Hypertensive disorders of pregnancy (HDP) and offspring autism and/or ADHD meta-analysed

"Pooled estimates from this systematic review and meta-analysis of 61 studies suggest that exposure to hypertensive disorders of pregnancy is associated with a small yet statistically significant increase in the odds of autism spectrum disorder and attention-deficit/hyperactivity disorder in offspring compared with no exposure."

So concluded the review and meta-analysis published by Gillian Maher and colleagues [1] that collected and analysed the current peer-reviewed research literature (up to June 2017) looking at hypertensive disorders of pregnancy (HDP) and offspring developmental outcomes. Continuing an important research theme (see here), authors observed something around "a 35% increased odds of ASD [autism spectrum disorder] compared with nonexposure" and that children were "30% more likely to have ADHD compared with unexposed offspring."

HDP according to Maher et al, covers quite a bit of diagnostic ground: "chronic hypertension (essential/secondary), white-coat hypertension, masked hypertension, transient gestational hypertension, gestational hypertension, and preeclampsia (de novo or superimposed on chronic hypertension)." The primary characteristic is "high blood pressure that either precedes pregnancy, is diagnosed within the first 20 weeks of pregnancy, or does not resolve by the 12-week postpartum checkup" [2].

There's little more to say about this area of research aside from the idea that findings "highlight the need for greater pediatric surveillance of infants exposed to HDP to allow early intervention that may improve neurodevelopmental outcome" and that more work on possible mechanism(s) need to be undertaken. On that last point the authors opine that "placental dysfunction, associated with HDP, may result in reduced placental perfusion and oxidative stress" or that: "Maternal inflammation may also play a key role." Both worthy areas for future research. The implication also, is that yet again, there may be some form of 'foetal programming' going on with regards to offspring autism that *could* be sensitive to intervention at some point...

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[1] Maher GM. et al. Association of Hypertensive Disorders of Pregnancy With Risk of Neurodevelopmental Disorders in Offspring: A Systematic Review and Meta-analysis. JAMA Psychiatry. 2018 Jun 6.

[2] Mammaro A. et al. Hypertensive Disorders of Pregnancy. Journal of Prenatal Medicine. 2009;3(1):1-5.

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"evidence that in utero exposure to certain AEDs can cause developmental problems in children"

AEDs mentioned in the title of this post refer to antiepileptic drugs, a class of medicines that provide life-enhancing and sometimes life-saving relief from symptoms of various conditions headed under the term epilepsy. As I've mentioned previously on this blog, the management of epilepsy is not something to be taken lightly given what the condition(s) can mean in terms of (life-threatening) risks. AEDs provide both an important management and preventative tool. Don't ever forget that.

The results published by Arron Lacey and colleagues [1] add to a bank of peer-reviewed research observing that whilst various AEDs provide an important service with regards to the management of epilepsy, they are not however without potential risks of their own. Indeed, the risks following consumption of such medicines - or at least certain AEDs - during pregnancy when it comes to offspring outcomes are seemingly becoming more and more evident as ever more [peer-reviewed] science appears...

I should at this point mention that no medical or clinical advice is given or intended on this blog. This is even more pertinent when it comes to this topic and what epilepsy means to many, many people. If you want further information about the topic discussed today, please, speak to your prescribing physician and don't make any medication changes without their input and say-so.

OK, Lacey et al started out with the aim of investigating "the effect of AED exposure in utero on the educational attainment of children born to mothers with epilepsy using anonymised, routinely collected healthcare records and the results of a standard national educational assessment." That anonymised database was something called the Secure Anonymous Information Linkage (SAIL) databank, a resource funded by Health and Care Research Wales, thus providing a clue as to the population on which this research was carried out with.

Researchers identified women diagnosed with epilepsy - "a diagnosis of epilepsy if their GP [general practitioner] record contained an epilepsy diagnosis code as well as a record of repeat AED prescriptions" - who had children, and looked also at their child's education attainment at 7 years of age. In case you might not be familiar with measuring educational attainment here in the UK (yes, Wales is a country part of the UK), the particular assessments taken at 7 years of age are called the Key Stage 1 (KS1) SATs. Maths and English made up the core topics alongside science at the study time in question. Educational data of offspring were included in the statistical mix and results reported as a function of maternal epilepsy and corresponding prescription of AEDs.

