"Maternal diabetes, especially GDM, is probably a risk factor for ADHD"

It's coincidental that as I write this post about the findings reported by Lifeng Zhao and colleagues [1] talking about how "Maternal diabetes, especially GDM [gestational diabetes mellitus], is probably a risk factor for ADHD [attention-deficit hyperactivity disorder]" so the BBC news website highlights how screening for gestational diabetes here in Blighty is still a bit of a hit-and-miss affair (see here).

That news report mentions how about a quarter of those mums-to-be who are most at risk of developing pregnancy diabetes - "having a high BMI [body mass index] or being of South Asian or Black Caribbean ethnicity" - did not get screened at all. Left untreated, gestational or pregnancy diabetes can increase the risk of various adverse events including "a baby that grows larger than usual, leading to problems in labour; premature birth; pre-eclampsia and stillbirth."

The Zhao findings - a meta-analysis - continue a theme suggesting that exposure to maternal diabetes, including pregnancy diabetes, seems to increase the risk of various other developmental and behavioural diagnoses also being present in offspring. The primary source material of this blog - autism - has been talked about on various occasions as being one of those developmental/behavioural diagnoses (see here and see here). That ADHD is quite often mentioned in the diagnostic mix when it comes to autism (see here) is another point to make.

The basics of the Zhao paper: a search of the peer-reviewed science literature was undertaken revealing nine studies that fitted the inclusion criteria including "7,218,903 participants." The quality of most studies was ranked as high. The results were interesting in that researchers "did not find significant association between maternal diabetes and ADHD risk (OR: 1.20, 95% CI: 0.96–1.49)." This observation is slightly at odds with the quote titling this post, which Zhao et al put down to the "high heterogeneity" detected among the included studies and their subgroup analysis of case-control studies (n=3).

Also... when it came to looking at another type of study - a cohort study (n=6) - "the meta-analysis demonstrated that maternal diabetes increased the risk of ADHD in offspring by 40%." Further, and bearing in mind the description 'diabetes' covers quite a bit of diagnostic ground, authors zoomed in on one particular 'type of diabetes', that called gestational diabetes (GDM) and looked at any effect. This is where things got a little more interesting as their results, based on four studies, indicated that "GDM exposure increased the risk of ADHD for children by 164%" in Caucasian children. Ergo, although a little mixed, the existing research literature at the time of analysis indicated that maternal diabetes during pregnancy, particularly GDM, *might* have some important effect on risk of offspring ADHD.

I'm not going to say much more at this point in time in terms of potential mechanisms that *might* elevate the risk of ADHD in offspring exposed to pregnancy diabetes. It's likely to be pretty complicated. Given also that GDM appears more often than not alongside other conditions (see here), it's not going to be easy to tease apart what might be the more important issues. Is it inflammation? Is something to do with blood sugar or insulin? At the moment, we just don't know enough...

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[1] Zhao L. et al. The association of maternal diabetes with attention deficit and hyperactivity disorder in offspring: a meta-analysis. Neuropsychiatr Dis Treat. 2019;15:675–684.
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Nicotine exposure and offspring ADHD (yet again)

The study findings reported by Andre Sourander and colleagues [1] talking about "an association with and a dose-response relationship between nicotine exposure during pregnancy and offspring ADHD [attention-deficit hyperactivity disorder]" continue an important research theme (see here and see here).

What was different about the Sourander results compared with some of the other studies in this area was their focus on the measurement of cotinine levels - cotinine being a biomarker for exposure to tobacco smoke - in mums-to-be as "measured by using quantitative immunoassays from maternal serum specimens collected during the first and second trimesters of pregnancy and archived in the national biobank." Indeed, such a biological marker measurement protocol mimics other research from members of this authorship group when looking at maternal nicotine exposure and offspring risk of schizophrenia for example (see here).

Based on the analyses of samples from over a thousand participants born in the late 1990s and diagnosed with ADHD compared with samples from a similar number of non-ADHD control participants, researchers came to their possible *link* observation. They mention how the relationship between maternal cotinine levels and offspring ADHD diagnosis was statistically significant even when other important, potentially confounding, variables were taken into account. When categorising their maternal cotinine results into bands approximating light to heavy nicotine exposure and the possibility of a link with offspring ADHD diagnosis, researchers also reported something that looked like a dose-response relationship. Ergo, a biomarker of nicotine exposure during pregnancy *looked* to be potentially linked to offspring risk of ADHD.

Although important work, my first thought when reading this research was about how these results are 'set' within the context that historically, smoking rates or tobacco exposure rates during pregnancy were so much larger decades ago than they are now (see here), but ADHD is seemingly showing only quite a recent rise in numbers (see here). Although no expert on pregnancy tobacco consumption during the 20th century, I'm assuming that all those adverts about smoking being 'healthy' in the 1940s and beyond (see here) probably meant that quite a few women smoked during their pregnancy in the belief that it was 'healthy'. At the very least, it probably meant that they were exposed to a lot more second-hand tobacco smoke as a result of smoking being allowed in various public places and also more likely to be observed in the home environment. Surely then we would have seen an explosion of ADHD diagnoses at that point in time if the link was so simple? That is, assuming that the tobacco of today is the same as the tobacco of yesteryear.

I'm also intrigued that within the various potentially confounding variables which Sourander and colleagues adjusted for - "maternal socioeconomic status, maternal age, maternal psychopathology, paternal age, paternal psychopathology, and child’s birth weight for gestational age" - there's another variable that could exert an effect on ADHD risk: relative age (see here and see here). Relative age refers to the observation that the youngest children in the school classroom compared to their older classmates, are more likely to be diagnosed with ADHD. It strikes me that alongside something like tobacco or nicotine exposure, so age and other effects could be important.

