings. Yes, the sample size is OK but not particularly large and yes, these were pretty healthy participants to start with, but the results are nonetheless important.

Obviously one has to be a little careful so as not to imply that being active is the only thing that leads to good health and wellbeing. Science has already heard about how 'you can't outrun a bad diet' [2] and for some people, walking 15,000 steps every day or even standing up for 7 hours a day is going to be a big ask. But as part of a package of 'interventions' to potentially ward off metabolic syndrome or related issues [3], the idea that we should all be quite a bit more active is one that really should be given a lot more consideration...

Music to close, and with the title to this post, what else could I offer?

----------

[1] Tigbe WW. et al. Time spent in sedentary posture is associated with waist circumference and cardiovascular risk. Int J Obes (Lond). 2017 Jan 31.

[2] Malhotra A. et al. It is time to bust the myth of physical inactivity and obesity: you cannot outrun a bad diet. Br J Sports Med. 2015 Aug;49(15):967-8.

[3] Alexander DD. et al. A Meta-Analysis of Randomized Controlled Trials and Prospective Cohort Studies of Eicosapentaenoic and Docosahexaenoic Long-Chain Omega-3 Fatty Acids and Coronary Heart Disease Risk. Mayo Clinic Proceedings. 2017; 92: 15-29.

----------

Tigbe WW, Granat MH, Sattar N, & Lean ME (2017). Time spent in sedentary posture is associated with waist circumference and cardiovascular risk. International journal of obesity (2005) PMID: 28138134

Maternal obesity and offspring autism meta-analysed (again)

Meta-analyses eh? You spend ages waiting for one and two come along in quick succession. Well today I'm posting about yet another meta-analysis of the peer-reviewed scientific literature suggesting that "excessive maternal BMI [body mass index] is associated with an increased ASD [autism spectrum disorder] risk in offspring." [1]

The review by Ying Wang et al follows hot on the heels of the meta-analysis by Li and colleagues [2] (see here for my take) but further looked at "the potential association of different category of BMI including overweight and underweight with ASD risk" among other things. BMI by the way, is a rough and ready way to quantify how much of a person there is according to height and weight. Whilst a useful statistic, it is not without its issues.

After taking into account data from "6 cohort studies and 1 case-control study involving 8,403 cases and 509,167 participants" the authors unsurprisingly came to the same conclusion as Li and colleagues that a higher BMI seems to confer more [relative] risk for offspring autism as an outcome. Authors even included a nice graphic (see here) suggesting something of a dose-response relationship between the two variables (based on data from four of the studies included in their meta-analysis).

What's more to say? Well, 'The maternal body as environment in autism science' returns into the frame and questions about possible mechanisms need to be asked/answered. No, such findings don't mean (a) every mum with a child with autism was overweight or obese before or during pregnancy or (b) every overweight or obese mum will have a child with autism: "Compared with children whose mothers were at normal weight, children born to overweight and obese mothers have a 28% and 36% higher risk of developing ASD, respectively." Such data does however open the door to the idea of foetal programming when it comes to potential offspring outcomes and how elevated BMI as possibly linking to facets of metabolic syndrome for example, might have some role to play for some (see here).

More investigations are indicated.

----------

[1] Wang Y. et al. Maternal Body Mass Index and Risk of Autism Spectrum Disorders in Offspring: A Meta-analysis. Scientific Reports. 2016; 6: 34248.

[2] Li YM. et al. Association Between Maternal Obesity and Autism Spectrum Disorder in Offspring: A Meta-analysis. J Autism Dev Disord. 2016 Jan;46(1):95-102.

----------

Wang, Y., Tang, S., Xu, S., Weng, S., & Liu, Z. (2016). Maternal Body Mass Index and Risk of Autism Spectrum Disorders in Offspring: A Meta-analysis Scientific Reports, 6 DOI: 10.1038/srep34248

Metformin to tackle medication induced weight gain in autism?

"Metformin may be effective in decreasing weight gain associated with atypical antipsychotic use and is well tolerated by children and adolescents with ASD [autism spectrum disorder]."

So said the paper by Evdokia Anagnostou and colleagues [1] (open-access) tackling an increasingly important health issue related to the pharmacological 'management' of some aspects of some autism.

Metformin is the treatment of choice when it comes to the management of type 2 diabetes (the one where "the pancreas doesn't produce enough insulin or the body's cells don't react to insulin"). It is thought to work by helping the liver to stop producing new glucose and also helping insulin carry more glucose into muscle cells more effectively. Alongside, an increasing body of research has also suggested that metformin might be a useful intervention measure to offset one of the quite well-known side-effects associated with various antipsychotic agents: weight gain.