Results: "We demonstrate through the analysis of linked data in the SAIL databank that mothers being prescribed multiple AEDs and those being prescribed sodium valproate have children with significantly poorer attainment in national tests at the age of 7." The authors once again (see here) specifically zoomed in on a role for valproate when it came to educational outcomes of offspring; where: "there was no difference seen in children exposed to carbamazepine, lamotrigine or mothers who did not take drugs during pregnancy." Importantly also, authors noted that: "We did not find a significant decrease in attainment in children born to mothers with epilepsy who were not prescribed an AED during pregnancy" indicating that maternal epilepsy was probably not a 'cause' of the results obtained. Finally, when cases of smoking during pregnancy - something that also seems to be able to affect offspring developmental and/or cognitive outcomes - were removed from the statistical mix, authors reported that the results did not notably change.

There are some important strengths associated with the study results by Lacey and colleagues. A large cohort, clinical information on the diagnosis of epilepsy and associated prescribed AEDs, and the reliance on "a standardised national assessment as a measure of performance" with "results [that] would closer reflect the learning experience of children at this age compared with an IQ test" all add up to something pretty impressive. The authors note that they did not / were not able to control for other potentially important variables such as parental characteristics that may have impacted on the study results but no investigation is perfect. That analysis based on epilepsy medicated vs. not medicated during pregnancy kinda helps matters but does not mean every potentially important variable was controlled for.

So yet again, valproate use crops up and yet again it seems to be earning its 'black triangle' status. I've lost track of the number of health-related agencies that have provided guidance on valproate use during pregnancy - one of the latest seems to be the European Medicines Agency that recently recommended "new measures to avoid exposure of babies to valproate medicines in the womb." Also going as far as noting that: "Babies exposed are at risk of malformations and developmental problems." There's even a call for it to be "compulsory to enrol all women who take valproate into a national registry" [2].

How much more evidence is required? Indeed, how much more evidence [3]...

Then the question remains: how does gestational exposure to valproate affect something like academic achievement and developmental course? Well, we have some clues (see here) but further investigations are of course implied.

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[1] Lacey AS. et al. Educational attainment of children born to mothers with epilepsy. J Neurol Neurosurg Psychiatry. 2018. March 27.

[2] Thomas RH. Valproate: life-saving, life-changing. Clin Med (Lond). 2018 Apr 1;18(Suppl 2):s1-s8.

[3] Paton C. et al. A UK clinical audit addressing the quality of prescribing of sodium valproate for bipolar disorder in women of childbearing age. BMJ Open. 2018 Apr 12;8(4):e020450.

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Gestional exposure to Group B Streptococcus and an autism model

"Overall, these data show for the first time that gestational exposure to GBS [Group B Streptococcus] plays an important role in the generation of neurodevelopmental abnormalities reminiscent of human autism spectrum disorders (ASD)."

I chose to discuss the findings reported by Marie-Julie Allard and colleagues [1] on this blog for various reasons. That this research team already have some research 'form' when it comes to looking at GBS [2] is one; another is the idea that they report "new evidence in favor of the role of a common and modifiable infectious/inflammatory environmental factor in human ASD pathophysiology." With all the focus these days on how there may be some kind of foetal programming going on during the nine months that made us pertinent to the risk of developing autism for some, this line of research also potentially offers up the idea that said programming needn't always be related to the genome we are born with.

GBS infection during pregnancy and birth is not something to be taken lightly. As a primary cause of bacterial infections in newborns, this type of infection can in extreme cases lead to septicaemia (blood poisoning) and also meningitis. This all stems from the fact that around 25-30% of healthy human adults carry this bacteria around in their gut and/or genitourinary tract with no apparent issues for the majority. In rare cases however, infants traversing the birth canal of a mother carrying GBS can come into contact with the bacteria and processes are then set in motion...