I'm not trying to poo-poo the link that Sourander and various other research teams have independently observed. I'm also not trying to downplay the harms that tobacco (nicotine) exposure can have for the unborn child. I merely suggest that with typically falling rates of (reported) tobacco exposure during pregnancy in many countries (see here) and increasing levels of childhood (and adulthood) ADHD being reported, there must be other factors at work in any such relationship (see here for example).

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[1] Sourander A. et al. Prenatal Cotinine Levels and ADHD Among Offspring. Pediatrics. 2019. Feb 25.

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Maternal prenatal acetaminophen use and the risk of ADHD in offspring (again)

By discussing the findings - meta-analysis findings - published by Xiaoyun Gou and colleagues [1] I once again approach the topic of whether some medicines use during pregnancy might have some important implications for offspring development. And yet again we're talking about the use of acetaminophen a.k.a paracetamol, during pregnancy and how it *might* have some important implications when it comes to offspring development (see here and see here and see here for other blogging examples on this subject).

The Gou study focused on the risk of an offspring diagnosis of attention-deficit hyperactivity disorder (ADHD) following maternal exposure to paracetamol during pregnancy. And whether timing of said exposure and/or duration of exposure showed any *association* to risk of offspring ADHD.

As per the opening sentence to this post, the Gou study was a meta-analysis, meaning that it was a synthesis of the available peer-reviewed research literature. Indeed, authors identified 8 studies published up to November 2018 that included data on nearly a quarter of a million participants in total.

Given the quite consistent consensus already seen in the science on this topic (see here for example) it's probably not unexpected that that authors concluded that: "Maternal exposure to acetaminophen during pregnancy increased the risk of attention deficit/hyperactivity disorder in offspring with a pooled adjusted risk ratio of 1.25." Further: "Children exposed prenatally to acetaminophen in the third trimester seemed to have the greatest risk of developing attention deficit/hyperactivity disorder" and "a longer duration of maternal acetaminophen use during pregnancy was correlated with a higher risk ratio."

Of course such findings, even such meta-analysis findings, come with cautions about correlation not necessarily being the same as causation given the observational nature of the studies included for review. There are also a myriad of other potential factors that seemingly impact on offspring risk for ADHD (see here and see here for some other possible examples) which perhaps require consideration at the same time.

But... this is a topic that requires a lot more investigation. Investigations into whether (a) the association is indeed a real one and not just epiphenomenal, (b) the reasons leading to paracetamol use during pregnancy which may also exert an effect on offspring risk, and (c) which biological mechanisms may be pertinent to any connection (see here and see here), are all indicated. As for where medical opinion stands on this topic at the moment, well, minus any medical or clinical advice from me, I go with the research literature on this topic [2] and would suggest that if you're in doubt, talk to your medical professional...

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[1] Gou X. et al. Association of maternal prenatal acetaminophen use with the risk of attention deficit/hyperactivity disorder in offspring: A meta-analysis. Aust N Z J Psychiatry. 2019 Jan 17:4867418823276.

[2] Andrade C. et al. Use of acetaminophen (paracetamol) during pregnancy and the risk of attention-deficit/hyperactivity disorder in the offspring. J Clin Psychiatry. 2016 Mar;77(3):e312-4.

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Hyperemesis gravidarum exposure as a risk factor for autism?

Hyperemesis gravidarum mentioned in the title of this post refers to "prolonged and severe nausea and vomiting" during pregnancy alongside other symptoms. It's thought to affect only a relatively small percentage of pregnant women despite vomiting and nausea being pretty common throughout many pregnancies. Indeed, hyperemesis gravidarum (HG) is much more than just nausea and vomiting.

The findings reported by Marlena Fejzo and colleagues [1] looked at the "neurodevelopmental outcomes of 267 children delivered by 177 mothers with HG were compared to neurodevelopmental outcomes from 93 children delivered by 60 unaffected mothers." The study was undertaken on the basis that previous published research from this study group [2] had identified "neurodevelopmental delay" as a possible *correlate* tied to HG exposure during pregnancy. That being said, on that last occasion researchers also described finding "no evidence for increased risk of 13 emotional, behavioral, and learning disorders, including autism, intellectual impairment, and obsessive-compulsive disorder" in their cohort.

This time around: "Similar to at age 8, the children (now 12) exposed in utero to HG had over 3-fold increase in odds of neurodevelopmental disorders including attention, anxiety, sensory, sleep difficulty, and social development delay/social anxiety." With a longer follow-up period, researchers also reversed their 'no evidence for increased risk' sentiments with regards to a diagnosis of autism in their cohort. So: "there was also a significant increase in Autism Spectrum Disorder (ASD), reported in 22/267 (8%) of children exposed to HG in utero and no unexposed children."

Let me be clear on this: these latest results on their own don't necessarily mean that HG *causes* offspring autism. Although 8% of the HG exposed group reporting autism or ASD seems quite high, it has to be seen in light of an increasing (estimated) prevalence of autism more generally (see here and see here). I'd also suggest that as with many other pregnancy/gestational factors put forward as potentially influencing offspring autism risk, one needs to be mindful of the issues involved in teasing out which is the important variable from potentially many (see here and see here).

But... further investigation is indicated in this area. Indeed, I hark back to the findings reported by Andrew Whitehouse and colleagues [3] who observed a "strong, positive association between increasing frequency and severity of NVP [nausea and vomiting during pregnancy] and ASD severity in offspring." No, not necessarily HG, but an implication that some of the overt features of HG might hold some *connection* to offspring autism risk for whatever reasons...

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[1] Fejzo M. et al. Analysis of neurodevelopmental delay in children exposed in utero to hyperemesis gravidarum reveals increased reporting of autism spectrum disorder. Reprod Toxicol. 2018 Dec 27. pii: S0890-6238(18)30558-6.

[2] Fejzo MS. et al. Neurodevelopmental delay in children exposed in utero to hyperemesis gravidarum. Eur J Obstet Gynecol Reprod Biol. 2015 Jun;189:79-84.