So Anagnostou et al set about looking to "assess the safety, tolerability, and efficacy of metformin to decrease weight gain associated with the use of atypical antipsychotic medication in children with ASD." They did this using the gold-standard in clinical trial designs: the "double-blind, placebo-controlled, randomized clinical trial" where some 60 children and young adults diagnosed with an ASD and receiving a stable dose of an atypical antipsychotic received either metformin (Riomet) or a placebo over the course of 16 weeks. "The primary outcome measure was change in body mass index (BMI) z score during 16 weeks of treatment. Secondary outcomes included changes in additional body composition and metabolic variables." The study protocol was also registered with ClinicalTrials.gov.

As per the opening sentence, there were some important differences in body mass index (BMI) z-scores suggestive that compared with a placebo, those prescribed metformin saw decreases in weight gain. The range of decrease in BMI were in some cases between about 8-9% over the course of the 16 week study period (most of the benefits seemed to be apparent after about 8 weeks of metformin use). Insofar as those secondary variables also examined during the course of the study (glucose levels, insulin, triglycerides, etc.) no significant differences were noted across the study. When it came to the important issue of side-effects, the authors noted that gastrointestinal (GI) effects seemed to be more apparent in the group taking metformin during treatment days. Aside from that, short-term side-effects seemed to be few and far between.

The authors note that their trial "did not address the question of whether coadministration of metformin at the onset of atypical antipsychotic use prevents initial weight gain" but rather whether metformin use after weight gain associated with antipsychotic use could be effective. In that light, these are important results that very much require further independent investigation.

Quite a few times on this blog I've talked about how the physical health of those on the autism spectrum is sometimes neglected as a function on the focus on mental health or behaviour. There is a growing recognition that autism, or at least some of the important comorbidities associated with autism, might somehow predispose to a more sedentary lifestyle and the accompanying health issues that this can bring. Throw into the mix the possibility that some of the pharmacotherapy used in autism might also contribute to something like weight issues [2], and you have a recipe for some pretty severe health issues potentially building up in later life. These latest findings are therefore welcomed as a way to potentially lower the burden of an elevated BMI in cases where such medication is prescribed.

I do have questions however about this approach and how one perhaps needs to be slightly cautious about slipping into the old 'medication to tackle medication side-effects' routine with autism in mind (something noted in an accompanying editorial to the Anagnostou study). Metformin, whilst a very useful drug, is not without side-effects as was noted in the Anagnostou study and given the quite high rates of GI issues noted in cases of autism (see here), one really does not want to make this any worse. I would also like to see more data on the use of metformin in antipsychotic-induced weight gain in autism with a focus on other parameters thought to be altered by such antipsychotic use such as the issue of prolactin levels for example (see here). Yes, there is data to suggest that metformin might more generally work on prolactin levels too [3] but does this similarly apply to children on the autism spectrum? And then also there is the issue of sleep [4]...

----------

[1] Anagnostou E. et al. Metformin for Treatment of Overweight Induced by Atypical Antipsychotic Medication in Young People With Autism Spectrum Disorder. JAMA Psychiatry. 2016. Aug 24.

[2] Shedlock K. et al. Autism Spectrum Disorders and Metabolic Complications of Obesity. Journal of Pediatrics. 2016. Sept 2.

[3] Krysiak R. et al. The effect of metformin on prolactin levels in patients with drug-induced hyperprolactinemia. Eur J Intern Med. 2016 May;30:94-8.

[4] Kajbaf F. et al. The relationship between metformin therapy and sleep quantity and quality in patients with Type 2 diabetes referred for potential sleep disorders. Diabet Med. 2014 May;31(5):577-80.

----------

Anagnostou E, Aman MG, Handen BL, Sanders KB, Shui A, Hollway JA, Brian J, Arnold LE, Capano L, Hellings JA, Butter E, Mankad D, Tumuluru R, Kettel J, Newsom CR, Hadjiyannakis S, Peleg N, Odrobina D, McAuliffe-Bellin S, Zakroysky P, Marler S, Wagner A, Wong T, Macklin EA, & Veenstra-VanderWeele J (2016). Metformin for Treatment of Overweight Induced by Atypical Antipsychotic Medication in Young People With Autism Spectrum Disorder: A Randomized Clinical Trial. JAMA psychiatry PMID: 27556593

Expanding MAR autism

MAR autism - maternal autoantibody-related autism - is a term that has graced this blog before (see here). Describing a state where autoantibodies directed against foetal brain proteins have been detected in some mothers who have children diagnosed with an autism spectrum disorder (ASD), the suggestion is that such evidence further substantiates a role for various maternal immune functions and processes when it comes to offspring risk of at least some types of autism.

Although interesting, the research road travelled by MAR autism has not been a smooth one (see here). Indeed one of the outstanding questions has been whether the detection of such autoantibodies is more or less likely when various other conditions affecting the mother might be present (see here) and perhaps synergistically elevating the risk of offspring autism. The paper by Paula Krakowiak and colleagues [1] further explored this question and concluded that: "mothers whose children had severe ASD and who experienced diabetes were more likely to have anti-fetal brain autoantibodies 2–5 years later."