Allard et al started with the hypothesis that "GBS-induced gestational infection/inflammation has a deleterious neurodevelopmental impact on uninfected offspring" and set about looking at this potential issue in a rodent model - "a new preclinical rat model" no less. They reported that placentas exposed to GBS "exhibited chorioamnionitis characterized by the presence of Gram-positive cocci and polymorphonuclear cells, with the latter being significantly more prominent in the labyrinth of male offspring." Whilst interesting, this is not necessarily new news. But... when it came to looking at the brain and behaviour of male rat offspring exposed to GBS, there appeared to be a few features potentially "reminiscent of human autism spectrum disorders (ASD)." So: "autistic-like behaviors, such as abnormal social interaction and communication, impaired processing of sensory information and hyperactivity" were noted in this group. The conclusion being that science may have yet another animal model of autism (is this a good or bad thing?) and that GBS-exposed placentas might have implications for offspring developmental outcome.

The previous research paper by this group [2] had already provided some important details pertinent to this line of investigation. "Surprisingly, only male offspring were affected by these combined autistic-like traits" went one of their conclusions on that previous research occasion, insofar as GBS-exposed placentas and their onward effects. They also suggested that there may be some important effects to be had from the "materno-fetal inflammatory response to GBS" coinciding with quite a lot of peer-reviewed data suggesting immune system and inflammatory signalling involvement when it comes to pregnancy and offspring risk of autism (see here and see here).

Stressing that animal models of autism are not necessarily the same as the complexity of autism in it's lived form, the Allard findings are potentially important. Added to something of an important body of research looking at artificial modelling of bacterial infection and its potential importance to offspring outcomes (see here) one can see that the so-called protective cocoon of our mother during the months of our earliest development is not an impenetrable force-field by any stretch of the imagination. Indeed, such an association may go much further than just autism (see here).

Insofar as the 'where next?' in terms of research in this area, well, I might suggest that looking at the rates of offspring autism in women positive or negative to GBS could represent a good research start and perhaps taking things from there. Although there may be some way to go in determining the precise mechanism of GBS exposure in-utero in relation to any possible heightened risk of autism, science might also consider other findings from this research group [3] on how 'intervening' in issues related to inflammation at certain critical periods, might eventually provide some 'protection' for the developing brain...

Oh, and I'll be coming to the paper by Jiang and colleagues [4] in a future post.

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[1] Allard MJ. et al. A sexually dichotomous, autistic-like phenotype is induced by Group B Streptococcus maternofetal immune activation. Autism Res. 2016 May 25.

[2] Bergeron JD. et al. White matter injury and autistic-like behavior predominantly affecting male rat offspring exposed to group B streptococcal maternal inflammation. Dev Neurosci. 2013;35(6):504-15.

[3] Girard S. et al. IL-1 receptor antagonist protects against placental and neurodevelopmental defects induced by maternal inflammation. J Immunol. 2010 Apr 1;184(7):3997-4005.

[4] Jiang HY. et al. Maternal Infection during Pregnancy and Risk of Autism Spectrum Disorders: A Systematic Review and Meta-analysis. Brain Behav Immun. 2016 Jun 7. pii: S0889-1591(16)30154-4.

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Allard MJ, Bergeron JD, Baharnoori M, Srivastava LK, Fortier LC, Poyart C, & Sébire G (2016). A sexually dichotomous, autistic-like phenotype is induced by Group B Streptococcus maternofetal immune activation. Autism research : official journal of the International Society for Autism Research PMID: 27220806

The inter-pregnancy interval and risk of autism reviewed

"Short IPIs [interpregnancy intervals] are associated with a significantly increased risk of ASD [autism spectrum disorder]. Long IPIs also appear to increase the risk of ASD.

So said the results of the systematic review undertaken by Agustín Conde-Agudelo and colleagues [1] into how birth spacing might impact on the risk of a child developing an ASD. Drawing on data from 7 studies that "reported an association between short IPIs and increased risk of ASD" including over 1.1 million children, the authors confirmed what quite a few people already suspected: "children born to women with IPIs of <12 months had a significantly increased risk of any ASD." 'Autistic disorder' a.k.a autism (over other ASDs such as Asperger syndrome) seemed to shoulder the largest risk following a short IPI.