[3] Whitehouse AJO. et al. Symptom severity in autism spectrum disorder is related to the frequency and severity of nausea and vomiting during pregnancy: a retrospective case-control study. Mol Autism. 2018 Jun 19;9:37.

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

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

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

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

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

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

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

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

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Prevalence of autism in preterm infants meta-analysed

"The prevalence of ASD [autism spectrum disorder] is significantly high in the preterm population. Adequate resources are needed to improve the outcomes of these children."

So said the findings reported by Sachin Agrawal and colleagues [1] who present the results of yet another meta-analysis with autism in mind; yet again on a topic that has filled quite a few peer-reviewed science column inches (see here and see here for examples).

'Preterm' typically refers to babies who are born alive but before completing the usual 37 weeks of gestation. It is further sub-categorised into extremely (less than 28 weeks), very (born between 28 and 32 weeks gestation) and moderate-to-late (born between 32 and 37 weeks gestation) preterm. The risk of a wide variety of 'adverse' outcomes seems to be significantly heightened following preterm birth, covering both physical (somatic) and psychological/developmental domains. Outside of the very final outcome that is early mortality, longer-term issues, particularly associated with brain development occurring outside of the womb, have been a feature of several results. Autism has also been mentioned in this context (see here).

Agrawal et al set about analysing the data pertinent to autism risk and preterm birth. They talk about the scenario of a 'perfect storm' whereby "whatever initiates the preterm birth process might also initiate abnormal pathways of brain development" as being potentially pertinent to autism. Covering the research literature up to May 2017, some 18 studies including over 3300 preterm infants were included for analysis. They specifically included studies that utilised known diagnostic tests for autism or ASD (ADOS, ADI, DAWBA) rather than those that used only "ASD screening tools" and looked up the cumulative prevalence rate for autism.

Results: 7%. That was the overall autism prevalence rate among preterm infants included in the various studies analysed. There was quite a bit of variation across the studies and the prevalence figure fluctuated to some degree as and when children with disabilities were included or not, but the 7% figure seemed to be an accurate one. Authors also put the 7% figure into some 'real world' perspective too: "This equates to ∼900 000 additional children each year who will develop ASD given that globally ∼15 million infants are born preterm (before 37 weeks’ gestation), of whom 13 million survive." Kinda takes your breath away doesn't it?

A couple of other important details are worthwhile mentioning too. So: "Our meta-regression analysis revealed no significant association between gestational age, birth weight, and prevalence of ASD in preterm infants." This doesn't totally rule out such factors as exerting an effect, but...

What else to say? Well preferential screening for autism or ASD in cases of preterm birth could be indicated. The allocation of further research resources into how and why preterm birth occurs could also be useful, focusing on how and why the infant brain seems to be so sensitive to maturation outside of mum's body. And then in relation to all those 'we don't know what causes autism' sentiments that continue to be expressed, well, add prematurity to the growing list of strong possibilities (see here and see here for other examples).

Oh and minus any medical or clinical advice being given or intended, it appears that nutrition, particularly omega-3 fatty acid levels, *might* play 'some' role in some preterm births [2] with some intriguing possibilities for supplementation (minus sweeping generalisations)...

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[1] Agrawal S. et al. Prevalence of Autism Spectrum Disorder in Preterm Infants: A Meta-analysis. Pediatrics. 2018 Aug 3. pii: e20180134.

[2] Olsen SF. et al. Plasma Concentrations of Long Chain N-3 Fatty Acids in Early and Mid-Pregnancy and Risk of Early Preterm Birth. EBioMedicine. 2018 Aug 2. pii: S2352-3964(18)30252-4.

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"DNA methylation data from neonatal blood spots can be used to accurately predict age and maternal smoking status"

There were two primary reasons why I wanted to blog about the findings reported by Eilis Hannon and colleagues [1]: first, the focus of the study was "to identify DNA methylation biomarkers of ASD [autism spectrum disorder] detectable at birth", and second, the authors actually "identified robust epigenetic signatures of gestational age and prenatal tobacco exposure, confirming the utility of DNA methylation data generated from neonatal blood spots."

The first reason, looking at DNA methylation biomarkers in relation to autism, follows other similar initiatives down the years (see here for example) on the back of some significant interest in how "epigenetic variation induced by non-genetic exposures" might complement/fill in some gaps left by more traditional genetic studies. Epigenetics by the way, seemingly means different things to different people, but is currently summarised as "the study of heritable changes in gene function that do not involve changes in the DNA sequence." DNA methylation reflects one epigenetic process (there are others). The second reason - robust epigenetic signatures linked to gestational age and prenatal tobacco exposure - actually turned out to be the more important finding, or at least the more significant finding, reported by Hannon et al hence the title of this post...

'Guthrie cards' are mentioned as the starting material for the Hannon paper, and yet another hat-tip to a true medical pioneer, Robert Guthrie (and his team), who has saved multitudes of lives with his cards used to collect and store neonatal blood spots. As well as being used to screen for various potential inborn errors of metabolism (some of which seem to have something of a relationship with some autism), those archived blood spot cards have also proved to be important research fodder too (see here).

Hannon garnered neonatal methylomic data for approaching 1300 individual - "comprising equal numbers of ASD cases and matched controls, 50% male/female" - derived from "the iPSYCH case–control sample" based in Denmark. We are told that: "DNA methylation was quantified across the genome using the Infinium HumanMethylation450k array" bearing in mind this technique/system "only assays ~ 3% of CpG sites in the genome." Alongside: "Matched genome-wide single nucleotide polymorphism (SNP) genotyping data from the same individuals enabled us to undertake an integrated genetic–epigenetic analysis of ASD, exploring the extent to which neonatal methylomic variation at birth is associated with elevated polygenic burden for ASD."