Some media about the Krakowiak study can be seen here. Based on participants - "227 mothers of 2–5 year old children with confirmed ASD" - all enrolled in CHARGE (be in CHARGE!) researchers set about looking at whether "ASD-specific maternal autoantibodies identified postnatally were associated with metabolic conditions (MCs) during gestation." Said metabolic conditions (MCs) included "diabetes, hypertensive disorders, and prepregnancy obesity or overweight, ascertained from medical records or structured telephone interviews." Indeed Paula Krakowiak has some research history with MCs in mind (see here) that has subsequently been replicated in other cohorts (see here).

Results: well, aside from a quarter of mothers presenting with those autoantibodies (based on the analysis of archived blood samples) authors reported that: "Ab+ [anti-fetal brain autoantibodies positive] prevalence was higher among mothers with diabetes, hypertensive disorders, or overweight compared to healthy mothers, but differences were not statistically significant." What this means is that overall there was a trend towards elevated risk of Ab+ in  those mothers with various metabolic conditions but this might have just been a chance finding. Unfortunately some of the media reports on this specific point are found wanting...

When it came however to looking at those mothers who had children who "exhibited severe ASD" they suggested that those diagnosed with type-2 diabetes or gestational diabetes "were 2.7-fold more likely to be Ab+." Further: "Gestational diabetes specifically was associated with a 3.2-fold increased Ab+ prevalence."

As per some of the media interest in these results there are a few [cautious] 'take-away messages' from the findings. The idea for example, that the presence of certain metabolic conditions "may alter the maternal immune tolerance to the fetus during pregnancy" is an important one in the context of words like 'inflammation' being potentially involved (see here for another example of this). I would however like to see a little more science done on the specific biology of how obesity might bring about autoantibodies with autism specifically in mind based on other findings [2].

That preferential screening of the offspring of those mothers diagnosed with a metabolic condition either before or during pregnancy might be offered is another message bearing in mind how stretched screening and diagnostic services seem to be in many parts of the world. The idea also that where and when 'severe ASD' is reported, further research investigations might focus in further on this topic and how findings might manifest in the children with ASD themselves is also deserving of attention.

Oh, and then there is the further evidence afforded to the term 'the autisms' by the Krakowiak results...

----------

[1] Krakowiak P. et al. Autism-specific maternal anti-fetal brain autoantibodies are associated with metabolic conditions. Autism Research. 2016. June 17.

[2] Arai S. et al. Obesity-associated autoantibody production requires AIM to retain the immunoglobulin M immune complex on follicular dendritic cells. Cell Rep. 2013 Apr 25;3(4):1187-98.

----------

Krakowiak P, Walker CK, Tancredi D, Hertz-Picciotto I, & Van de Water J (2016). Autism-specific maternal anti-fetal brain autoantibodies are associated with metabolic conditions. Autism research : official journal of the International Society for Autism Research PMID: 27312731

Vitamin D deficiency and psychosis

In amongst my various ramblings about how vitamin D - the sunshine vitamin/hormone - might show more than a few connections to conditions/labels outside of just the English disease (see here), I've covered some science on a possible connection with psychosis (see here) and schizophrenia (see here). There are still gaps in terms of the hows and whys of vitamin D insufficiency and deficiency when it comes to this area of psychiatry, but I believe there is enough science in this area to initially warrant screening of vitamin D levels as and when a diagnosis is received. This similarly extends to other labels too (see here and see here).

The paper by Lally and colleagues [1] (open-access) puts a little more scientific flesh on the bones about how vitamin D insufficiency/deficiency might manifest in cases of psychosis, with a particular focus on "increased cardiovascular disease risk factors and in particular metabolic syndrome [MetS]."

With thanks to Brendon Stubbs (one of the authors of the paper) for bringing the findings to my attention, researchers set about looking at "the prevalence of vitamin D deficiency in a cohort of community patients with established psychotic illnesses" (N=324). Given my earlier mention of the 'English disease', the cohort were indeed all living in England and drawn from a larger study initiative. Vitamin D levels were assayed via a chemiluminescence immunoassay based on the examination of serum samples. Various other measures were also included for study around the issue of cardiovascular risk factors including body mass index (BMI), waist circumference, blood pressure, serum cholesterol levels and glucose levels. High sensitivity serum C-reactive protein (HS-CRP) was also included.

Results: "Almost half of the sample (48.8 %, n = 158) were deficient in vitamin D while only 13.9 % (n = 45) had sufficient vitamin D." Ethnicity seemed to play a role in those determinations of deficiency/sufficiency with vitamin D levels generally lower in those who were black African or black Caribbean. Likewise the season of testing showed an effect. When it came to determining whether there was an association between vitamin D status and mental state, researchers reported nothing significant based on the use of the Positive And Negative Syndrome Scale (PANSS) and related measures.