Of course we've been here before on the topic of IPI and autism risk (see here and see here) and as such the latest review results are not a complete surprise. What perhaps science does have to start thinking about are the various ways and means that a short IPI might confer additional risk of offspring autism. Personally, I'd initially go with the issue of a 'depletion of micronutrients' as being a prominent possible factor, as per what other research in this area has speculated on (see here). Combined with the so-called 'foetal programming hypothesis' (see here) drawing on the work of the late David Barker and others, the 'nine months that made us' is indeed an extremely important time from a nutritional point of view and potentially very relevant to at least some autism.

To close: Victoria Wood - Brief Encounter. RIP mince pie in the eye...

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[1] Conde-Agudelo A. et al. Birth Spacing and Risk of Autism and Other Neurodevelopmental Disabilities: A Systematic Review. Pediatrics. 2016. April 7.

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Conde-Agudelo, A., Rosas-Bermudez, A., & Norton, M. (2016). Birth Spacing and Risk of Autism and Other Neurodevelopmental Disabilities: A Systematic Review PEDIATRICS DOI: 10.1542/peds.2015-3482

The transgenerational effects of prenatal immune activation?

The paper by Ulrike Weber-Stadlbauer and colleagues [1] provides some food for thought today with the suggestion that the concept of prenatal immune activation might have consequences further than just to exposed offspring.

For those not familiar with the concept of prenatal immune activation, it refers to the process(es) that occur following "exposure to infectious or inflammatory insults" during the nine months that made us. As you'll probably be aware, our nine months of watery 'captivity' is an important time in making us who we are. It is also a time when we are unfortunately vulnerable to quite a few factors that can adversely affect our stay in the womb (see here and see here for examples) and indeed, that can have repercussions for our future development and wellbeing. Among the vast number of agents that can and do affect pregnancy, various infectious agents (such as viruses and bacteria) that have been with humankind since the year dot play a prominent role; either through their own actions or via what biochemical processes they initiate as a mother's body seeks to protect itself and its unborn child. In short, the maternal immune system might itself, at this crucial time of reprogrammed immune tolerance, exert a less than positive effect on the foetus as a result. The sorts of outcomes potentially linked to exposure to this prenatal immune activation are varied to say the least (see here).

Weber-Stadbauer et al looking at a mouse model of prenatal immune activation - that's MOUSE model - took things one stage further by asking whether effects of such immune activation exposure might persist beyond just one generation of offspring. So: "Using an established mouse model of prenatal immune activation by the viral mimetic poly(I:C), we show that reduced sociability and increased cued fear expression are similarly present in the first- and second-generation offspring of immune-challenged ancestors." Further: "These transgenerational effects are mediated via the paternal lineage and are stable until the third generation, demonstrating transgenerational non-genetic inheritance of pathological traits following in-utero immune activation."

When the authors suggest that their results "demonstrates for, we believe, the first time that prenatal immune activation can negatively affect brain and behavioral functions in multiple generations" they aren't kidding. Indeed, accompanied by the rise and rise of research talking about transgenerational inheritance not primarily mediated by more traditional structural genetics (as far as we know) the possibilities are truly endless if said processes are indeed transferable from mouse to humans.

But just before we do get too carried away, let's be a little cautious. Aside from the fact that mice are mice and not humans (see here) and that complex behaviours like human sociability are probably not best served by looking solely at mice, these data need to be independently replicated. I note from other research by members of this authorship group [volumes of research it has to be said] the interest in how a label like 'schizophrenia' (or should that be schizophrenias?) might have a 'developmental neuroinflammation' element to it [2] implies that priming of the immune system should be something that is detectable (see here) and hence potentially amenable to change. Indeed, this may very well tie into the increasingly popular idea that immunopsychiatry is here to stay (see here). I would therefore, like to see a little more on how prenatal immune activation presents in immune system terms down the generations over and above "unique and overlapping genome-wide transcriptional changes in first- and second-generation offspring of immune-challenged ancestors." Does, for example, this imply that there is a potential biomarker set consisting of biochemical, epigenetic and transcriptional data that might characterise those at risk of such consequences? And indeed, are we all potentially the result of our grandmother's immune experiences as we might be her dietary patterns?