Results: with regards to a neonatal methylomic 'signature' for autism or ASD, nothing significant was detected. Obviously one has to bear in mind the limitations of the assay/method used and the fact that blood from bloodspots represents only one type of tissue (DNA methylation patterns are not necessarily the same across different tissues). I was also interested to see the authors talk about "the chronology of sample collection prior to ASD diagnosis" and the 'plausability' that they were "looking too early on in the disease process." No, autism isn't 'a disease', but this work might provide some support for the idea that the processes and onset of autism is not always set either during conception nor during gestation (see here). Dangerous thinking for some people of a sweeping generalisation ilk...

Having said all that, researchers did talk about a "significant association between increased polygenic burden for autism and methylomic variation at specific loci" but I'd like to see replication of this effect before any big claims are made.

Then to those other findings of "robust epigenetic signatures of gestational age and prenatal tobacco exposure" and what that could mean to several different areas of research, autism and beyond. I'm a little surprised that the authors didn't make more of their 'robust findings' in their discussion of these results. I appreciate that their primary aim to "identify DNA methylation biomarkers of ASD detectable at birth" was not met with startling success but the suggestion of a tell-tale epigenetic sign of exposure to maternal smoking during pregnancy for example is, I would have thought, an important advance. Certainly one that could be at least relevant to various other studies, including those related to an important comorbidity that seems to be 'over-represented' in relation to some autism (see here) and perhaps more.

To close, it's not the first time that the Star Wars universe has been subject to peer-reviewed 'science' but the paper by Hatters Friedman and colleagues is an interesting one...

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[1] Hannon E. et al. Elevated polygenic burden for autism is associated with differential DNA methylation at birth. Genome Med. 2018 Mar 28;10(1):19.

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ALSPAC does... prenatal mercury exposure and autism or autistic traits

The ALSPAC - Avon Longitudinal Study of Parents and Children - mentioned in the title of this post is something of quite a regular feature on this blog (see here and see here for examples).

On this particular blogging occasion I'm heading into the findings reported by Jean Golding and colleagues [1] who utilised this fabulous research resource to examine whether "prenatal exposure from total maternal blood Hg [mercury] in the first half of pregnancy is associated with the risk of autism or of extreme levels of autistic traits." They concluded that there were "no adverse effect of prenatal total blood Hg on autism or autistic traits provided the mother ate fish."

OK, mention of the heavy metal mercury in the context of autism and/or autistic traits can be a touchy subject for some. I'm talking about the various 'discussions' that have taken place both in the lay and peer-reviewed science arenas concerned with the exposure patterns relevant to mercury in the context of autism (see here and see here). This, on the basis that mercury exists in several 'forms', and those different forms have different potential exposure routes.

Golding et al relied on some of the gold-standard analytical methods for the analysis of whole blood Hg collected in the most part "at < 18 weeks gestation": "inductively coupled plasma dynamic reaction cell mass spectrometry (ICP-DRC-MS)." Variations on this method - ICP mass spectrometry - have been previously reported on in the context of mercury and autism research (see here and see here). Alongside, they looked at measured levels of mercury in relation to various behavioural and other variable groupings: "(1) direct comparison of 45 pregnancies resulting in children with diagnosed autism from a population of 3840, (2) comparison of high scores on each of the four autistic traits within the population at risk (n~2800), and (3) indirect measures of association of these outcomes with proxies for increased Hg levels such as frequency of fish consumption and exposure to dental amalgam (n > 8000)." They however cautioned that: "Although we accounted for several important confounders which are relevant to Hg levels and autism, the possibility of unmeasured confounding cannot be ruled out." I can think of one potential confounder that was not seemingly included in their list outside of fish consumption and dental amalgams but ho-hum...

Alongside their overall 'no relationship' results, a few other details are noteworthy. First: "all correlations indicated that with increasing levels of [maternal] mercury, the signs of autism [in offspring] were slightly less, but none were statistically significant." Interesting idea - higher maternal levels of mercury during pregnancy 'correlates' with 'less' autistic traits in offspring in childhood - but to reiterate, not statistically significant. Second was that 'provided the mother ate fish' detail attached to the main findings. So: "we have shown a differential relationship between the social cognition trait and prenatal Hg exposure, such that there was a significant difference in apparently protective effects contingent upon whether the mother ate fish." The authors opine as to what it is about fish consumption that might "counteract any possible adverse cognitive and behavioral differences that may be caused by prenatal exposure to Hg" including "the beneficial components of fish such as the omega-3 fatty acids, iodine, and vitamins D and B2." This in the context that omega-3 fatty acids have some research form in relation to autism (see here) as does the sunshine vitamin/hormone that is vitamin D (see here).

One has to be slightly careful with the Golding results given the focus on prenatal exposure, and prenatal exposure at only one early point in pregnancy, as well as also not actually looking at mercury levels in the children themselves. The current results say nothing for example, about any possible direct or acquired role for mercury in relation to autism as per other findings published during the same period [2]. Neither do they offer any additional information on the idea that exposure issues to such heavy metals may be only one part of the story, and that the biological processes involved in removing such heavy metals may be somehow perturbed in relation to some autism (see here).

But... set within the idea that prenatal mercury exposure may be linked to the 'etiology' of at least some autism, the Golding findings represent pretty strong evidence suggestive of no connection.

Music to close, and could I recommend the soundtrack to Sonic 3 while you work?

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[1] Golding J. et al. Prenatal mercury exposure and features of autism: a prospective population study. Molecular Autism. 2018; 9: 30.

[2] Qin YY. et al. A comparison of blood metal levels in autism spectrum disorder and unaffected children in Shenzhen of China and factors involved in bioaccumulation of metals. Environ Sci Pollut Res Int. 2018 Apr 22.

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Low gestational age is associated with risk for autism

The results published by Robert Joseph and colleagues [1] provide some blogging fodder today, observing that as part of the ELGAN (Extremely Low Gestational Age Newborns) Research Study, gestational age might matter when it comes to offspring risk of autism spectrum disorder (ASD).