But... there might be quite a bit more to look at when taking into account those cardiovascular disease risk factors and vitamin D levels as the authors reported various significant correlations. So: "those with the highest levels of vitamin D have a lower prevalence of MetS (20.5 %), compared to those in the lowest (39.1 %), second (48.3 %) and third quartile (43.1 %) of vitamin D." Indeed, just about every measure of cardiovascular risk showed an association with measured serum vitamin D levels when controlling for "age, gender, ethnicity and season of 25-OHD blood sampling." The authors also add that: "Those engaging in low intensity physical activity over the week prior to sampling... had significantly lower 25-OHD levels... than those who engaged in moderate or high intensity physical activity."

Teasing apart what might actually be doing what is a difficult task in such studies where various outcome measures might be implicated. The authors do speculate on how for example, their finding of "raised CRP and vitamin D deficiency in established psychosis" might tie into other research on inflammation or inflammatory processes with both variables in mind (see here and see here). Indeed, this might also tie in with calls for further integration of immunopsychiatry with psychotic disorders in mind [2]. But there remains more to do, including the intriguing question: "would the supplementation of vitamin D in psychosis prevent and/or ameliorate cardiovascular and metabolic risk?"

I do have some small points to make about the study that might also require attention in follow-up work, not least the idea that immunoassay for determining functional vitamin D levels might not be the most accurate method [3]. Indeed, the authors make this point in their conclusions. One might also hope that comparisons with other patient groups might offer some further information about how specific the findings are to just psychosis or other psychiatric groupings. If found in a more general sense, the idea that vitamin D is related to variables affecting cardiovascular risk in such groups could make lots and lots of waves.

For now however, this research extends the ideas that: (a) preferential screening for vitamin D might be indicated for this group/label, and (b) the focus on psychiatric presentation should not be made at the expense of somatic presentation. Parity of esteem and all that; or rather just making sure that health inequality does not follow from receipt of a psychiatric label...

----------

[1] Lally J. et al. Clinical correlates of vitamin D deficiency in established psychosis. BMC Psychiatry. 2016; 16: 76.

[2] Leboyer M. et al. Is it time for immunopsychiatry in psychotic disorders? Psychopharmacology (Berl). 2016 Mar 18.

[3] Yang Y. et al. High-throughput measurement of 25-hydroxyvitamin D by LC-MS/MS with separation of the C3-epimer interference for pediatric populations. Clin Chim Acta. 2016 Feb 15;454:102-6.

----------

Lally, J., Gardner-Sood, P., Firdosi, M., Iyegbe, C., Stubbs, B., Greenwood, K., Murray, R., Smith, S., Howes, O., & Gaughran, F. (2016). Clinical correlates of vitamin D deficiency in established psychosis BMC Psychiatry, 16 (1) DOI: 10.1186/s12888-016-0780-2

Maternal obesity and offspring autism meta-analysed

So: "The meta-analysis results support an increased risk of autism spectrum disorder in children of women who were obese during pregnancy. However, further study is warranted to confirm these results."

That was the conclusion reached by Ya-Min Li and colleagues [1] looking at the collected peer-reviewed data currently available on how maternal weight might impact on offspring neurodevelopmental outcomes. Without wishing to blame or stigmatise (this is a blog based on the examination of cold, objective, peer-reviewed science) such results are not altogether unexpected based on instances where maternal weight might impact on offspring autism risk have been discussed (see here).

There are caveats to ideas of such an association. Not least that observational studies for example, often provide little information on 'cause and effect'. That not every child born to a mum who is overweight and/or obese develops autism should also be kept firmly in mind, as should the idea that overweight and/or obesity can sometimes sit with other comorbidity as part of the 'metabolic syndrome' so potentially introducing other variables into any association (see here). I might add that an array of other factors cross obesity and autism risk areas, not least mothers' nutritional status before and during pregnancy for example (see here).

That all being said, there is more science to do in this area. Thinking back to other discussions on data about how father's weight might also influence offspring autism risk (see here) and the idea of foetal programming [2] based to a large extent on the writings of the late David Barker, one gets some ideas of where science might want to start heading in continuing this line of inquiry.

Music: Keane - Everybody's Changing.

----------

[1] Li YM. et al. Association Between Maternal Obesity and Autism Spectrum Disorder in Offspring: A Meta-analysis. J Autism Dev Disord. 2015 Aug 9.

[2] Lau C. & Rogers JM. Embryonic and fetal programming of physiological disorders in adulthood. Birth Defects Res C Embryo Today. 2004 Dec;72(4):300-12.

----------

Li YM, Ou JJ, Liu L, Zhang D, Zhao JP, & Tang SY (2015). Association Between Maternal Obesity and Autism Spectrum Disorder in Offspring: A Meta-analysis. Journal of autism and developmental disorders PMID: 26254893

Probiotics, schizophrenia and inflammation

I have to say that I was initially pretty interested to read the paper by Jakub Tomasik and colleagues [1] (open-access available here) discussing results examining the "possible immunomodulatory effects of probiotic supplementation in chronic schizophrenia patients."