To close, following the sad news that Gareth 'Blake's 7' Thomas has died, that theme tune...

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[1] Weber-Stadlbauer U. et al. Transgenerational transmission and modification of pathological traits induced by prenatal immune activation. Mol Psychiatry. 2016 Mar 29.

[2] Meyer U. Developmental neuroinflammation and schizophrenia. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2013; 42: 20-34.

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Weber-Stadlbauer U, Richetto J, Labouesse MA, Bohacek J, Mansuy IM, & Meyer U (2016). Transgenerational transmission and modification of pathological traits induced by prenatal immune activation. Molecular psychiatry PMID: 27021823

One more time... the interpregnancy interval and risk of offspring autism

"Children born after an IPI [interpregnancy interval] of <12 months or ≥72 months had a 2- to 3-fold increased ASD [autism spectrum disorder] risk compared with children born after an interval of 36 to 47 months."

So said the study results published by Ousseny Zerbo and colleagues [1] looking at the increasingly interesting area of the autism research landscape: the interpregnancy interval (the time from the birth of an index child to the next conception/pregnancy of a sibling).

Looking at data derived from children "born at Kaiser Permanente Northern California (KPNC) between 2000 and 2009", researchers examined the IPI to evaluate the risk of ASD in second-born children. Various hazard ratios (HRs) are reported based on the spacing between children: "<6 months, 3.0 (1.9–4.7); 6 to 8 months, 2.1 (1.4–3.3); 9 to 11 months, 1.9 (1.3–2.1); 12 to 23 months, 1.5 (1.1–2.1); and ≥72 months, 2.4 (1.5–3.7)." Following a sort of U-shaped response curve and taking into account various factors that may potentially impact on offspring autism risk, researchers concluded that: "Children born after interpregnancy intervals <2 years or >6 years may be at increased risk of ASD."

Whilst the Zerbo findings have attracted some media attention (see here and see here) it is not necessarily new news that the IPI might show some connection to offspring autism risk. I've covered the topic on at least two other occasions on this blog (see here and see here) outside of other research suggesting similar things [2]. The findings are fairly robust and importantly, seem to cross different geographies and different ethnicities, suggesting that the IPI might be something generalisable to autism across the globe.

As per my other musings on this topic, there are several possibilities as to how a short (or long) IPI might impact on offspring autism risk, mainly associated with more general research on how IPI might influence various birth outcomes (albeit with caveats [3]). Having watched the recent BBC series called 'Countdown to Life' documenting the nine months that made us, I'm particularly interested in the idea that there may be more than one mechanism at work depending on the IPI. Specifically, whether a short IPI where the greatest HR was reported by Zerbo, might be related to a depletion of maternal stores of various micronutrients (the authors have talked about folate although I'd be careful there, indeed very careful there [4]) that comes with pregnancy and David Barker style (see here) whether intrauterine health might be a factor in the elevated risk?

Music, and something a little 'cool' today: The Specials And Fun Boy Three - Our Lips Are Sealed (complete with a sample of the Go-Go's).

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[1] Zerbo O. et al. Interpregnancy Interval and Risk of Autism Spectrum Disorders. Pediatrics. 2015. Sept 14.

[2] Coo H. et al. The association between the interpregnancy interval and autism spectrum disorder in a Canadian cohort. Can J Public Health. 2015 Feb 3;106(2):e36-42.

[3] Ball SJ. et al. Re-evaluation of link between interpregnancy interval and adverse birth outcomes: retrospective cohort study matching two intervals per mother. BMJ. 2014; 349: g4333.

[4] Virk J. et al. Preconceptional and prenatal supplementary folic acid and multivitamin intake and autism spectrum disorders. Autism. 2015 Sep 25. pii: 1362361315604076.

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Zerbo, O., Yoshida, C., Gunderson, E., Dorward, K., & Croen, L. (2015). Interpregnancy Interval and Risk of Autism Spectrum Disorders PEDIATRICS DOI: 10.1542/peds.2015-1099

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.

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[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.

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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

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