Gestational age is a measure of how far along a pregnancy is but in the context of the Joseph study refers to premature birth or those "born at least 3 months early." Researchers included data for nearly 1000 children born extremely premature using a prospective (rather than retrospective) methodology who, at age 10, were "evaluated for ASD and ID [intellectual disability]." They also took into account various other 'pregnancy information' derived from both medical records and interviews with mums. This included instances of cervical-vaginal ‘infection’ among other things.

The results: over 90% of their cohort were assessed for autism/ASD and ID. Rates of ASD alone (without ID) were 3.2%. Some 3.8% of participants screened positive for autism and ID and 8.5% of participants presented with ID but not autism. Whilst these autism (with or without ID) rates might seem high, I'm not actually convinced that they are 'significantly higher' than that suggested in modern times (see here). The authors also noted that: "The lowest gestational age category (23-24 weeks) was associated with increased risk of ASD+/ID+... and ASD+/ID-."

Also: "Maternal report of presumed cervical-vaginal ‘infection’ during pregnancy was associated with increased risk of ASD+/ID+." The sorts of things included under the heading of cervical-vaginal infection were "bacterial infection (n = 4), bacterial vaginosis (n = 30), yeast infection (n = 62), mixed infection (n = 4) or other/unspecified infection (n=43; e.g., chlamydia, trichomonas or herpes, etc.)."

I agree with the authors that "low gestational age is associated with increased risk for ASD" and this research does seem to tally with other studies on this topic (see here for example). The one caveat I do want to make however is that the absolute numbers of children diagnosed with autism (with or without ID) were quite low (27 and 32 children respectively out of a total of 840) and somewhat dwarfed in comparison to those presenting with ID without autism (71 children out of 840). Still, preferential screening for autism and ID might be implied from these results; assuming that is, that the screening instrument in question is up to the job [2].

As to potential mechanisms of effect... well, it's rather difficult to pin any 'excess autism risk' to any one mechanism in light of the various factors that can accompany prematurity. Aside from the immaturity of various biological system associated with premature birth (including the brain), the obvious effect of a reduced birth weight is something to consider (see here). I am also interested in the idea that infection (using the term quite broadly) during pregnancy might also impact on offspring autism risk in light of other data (see here). Specific pathogens during pregnancy affecting offspring developmental risks have already made a mark on the peer-reviewed research literature (see here for example) and could provide a template for the processes pertinent to infection plus prematurity too.

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[1] Joseph RM. et al. Extremely low gestational age and very low birth weight for gestational age are risk factors for ASD in a large cohort study of 10-year-old children born at 23-27 weeks gestation.  American Journal of Obstetrics and Gynecology. 2016. Aug 13.

[2] Kim SH. et al. Predictive Validity of the Modified Checklist for Autism in Toddlers (M-CHAT) Born Very Preterm. J Pediatr. 2016 Nov;178:101-107.e2.

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Joseph, R., Korzeniewski, S., Allred, E., O’Shea, T., Heeren, T., Frazier, J., Ware, J., Hirtz, D., Leviton, A., & Kuban, K. (2016). Extremely low gestational age and very low birth weight for gestational age are risk factors for ASD in a large cohort study of 10-year-old children born at 23-27 weeks gestation American Journal of Obstetrics and Gynecology DOI: 10.1016/j.ajog.2016.11.1009

Pregnancy hypertension and offspring autism

"Hypertension in pregnancy was associated with ASD [autism spectrum disorder] in this population even after controlling for known confounders."

So said the findings reported by Eileen Curran and colleagues [1] who, once again (see here), relied on "data from the Millennium Cohort Study" to produce some potentially important information about how adverse pregnancy conditions may/may not impact on offspring behaviour and development.

Hypertension (a.k.a high blood pressure) during pregnancy is something to watch out for given the association with another condition: pre-eclampsia; something else that has been linked with various outcomes to offspring including autism as one possibility (see here). I might also point out that the evidence looking at pre-eclampsia and offspring autism risk is not however exactly all one-way traffic [2].

OK one needs to be a little careful with the Curran findings given that: "Mothers were asked if they experienced any illnesses during pregnancy for which they needed medical attention" where hypertension in pregnancy - "HIP" -  was one of the options. This alongside the fact that "ASD was parent-reported based on a diagnosis by a doctor or health care professional." It's not that science should disbelieve parental report (indeed, quite the contrary) but rather that when it comes to medical diagnoses such as HIP, access to medical records where facts are recorded rather than retrospectively recalled is always going to be more authoritative.

Anyhow, from the 13,000+ people who "responded to the question on health during pregnancy and ASD" researchers reported that there did seem to be something more to see when it came to the connection between HIP and autism. Such a relationship held over various different statistical models (adjusted - unadjusted, maternal age, etc.) Given also the effect of HIP on placental functions in particular, the authors suggest that their results "raises the possibility of using clinical data regarding the clinical course of pregnancy and the molecular characteristics of the placenta at birth to predict a child risk of future ASD." Big words, I'm sure you'll agree.

So, here we are again talking about 'the maternal body as environment' with autism in mind (see here). Here we are again talking about 'risk factors' for autism and particularly those linked into the nine months that made us. I know from some comments about some of my previous posts (this one for example) there is a degree of 'so what?' when it comes to this type of research and indeed, subtle shades of brow furrowing that such work is seemingly being done at all. I agree that autism research needs to broaden it's horizons quite a bit to focus more on what matters to people on the autism spectrum but I also see the value in this type of approach focused on pregnancy and even before. I say this on the basis that clues to some of the underlying biology of at least some autism may one day be gleaned from such data (indeed, some might argue it already has) and could potentially (somehow) translate into interventions supporting more traditional ones. Obviously one also needs to also bear in mind that not all autism is necessarily 'programmed' during pregnancy or before (see here).

Finally, the question of how HIP or other related pregnancy factors might impact on offspring behaviour and development still needs answering. Yes, there is the concept of 'inflammation' creeping into this question [3], made all the more plausible by the fact that mothers body has to alter during pregnancy to accommodate that foreign body known as a foetus together with its placenta. Combined with the already known about idea that HIP can seemingly impact on the flow of nutrients through the placenta (made all the more convincing as a consequence of findings linking the inter-pregnancy interval to autism) and there are a few research avenues potentially ripe for further investigation.