Interested because not only was this a partnership paper including Robert Yolken and Faith Dickerson on the authorship list (names who have appeared a few times on this blog) but also because of the subject matter extending some research interest into how gastrointesinal (GI) 'functions' may very well have some important implications for at least some cases of schizophrenia (see here) particularly linked to the concept of inflammation. This area of research on a 'gut-brain connection', also links into a body of work with autism in mind (see here) and with that autism connection, mention of one Sabine Bahn as a co-author and some research she has published [2] is also worth noting.

In the current paper, Tomasik et al describe work following on from a previous study by Dickerson and colleagues [3] suggesting that adjuvant probiotic use may "help to prevent severe bowel difficulty in patients with schizophrenia" even if not significantly affecting the behavioural presentation of schizophrenia on that research occasion. With no endorsement given or intended, the probiotic preparation in question was called Bifiform Balance and contained "the probiotic organism L. rhamnosus GG and... colony forming units of the probiotic organism Bifidobacterium animalis subsp. lactis BB12 (Ferrosan)." Lactobacillus rhamnosus GG has appeared before on this blog (see here) so I was intrigued as I always am when it comes to gut bacteria and health / behaviour.

Authors describe how blood samples from 58 participants who completed the previous Dickerson trial ("31 in the probiotic arm and 27 in the placebo arm") were collected pre- and post-trial (after 14 weeks) and serum samples analysed by immunoassay "targeting selected inflammatory markers, including cytokines, chemokines, and acute-phase reactants."

Results: "Probiotic add-on treatment significantly reduced levels of von Willebrand factor (vWF) and increased levels of monocyte chemotactic protein-1 (MCP-1), brain-derived neurotrophic factor (BDNF), RANTES, and macrophage inflammatory protein-1 beta (MIP-1) beta with borderline significance (P ≤ 0.08)." Actually, the only significant effect was noted for vWF (p=0.047) for which levels seemed to drop following probiotic use. Also interesting was the finding that within the group taking the placebo (although I'm not altogether sure what this contained) there were significant pre- and post-intervention differences for compounds such as vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1); both showing reductions.

The authors note that the significant reduction in levels of vWF within the context of probiotics as an add-on treatment alongside more commonplace pharmacotherapy for schizophrenia might have some important implications for "certain cardiovascular risk parameters" for example. This statement is rooted in the idea that vWF has some research history when it comes to schizophrenia both outside [4] and inside this connection [5]. Certainly, vWF shows a link to inflammation and with mention of the words adhesion too. In the context of schizophrenia, inflammation is of growing interest...

"We conclude that probiotics have immunomodulatory effects in schizophrenia patients, affecting molecules that do not respond to standard antipsychotic therapy." If one goes by the statistical book, I'm not entirely sure that the current findings are completely in line with that last statement. Yes, vWF showed something of a 'relationship' to the probiotic use but the other results with "borderline significance" and the fact that authors "were not able to detect all targeted cytokines in [their] clinical samples", I'd be a little cautious about saying too much more.

Music: House Of Love - Destroy The Heart.

----------

[1] Tomasik J. et al. Immunomodulatory Effects of Probiotic Supplementation in Schizophrenia Patients: A Randomized, Placebo-Controlled Trial. Biomark Insights. 2015 Jun 1;10:47-54.

[2] Schwarz E. et al. Sex-specific serum biomarker patterns in adults with Asperger's syndrome. Mol Psychiatry. 2011 Dec;16(12):1213-20.

[3] Dickerson FB. et al. Effect of probiotic supplementation on schizophrenia symptoms and association with gastrointestinal functioning: a randomized, placebo-controlled trial. Prim Care Companion CNS Disord. 2014;16(1). pii: PCC.13m01579.

[4] Hope S. et al. Similar immune profile in bipolar disorder and schizophrenia: selective increase in soluble tumor necrosis factor receptor I and von Willebrand factor. Bipolar Disord. 2009 Nov;11(7):726-34.

[5] Dieset I. et al. Cardiovascular risk factors during second generation antipsychotic treatment are associated with increased C-reactive protein. Schizophr Res. 2012 Sep;140(1-3):169-74.

----------

Tomasik J, Yolken RH, Bahn S, & Dickerson FB (2015). Immunomodulatory Effects of Probiotic Supplementation in Schizophrenia Patients: A Randomized, Placebo-Controlled Trial. Biomarker insights, 10, 47-54 PMID: 26052224

Severe obesity pre-pregnancy and offspring developmental outcome

"Children whose mothers were severely obese before pregnancy had increased risk for adverse developmental outcomes."

That was the conclusion reached in the paper by Heejoo Jo and colleagues [1] based on results derived from the Infant Feeding Practices Study II (IFPS II) "a US nationally distributed longitudinal study of maternal health and infant health and feeding practices." Said data included information on "maternal prepregnancy BMI [body mass index] and child psychosocial development in 1311 mother–child pairs." Child development was measured in a number of ways including scores on the Strengths and Difficulties Questionnaire and other indications of diagnoses linked to child development.

Various results are presented including the suggestion that mothers with a prepregnancy BMI above 35 - classed as obese II and III - were potentially quite a bit more likely to have a child presenting with various "emotional symptoms" or "psychosocial difficulties" compared with those children of mothers with a more typical weight (BMI 18.5–24.9). When it came to specific developmental diagnoses, the children of obese mothers as a group were also at greater risk of receipt of a label of attention-deficit hyperactivity disorder (ADHD) and/or autism spectrum disorder (ASD) or developmental delay too. Importantly the authors note that: "Adjustment for potential causal pathway factors including pregnancy weight gain, gestational diabetes, breastfeeding duration, postpartum depression, and child’s birth weight did not substantially affect most estimates."

Without wishing to blame or stigmatise, the finding that maternal prepregnancy BMI might be a specific risk factor for offspring receipt of a diagnosis of ASD or developmental delay "(aOR [adjusted odds ratio] 3.13; 95% CI, 1.10–8.94)" is what grabbed my attention. Harking back to previous posts on this blog (see here) specifically discussing the paper by Paula Krakowiak and colleagues [2] (open-access), it is not necessarily new news that issues with maternal weight/BMI and it's association with various metabolic conditions, might place offspring at some increased risk of subsequent autism or ASD. This includes the increasingly strong evidence pointing towards gestational diabetes - an outcome associated with elevated maternal weight - as potentially increasing the risk of offspring autism (see here).

Allowing for the fact that there may be lots of interfering pregnancy variables influencing the risk of autism [3] (see here), some perhaps working synergistically, there are perhaps some important public health messages to take from the Jo paper and other peer-reviewed studies [4]. Weight loss is one modifiable option that might be considered following this body of data; although as per important recommendations: "If you are very overweight and pregnant, don't try to lose weight during your pregnancy, as this may not be safe." There is also still some debate about the best way to achieve weight loss (before pregnancy) as has been played out recently with headlines such as 'Exercise 'not key to obesity fight'' on the back of the editorial by Malhotra et al and not being able to 'outrun a bad diet'. I might add that the simple 'calories in - energy out' formula might also not be as useful as one might first think (see here).

The issue of risk factors for autism is a complicated and often emotive topic when periods such as pregnancy are thrown into the mix. I've covered lots of research on them down the years of this blog and although I've tried to handle them as sensitively as possible, there is always the risk that correlation/association might be viewed as 'blame'. Blame is certainly something that I've not intended in summarising such research and hopefully not interpreted that way by readers. Wearing the objective goggles of science, I would champion continued research on the possible mechanisms behind obesity and specific issues such as gestational diabetes when it comes to offspring outcomes, simply because they may provide important clues as to the underlying nature of at least some autism as well as other conditions [5]. I'd also suggest that when it comes to the topic of parental weight and something like offspring autism, one also might need to take into account other potentially important correlations too (see here).

Music: David Bowie - Starman.

----------

[1] H Jo. et al. Maternal Prepregnancy Body Mass Index and Child Psychosocial Development at 6 Years of Age. Pediatrics. 2015. April 27.

[2] Krakowiak P. et al. Maternal Metabolic Conditions and Risk for Autism and Other Neurodevelopmental Disorders. Pediatrics. 2012;129(5):e1121-e1128.

[3] Walker CK. et al. Preeclampsia, placental insufficiency, and autism spectrum disorder or developmental delay. JAMA Pediatr. 2015 Feb;169(2):154-62.

[4] Reynolds LC. et al. Maternal obesity and increased risk for autism and developmental delay among very preterm infants. J Perinatol. 2014 Sep;34(9):688-92.

[5] Hussen HI. et al. Maternal overweight and obesity are associated with increased risk of type 1 diabetes in offspring of parents without diabetes regardless of ethnicity. Diabetologia, April 2015.

----------

Jo, H., Schieve, L., Sharma, A., Hinkle, S., Li, R., & Lind, J. (2015). Maternal Prepregnancy Body Mass Index and Child Psychosocial Development at 6 Years of Age PEDIATRICS, 135 (5) DOI: 10.1542/peds.2014-3058

Maternal recall vs. medical records: implications for autism research

I don't want to dwell too much on the findings reported by Paula Krakowiak and colleagues [1] talking about the accuracy of "maternally-reported diabetes and hypertensive disorders, and reliability of BMI [body mass index] measurements during periconception and pregnancy compared with medical records when mothers are interviewed 2-5 years after delivery" but they are potentially important.