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[1] Curran EA. et al. Hypertension in pregnancy and autism spectrum disorder in a British cohort: Long term consequences for mother and child. Pregnancy Hypertension: An International Journal of Women's Cardiovascular Health. 2016; 6: 153.

[2] Gardener H. et al. Prenatal risk factors for autism: comprehensive meta-analysis. Br J Psychiatry. 2009 Jul;195(1):7-14.

[3] LaMarca BD. et al. Inflammatory cytokines in the pathophysiology of hypertension during preeclampsia. Curr Hypertens Rep. 2007 Dec;9(6):480-5.

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Eileen A. Curran, Ali S. Khashan, Gerard W. O’Keeffe, & Louise C. Kenny (2016). 35 Hypertension in pregnancy and autism spectrum disorder in a British cohort regnancy Hypertension: An International Journal of Women's Cardiovascular Health., 6

"The maternal body as environment in autism science"

Although I'm not really one for deep philosophical discussions or anything related (unless linked to a specific galaxy far, far away...), I was recently interested to read the paper by Martine Lappé [1] talking about how "complex narratives of autism’s causes and social anxieties surrounding child development have helped situate autism risk in women’s bodies before and during pregnancy."

I'm as guilty as anyone for discussing the pretty constant stream of peer-reviewed research evidence suggesting that what goes on before and during the nine months that made us might have some important bearing on offspring in terms of behaviour and development. The wide range of potential variables laid at mum's pregnancy doorway with autism risk in mind have grown to overwhelming proportions in recent time, as just about every week some factor or another is said to show involvement.

Lappé suggests that such research has turned pregnancy into 'environment' when it comes to discussions about possible autism aetiology and involves "three characteristics: the molecularization of the environment, an individualization of risk, and the internalization of responsibility."  The result being that 'larger questions' have been put to one side, particularly related to the continued medicalisation of the autism label (and various other labels), alongside the idea that within the large heterogeneity of autism, pregnancy factors might not necessarily figure significantly in every single case.

I can kinda see where the author is coming from in this article, particularly how suggestions that factor X or Y during pregnancy might increase offspring autism risk does to some extent mirror the darker days of autism research in terms of 'blame'. Where once popular opinion was that autism was due to parenting issues, so now the suggestion that maternal obesity for example, might somehow increase the risk of offspring autism continues the blame-game and indeed, pushes the 'blame window' further back temporally speaking. Yes, parenting style and obesity are not one and the same thing but the common element they possess is the perception that somehow there is a choice being made; a choice to parent one way or another, to become obese or not. That idea of 'choice' moves some people's minds to the concept of blame, and onwards the blame-game once again gathers momentum. The same logic around choice can similarly hold when it comes to whether pharmaceutic A or B taken during pregnancy might elevate offspring autism risk too...

There is no easy answer to what to do about turning the maternal [pregnancy] body into 'environment' when it comes to the big question: how does autism come about? Generalising the word 'autism' to denote 'all autism' means that we don't know really know how autism comes about or whether anything can be done more generally to modify a person's risk of autism. Accepting that some people don't even wish to see the words 'modify' and 'risk' in the context of autism, I personally see such philosophical discussions in a more plural context as per all that chatter about 'the autisms' and the label(s) not necessarily existing in some sort of diagnostic vacuum (see here).

I for example, look towards the increasingly important idea that for all the different 'types' of autism out there, there may be a similar number of genetic and non-genetic factors playing some role; for some, issues during pregnancy are likely to impact on offspring autism risk more than others. The specific idea that immune function and/or 'inflammation' during critical periods of pregnancy might have offspring outcomes (see here for example) is particularly appealing, given that the whole concept of immune function is moving well outside of the realms of just infection or pathogen identification and control. Accepting also that pregnancy is characterised by a change in maternal immune function (y'know, to accommodate that foreign entity that resides inside mum's body) there is plenty of scope for such tolerance to be affected by one or more agents in quite a few ways.

Ultimately, 'the maternal body as environment in autism science' is probably here to stay. The language however of how we chose to represent and transmit information about pregnancy risk factors and autism perhaps requires some further philosophical discussions...

And speaking of philosophy, a link to a book that I once enjoyed reading.

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[1] Lappé M. The maternal body as environment in autism science. Social Studies of Science. 2016; Aug 19.

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Lappe, M. (2016). The maternal body as environment in autism science Social Studies of Science DOI: 10.1177/0306312716659372

Induced labour and autism (again)

"In this nationwide sample of live births we observed no association between induction of labor and offspring ASD [autism spectrum disorder] within sibling comparison. Our findings suggest that concern for ASD should not factor into the clinical decision about whether to induce labor."

So said the findings reported by Anna Sara Oberg and colleagues [1] supposedly providing some reassurance to mums-to-be and other groups around the likelihood of offspring autism when birth or labour has to be induced. Based on the analysis of one of those oh-so important Scandinavian health registries, researchers followed all the live births recorded in Sweden between 1992 and 2005 looking for signs that labour was induced. As per some media discussion of the study: "Methods to induce labor include rupturing of membranes, mechanical or pharmacological ripening of the cervix, and administration of oxytocin, either used alone or in combination." They also followed the cohort, numbering above a million offspring, looking for recorded diagnoses of ASD in children and, taking into account "a wide range of measured confounders" examined whether induced labour might elevate the risk of offspring ASD.

The headlines suggesting 'no link' between induced labour and offspring autism don't however actually tell the full story of these findings. When taking into account the full cohort - "1 362 950 births"- there did seem to be a slight increased risk of offspring autism associated with labour induction. This association persisted "after adjustment for measured potential confounders" albeit to an even lesser degree. The 'no link' headlines seemed to have focused on further analysis where siblings, one who was induced, one who was not, were compared with regards to autism rates: "thus accounting for all environmental and genetic factors shared by siblings, labor induction was no longer associated with offspring ASD."