With authors such as Krakowiak and Irva Hertz-Picciotto on the paper in question, those who follow the autism research scene might have already made the connection back to the CHARGE (CHildhood Autism Risks from Genetics and the Environment) study (beincharge!) as the source of the current data. Indeed from CHARGE, findings such as a link between maternal obesity and offspring autism risk (see here) and maternal diabetes and autism (see here) have been previously discussed on this blog. For the most part, examination of such factors linked to subsequent offspring autism diagnosis has been through self-report and post-event questioning which potentially opens up such studies to various forms of bias.

The results from Krakowiak et al seemed to suggest when questioned about such issues: "self-reported diabetes and hypertensive disorders during periconception and pregnancy show high validity among mothers." Further: "Recall of pre-pregnancy BMI is reliable compared with self-reported values in medical records." In other words, still with some caution, families involved in initiatives such as CHARGE can and do quite accurately communicate their medical history. Of course this is not the first time that science has shown parentally-derived medical information to be pretty accurate when it comes to autism as per the Gorrindo findings [2]: "sensitive to the existence, although not necessarily the nature of" gastrointestinal issues related to autism (see here). That being said, developmental history recall is still subject to some forms of bias (see here).

There's little more for me to say about this topic aside from highlighting how: "Multiparity was associated with higher discrepancies in BMI and misreporting of hypertensive disorders" suggestive that 'the state of having borne a number of children' might interfere with recall in these areas. Still, when it comes to asking parents about their health and wellbeing before, during and after the birth of their children with autism research in mind and without over-generalising, one might be a little less critical of the value of the information received.

Music to close: The Flaming Lips and Race For The Prize. Scientists... don't race for the prize!

----------

[1] Krakowiak P. et al. Maternal Recall Versus Medical Records of Metabolic Conditions from the Prenatal Period: A Validation Study. Matern Child Health J. 2015 Feb 6.

[2] Gorrindo P. et al. Gastrointestinal dysfunction in autism: parental report, clinical evaluation, and associated factors. Autism Res. 2012 Apr;5(2):101-8.

----------

Krakowiak P, Walker CK, Tancredi DJ, & Hertz-Picciotto I (2015). Maternal Recall Versus Medical Records of Metabolic Conditions from the Prenatal Period: A Validation Study. Maternal and child health journal PMID: 25656730

Features of autism in childhood epilepsy

"In conclusion, features of ASD [autism spectrum disorder] were common in children with epilepsy regardless of cognitive ability."

Whoa, whoa, whoa! Sorry, Blondie. I don't do backstory

So said Colin Reily and colleagues [1] in their paper examining facets of autism in cases of childhood epilepsy. Suggesting also that the Autism Spectrum Screening Questionnaire (ASSQ) might be "a useful screening instrument in this population, and combining parent and teacher forms was optimal in terms of screening properties", this work adds to other research voices suggesting a possible connection between autism/autistic traits and adult epilepsy too (see here).

I don't want to over-analyse the Reilly results beyond what they found and importantly, their limitations (as in the emphasis on 'features of autism' over and above an actual diagnosis of autism). One might see this research as further evidence of the intimate link between autism and epilepsy / seizure-type disorder(s) potentially intersecting with other issues such as sleep for example [2]. That also various other areas of biological functioning might also be related [3] makes for a potentially interesting future research agenda. Oh and then there is a possible connection with ADHD (attention-deficit hyperactivity disorder) to consider [4] too.

One of the other important issues potentially implied from the Reilly results is whether the possibility of an overlap between autistic traits and epilepsy might also have repercussions in relation to intervention and management. I say this on the basis for example, of the case report (stress: case report) recently described by Philip Bird [5] on the use of low-dose phenytoin - an anticonvulsant medicine - with a man diagnosed with ASD and the implications for various facets of functioning. Appreciating that certain anti-epileptic medications seem to have a rather less positive relationship with autism (see here), it strikes me that there may be more to see and do in this area for certain people...

Music then. I Am The Walrus. Not literally, but The Beatles song.

----------

[1] Reilly C. et al. Features of autism spectrum disorder (ASD) in childhood epilepsy: A population-based study. Epilepsy Behav. 2014 Dec 16;42C:86-92.

[2] Accardo JA. & Malow BA. Sleep, epilepsy, and autism. Epilepsy Behav. 2014 Dec 9. pii: S1525-5050(14)00533-2.

[3] Frye RE. Metabolic and mitochondrial disorders associated with epilepsy in children with autism spectrum disorder. Epilepsy Behav. 2014 Nov 4. pii: S1525-5050(14)00412-0.

[4] Ettinger AB. et al. Attention-deficit/hyperactivity disorder symptoms in adults with self-reported epilepsy: Results from a national epidemiologic survey of epilepsy. Epilepsia. 2015. 15 Jan.

[5] Bird P. The treatment of autism with low-dose phenytoin: a case report. Journal of Medical Case Reports 2015, 9:8

----------

Reilly C, Atkinson P, Das KB, Chin RF, Aylett SE, Burch V, Gillberg C, Scott RC, & Neville BG (2014). Features of autism spectrum disorder (ASD) in childhood epilepsy: A population-based study. Epilepsy & behavior : E&B, 42C, 86-92 PMID: 25529303

Screening for metabolic conditions in autism

I start with a question. It is not a question meant to offend anyone or provide a platform for extolling a particular view, merely a question that people probably come across quite regularly in relation to autism spectrum conditions.

What causes autism?

Your answer to this question will probably depend on lots of different factors: your relationship to autism, your interest in autism, your personal experiences of autism, your scientific/political/religious points of view and persuasions.

Some people might argue that this is not a question that needs answering and that autism, or at least a segment of the autism spectrum, is just neurodiversity. Other people might argue that autism, or again at least specific phenotypes of autism, is either genetically-controlled, a product of environment or lies somewhere in-between these concepts. Other people just sit on the fence.

I've thought long and hard about this question and the various answers given to it down the years. Those answers have really shaped the history of autism, from the dark times of the blame-game, to the hopefully more enlightened times we live in now. Whilst accepting that autism is in fact autisms, a heterogeneous group of conditions/perspectives/ways of thinking which span ability ranges from significant 'disability' to significant ability alongside the adage 'correlation does not imply causation', I am inclined to say that in some selected cases, science might be beginning to have some pretty good clues about how autism might come about. In much the same way that other behavioural, developmental conditions have been subject to such questioning, I reckon the evidence for causation in autism is probably on a par with things like ADHD.

Consider a few lines of inquiry (appreciating that this list may not be exhaustive).

First, the various research on Fragile X syndrome (which manifests autistic behaviours in some cases). Some might say Fragile X syndrome is not autism but rather autistic behaviours. Others might say, so what; autistic behaviours are autism - or at least autism spectrum. I note on the National Fragile X Foundation website, they use the word 'cause' to describe the relationship.

Second the growing evidence on things like the immune system, mitochondrial dysfunction, brain chemistry and architecture seen in some cases of autism: causative or coincidental?

Third are the various 'associations' between autism and environmental factors including that linking viral infections such as rubella and encephalitis. I did cover possible post-malarial autism in this post a while back. Whether there is any connection to other organisms (viral or bacterial) as there might be in some cases of schizophrenia remains unanswered.

Fourth, although taking a hit these past few weeks, the various genetic findings linked to cases of autism. You see them quite regularly in the scientific literature; this gene or that gene manifesting as autistic behaviours (we think).

Finally we have evidence from the various in-born errors of metabolism which forms the basis for this post.

I linked to a connection between PKU and autism when it came to listing inborn errors of metabolism simply because PKU is the archetypal metabolic condition and seems to show more than a passing relationship with autism. I suppose given the reports of dietary factors being also potentially linked to some cases of autism, it is perhaps all the more useful to list PKU as an example. When it comes to screening for inborn errors of metabolism, many parts of the world are actually getting quite good at this. Thanks to Robert Guthrie, who lent his name to the newborn heel prick test, several potentially life-changing conditions are screened for shortly after birth using the dried blood spot method. Importantly for some of these conditions, there are changes that can be made to off-set some of their effects on health and wellbeing.

My interest in metabolic conditions in relation to autism has been piqued recently following the publication of a couple of articles on the subject. This article by Schiff and colleagues reviewed a couple of hundred children with autism who passed through a French centre. They reviewed a variety of test results carried out including testing for disordered purine metabolism which has been discussed previously on this blog, and concluded that aside from 2 patients, there was no autism-specific relationship between indications of metabolic disorders and their cohort. At least one of their cohort who presented with abnormal results, one patient with elevated urinary creatine excretion, is interesting. Interesting because this is not the first time this has been reported either in the scientific literature or via a personal account.

A second article published in 2010 by Wang and colleagues suggested similar things with regards to there being no overall significant difference in the rates of creatine deficiency syndrome in autism vs. controls. That being said the authors did note elevated mean levels of urinary creatine in children with autism and their siblings as a result of several individuals in these groups showing elevated creatine levels. Importantly despite their 'negative' results, the authors do not rule out routine screening for such issues in autism.

There are various other 'associations' dotted around the autism research landscape. Glucose-6-phosphate dehydrogenase (G6PD) deficiency, L-2-hydroxyglutaric aciduria, and disorder of the urea cycle have all been mentioned. Autism and Smith-Lemli-Opitz syndrome is the topic of a blog post scheduled for the not-too-distant future on cholesterol and autism. Such conditions give us some interesting clues into the nature of autism (i.e. not necessarily 'caused' by only one factor) but also providing some interesting possibilities for management and intervention.

So back to the question of what causes autism, do we perhaps know more than we think?