I've talked about labour induction and autism risk before on this blog (see here) based on findings [2] that Oberg et al were knowledgeable about and that had reported something of an increased risk based on the analysis of over half a million births in a part of the United States. Personally, I do think there is a little more to see in this area than has hitherto been uncovered. The reasons for induction is something to focus on as per the observations that issues such as pre-eclampsia and gestational diabetes are mentioned and the body of research linking such factors to offspring autism risk (see here and see here for examples). That induction also might mean use of oxytocin (the cuddle hormone!) is something else that perhaps require further investigations too. Without trying to scaremonger, I do wonder whether further thought might be needed based on the findings reported by Leffa and colleagues [3] with oxytocin in mind.

The take-away message: induced labour is pretty unlikely to 'cause' offspring autism but beware of sweeping generalisations and media headlines...

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[1] Oberg AS. et al. Association of Labor Induction With Offspring Risk of Autism Spectrum Disorders. JAMA Pediatr. 2016. 25 July.

[2] Gregory SG. et al. Association of autism with induced or augmented childbirth in North Carolina Birth Record (1990-1998) and Education Research (1997-2007) databases. JAMA Pediatr. 2013 Oct;167(10):959-66.

[3] Leffa DD. et al. DNA damage after chronic oxytocin administration in rats: a safety yellow light? Metab Brain Dis. 2016 Aug 3.

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Oberg, A., D’Onofrio, B., Rickert, M., Hernandez-Diaz, S., Ecker, J., Almqvist, C., Larsson, H., Lichtenstein, P., & Bateman, B. (2016). Association of Labor Induction With Offspring Risk of Autism Spectrum Disorders JAMA Pediatrics DOI: 10.1001/jamapediatrics.2016.0965

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.

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[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.

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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 diabetes and offspring autism risk... again

"In this large, multiethnic clinical cohort of singleton children born at 28 to 44 weeks’ gestation, exposure to maternal GDM [gestational diabetes mellitus] diagnosed by 26 weeks’ gestation was associated with risk of ASD [autism spectrum disorder] in offspring."

That was the conclusion reached by Anny Xiang and colleagues [1] (open-access) following their analysis of some 3300 children diagnosed with ASD as part of a wider cohort of over 300,000 children "born in 1995-2009 at Kaiser Permanente Southern California (KPSC) hospitals." Records of children with and without autism were examined according to the presence or not of maternal type 2 diabetes or maternal GDM during pregnancy. "Diagnosis of GDM was based on laboratory values confirming a plasma glucose level of 200 mg/dL or higher on the glucose challenge test or at least 2 plasma glucose values meeting or exceeding the following values on the 100-g or 75-g oral glucose tolerance test: fasting, 95 mg/dL; 1 hour, 180 mg/dL; 2 hours, 155 mg/dL; and 3 hours, 140 mg/dL." Autism diagnosis was based on "ICD-9 codes 299.x or equivalent KPSC codes" covering "autistic disorders, Asperger syndrome, or pervasive developmental disorder not otherwise specified (PDD-NOS) and excluded childhood disintegrative disorder and Rett syndrome."

Results: of the 3388 children diagnosed with an ASD, a large majority were deemed 'unexposed' to either maternal type 2 diabetes or GDM (87%). What this tells us is that ideas about exposure to maternal diabetes being 'universally' associated with a diagnosis of ASD in offspring are incorrect. That being said, some 115 children were exposed to maternal type 2 diabetes and 310 GDM exposed.

Taking into account the timing of exposure as per the analysis of gestational weeks at diagnosis of GDM - "26 weeks or earlier (mean of 16 weeks), after 26 weeks but prior to 30 weeks (mean of 28 weeks), and 30 weeks or later (mean of 32 weeks)" - and controlling for various potentially confounding variables such as maternal age, parity, education, household income, race/ethnicity, history of comorbidity, and sex of the child, some interesting results are reported. GDM exposure diagnosed by 26 weeks gestation was associated with something of an increased risk (hazard ratio) of offspring autism to the tune of about a 40% increased risk. At the same time, exposure to maternal pre-existing type 2 diabetes did not seem to significantly elevate the risk of offspring ASD. The Autism Speaks write-up of the Xiang trial offers this helpful statement: "the increased autism risk seen with early gestational diabetes translated into roughly seven additional cases per 1,000 pregnancies."

The reason why I titled this post 'maternal diabetes and offspring autism risk... again' is because it is not new news that maternal diabetes might have some kind of effect on offspring autism risk. I covered this research area previously on this blog (see here) based on findings such as those from Xu and colleagues [2] (open-access). Other peer-reviewed research has similarly hinted at the possibility of an association between maternal diabetes and offspring autism as part of a wider spectrum of 'effects' on the developing child [3].

"The mechanisms underlying the effects of maternal hyperglycemia on the developing fetus may involve increased oxidative stress, hypoxia, apoptosis, and epigenetic changes" according to that paper by Ornoy and colleagues [3]. With autism in mind, most of those concepts have been banded around as being linked to cases at one time or another, perhaps only missing out on the 'inflammatory' element mentioned by Xiang et al. I wouldn't like to speculate any further on what specific process might be going on (more likely a combination of effects) but given the seemingly important variable of timing, as in exposure to GDM by 26 weeks gestation, I'd suggest that epigenetics might be a front-runner [4]. Foetal programming hypothesis and all that palaver...

"Our results also suggest that screening for GDM and control of glucose levels early in pregnancy may be important in reducing ASD risk for offspring. Whether early diagnosis and treatment of GDM can reduce the risk of ASD remains to be determined." I struggle to disagree with the closing sentiments from Xiang and colleagues.

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[1] Xiang AH. et al. Association of Maternal Diabetes With Autism in Offspring. JAMA. 2015; 313: 1425-1434.

[2] Xu G. et al. Maternal diabetes and the risk of autism spectrum disorders in the offspring: a systematic review and meta-analysis. J Autism Dev Disord. 2014 Apr;44(4):766-75.

[3] Ornoy A. et al. Effect of maternal diabetes on the embryo, fetus, and children: Congenital anomalies, genetic and epigenetic changes and developmental outcomes. Birth Defects Res C Embryo Today. 2015 Mar;105(1):53-72.

[4] Lehnen H. et al. Epigenetics of gestational diabetes mellitus and offspring health: the time for action is in early stages of life. Mol Hum Reprod. 2013 Jul;19(7):415-22.

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Xiang, A., Wang, X., Martinez, M., Walthall, J., Curry, E., Page, K., Buchanan, T., Coleman, K., & Getahun, D. (2015). Association of Maternal Diabetes With Autism in Offspring JAMA, 313 (14) DOI: 10.1001/jama.2015.2707

Maternal diabetes and offspring autism risk

The systematic review and meta-analysis reported by Xu and colleagues* caught my eye recently. Concluding that: "maternal diabetes was significantly associated with a greater risk of ASD in the offspring" my interest was truly piqued.

Insulin @ Wikipedia  

Diabetes in relation to autism has cropped up a few times on this blog. I've talked about the possibility of a more general connection (see here) and also more specific as part of some of the CHARGE results (see here).

Indeed those CHARGE results, based on the study by Paula Krakowiak and colleagues** (open-access) I remember generated quite a bit of discussion at the time of their publication given the suggested link with various facets making up metabolic syndrome in mums.

I'm not really surprised by the Xu results when you think that the association between gestational diabetes and offspring autism risk has been talked about before based on some pretty strong association data. I note for example, that the study by Lyall and colleagues*** (open-access) flagged up this association - "gestational diabetes was associated with a significantly increased risk of ASD" - based on quite a nice sample size. That and the paper by Hannah Gardener and colleagues**** (open-access) who suggested that gestational diabetes was perhaps one of several factors which might elevate offspring risk as per the Krakowiak results.

The question of mechanism of effect is slightly less clear it has to be said. In my first post on autism and diabetes, quite a lot was made of the connection between type 1 diabetes and autism as per the familial autoimmune connection (have a look at my Money post for example). Granted this doesn't really add anything more specific than to say that autoimmune conditions can 'club together' (see here) which might take us down some other avenues particularly when talking about at least some autism comorbidity (see here). That and the implication that autism might also be an autoimmune condition***** as some have implied.

As to any mechanism of gestational diabetes being linked to the aetiology of autism, well I'm afraid I can't offer anything too concrete at this point. There is some speculation that gestational diabetes might be linked to other cognitive and developmental issues as per the research on ADHD (Attention-deficit hyperactivity disorder)****** and schizophrenia*******. Indeed, that paper by Van Lieshout & Voruganti (open-access) on gestational diabetes and risk of offspring schizophrenia suggests: "at least 3 prenatal mechanisms: hypoxia, oxidative stress and increased inflammation" of potential effect. Suffice to say that all of them have also been banded around as being involved with cases of autism at various times (particularly the roles of inflammation and oxidative stress). I might also draw reader's attention to the paper by Nousen and colleagues******** too.

The take-home message whilst still one of caution in singling out one particular factors as being linked to autism (or should that be the autisms?) is that maternal diabetes should be registering on the various investigations into pregnancy and birth factors linked to offspring autism risk to further explore mechanisms. Whether altering the presentation of maternal diabetes (lifestyle changes or even reviewing medication*********) might also impact on offspring outcome is another question which should be on the lips of autism research...

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* Xu G. et al. Maternal Diabetes and the Risk of Autism Spectrum Disorders in the Offspring: A Systematic Review and Meta-Analysis. J Autism Dev Disord. 2013 Sep 22.

** Krakowiak P. et al. Maternal metabolic conditions and risk for autism and other neurodevelopmental disorders. Pediatrics. 2012 May;129(5):e1121-8. doi: 10.1542/peds.2011-2583.

*** Lyall K. et al. Pregnancy complications and obstetric suboptimality in association with autism spectrum disorders in children of the Nurses' Health Study II. Autism Res. 2012 Feb;5(1):21-30. doi: 10.1002/aur.228.

**** Gardener H. et al. Prenatal risk factors for autism: comprehensive meta-analysis. Br J Psychiatry. 2009 Jul;195(1):7-14. doi: 10.1192/bjp.bp.108.051672.

***** Ashwood P. & Van de Water J. Is autism an autoimmune disease? Autoimmun Rev. 2004 Nov;3(7-8):557-62.

****** Nomura Y. et al. Exposure to gestational diabetes mellitus and low socioeconomic status: effects on neurocognitive development and risk of attention-deficit/hyperactivity disorder in offspring. Arch Pediatr Adolesc Med. 2012 Apr;166(4):337-43. doi: 10.1001/archpediatrics.2011.784.

******* Van Lieshout RJ. & Voruganti LP. Diabetes mellitus during pregnancy and increased risk of schizophrenia in offspring: a review of the evidence and putative mechanisms. J Psychiatry Neurosci. 2008 Sep;33(5):395-404.

******** Nousen EK. et al. Unraveling the Mechanisms Responsible for the Comorbidity between Metabolic Syndrome and Mental Health Disorders. Neuroendocrinology. 2013. Sept 21.

********* Barnard KB. et al. Antidepressant Medication as a Risk Factor for Type 2 Diabetes and Impaired Glucose Regulation. Systematic review. Diabetes Care. 2013; 36: 3337-3345.

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Xu G, Jing J, Bowers K, Liu B, & Bao W (2013). Maternal Diabetes and the Risk of Autism Spectrum Disorders in the Offspring: A Systematic Review and Meta-Analysis. Journal of autism and developmental disorders PMID: 24057131