Breastfeeding and autism continued

"We found that the percentage of mothers who started breastfeeding was similar between the two groups, but mothers of children with ASD [autism spectrum disorder] breastfed for a shorter amount of time compared to mothers of children without ASD."

So said the findings reported by Gnakub Soke and colleagues [1] continuing a research theme that I've had some professional interest in down the years (see here) on whether breastfeeding (use, duration, etc) *might* have some important *links* to risk of offspring autism and/or related conditions (see here). The same caveats mention in some of my other musings on this topic come into effect when talking (briefly) about the Soke findings (i.e. no-one is saying that a lack of breastfeeding 'causes' autism). That being said, there might still however be some important science to do on how breastfeeding and/or the constituents of breast milk might have some important biological effects for the developing child (minus any psychobabble explanations).

The Study to Explore Early Development or SEED was the starting point for the Soke study (continuing an autism research theme), and specifically investigation into the: "associations between ASD and breastfeeding initiation (yes/no) and duration (months categorized in tertiles)." The findings suggested that (a) breastfeeding rates (initiation rates) were high in mums of children with ASD compared to not-autism controls (85% vs. 90%), and (b) "mothers of children with ASD were less likely to report duration of breastfeeding in the high (≥12 months) versus low tertile (<6 months)... or the middle (6-<12 months) versus low tertile."

I don't want to dwell too much on the whys-and-wherefores of the Soke findings but there are some important questions that need answering. Not least the question of why breastfeeding seems to end quicker for those mums of children who were subsequently diagnosed as having an ASD. Were these infants more difficult to feed (something which Kanner might have picked up on in his seminal paper describing autism)? What role does the presentation of the 'broader autism phenotype' (BAP) in mothers mentioned by Soke et al play in such findings? That last point in particular, draws on the need for lots more research into the experience of pregnancy and motherhood with the BAP (see here) and/or autism in mind (see here).

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[1] Soke GN. et al. Association Between Breastfeeding Initiation and Duration and Autism Spectrum Disorder in Preschool Children Enrolled in the Study to Explore Early Development. Autism Res. 2019 Mar 9.

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"Neurodevelopmental effects of prenatal vitamin D in humans"

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

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

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

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

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

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

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

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

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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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"parental asthma was associated with slightly elevated risk of ASD in offspring"

The paper by Tong Gong and colleagues [1] provides the blogging fodder today and the finding that "parental asthma was associated with slightly elevated risk of ASD [autism spectrum disorder] in offspring."

As unusual as it might sound to some people that a condition primarily affecting the lungs *might* show a connection to a developmental diagnosis in offspring, this is not the first time that asthma and autism has been talked about on this blog (see here and see here). Granted, much of that previous peer-reviewed research has been looking at the possible *connection* between asthma and autism diagnosed in the same person (albeit not necessarily always describing a link). But there is some research history connecting the two labels. Indeed, one of the primary comorbidities that can follow a diagnosis of autism - attention-deficit hyperactivity disorder (ADHD) - seems to have an even stronger *association* with asthma (see here).

Gong et al set out to investigate a few important issues: "the association between (a) maternal/paternal asthma and offspring ASD, and (b) prenatal exposures to β2-agonists, other asthma medications and offspring ASD." It would be difficult to describe the Gong study as 'underpowered' given that their use of those fabulous Scandinavian population registries - this time in Sweden - covering "all children (N=1,579,263) born in Sweden 1992-2007." From the total population, researchers identified some 22,000 children diagnosed with an ASD. They looked at their exposure to "parental asthma or prenatal asthma medications" and compared the data with other populations (not diagnosed with autism) including various degrees of siblings and extended family members.

As per the title of this post, a possible *association* was revealed between parental medical history of asthma and offspring risk of a diagnosis of ASD. Asthma in either parent seemed to show a connection, but maternal asthma showed the stronger connection. Also: "The risk of offspring ASD in mothers with asthma showed similar estimates when adjusting for shared familial factors among paternal half-siblings... full-cousins... and half-cousins." This suggests that familial factors were not 'confounding' factors. Another detail is important to mention: "Prenatal exposure to asthma medications among subjects whose mothers had asthma was not associated with subsequent ASD." This is an important detail. It mirrors the findings reported in the paper by Su and colleagues [2] looking at another Scandinavian cohort, and their conclusion: "children born to women who used β2AA [β2-adrenoreceptor agonist] during pregnancy have an increased risk of ASDs in later life" with the caveat that risk of offspring autism was "more likely due to underlying maternal diseases rather than the exposure to β2AA itself."

Implications? Well, several. Not least that more study is required looking at the biological and genetic links between autism and asthma. Y'know, something along the lines of the fact that 'autism genes are probably not just genes for autism' (see here) and how autism has been previously studied in the context of lung architecture too (see here).

What else? How about examining the possibility of some shared biological mechanisms also at work? Perhaps start with inflammation for example [3] and work through other potential immune-related issues as well (see here). And how about also thinking about the possibility of shared 'exposure' events being potentially important? Asthma is a condition affecting the lungs. Something like air pollution is therefore a prime suspect when it comes to the development and continuation of the condition. Likewise, air pollution is no stranger to the autism peer-reviewed research landscape (see here for example). Is it possible that air pollution might be implicated in asthma and autism?

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[1] Gong T. et al. Parental asthma and risk of autism spectrum disorder in offspring: a population and family based case-control study. Clin Exp Allergy. 2019 Feb 11.

[2] Su X. et al. Prenatal exposure to β2-adrenoreceptor agonists and the risk of autism spectrum disorders in offspring. Pharmacoepidemiol Drug Saf. 2017 Jul;26(7):812-818.

[3] Murdoch JR. & Lloyd CM. Chronic inflammation and asthma. Mutat Res. 2010;690(1-2):24-39.

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Maternal prenatal vitamin use and reduced risk of offspring autism recurrence

Question: "Is maternal use of prenatal vitamins associated with decreased risk for autism recurrence in siblings of children with autism spectrum disorder?" Answer: "Maternal prenatal vitamin intake during the first month of pregnancy may reduce ASD [autism spectrum disorder] recurrence in siblings of children with ASD in high-risk families." So that looks like a 'very possibly' then.

That was the long-and-short of the findings reported by Rebecca Schmidt and colleagues [1]. Some notable names are included on the authorship list of the Schmidt paper who are no strangers to the idea that maternal prenatal vitamin use may very well impact on offspring risk of autism or ASD (see here and see here for examples).

The Schmidt study on this occasion relied on data from the MARBLES (Markers of Autism Risk in Babies: Learning Early Signs) study, an important longitudinal initiative originally designed to investigate "possible pre-natal and post-partum biological and environmental exposures and risk factors that may contribute to the development of autism." Yes, you read that right, that's 'biological and environmental' exposures and risk factors (see here)...

In this "prospective cohort study" younger brothers and sisters deemed to be at high-risk of autism (N=241) by virtue of their older sibling having been diagnosed with autism were the target participant group. Said group were followed from 6 months to around about their third birthday and developmentally assessed. Mums of the children were also asked about their vitamin use during pregnancy via interview. All the collected data was crunched and results presented.

"The prevalence of ASD was 14.1% (18) in children whose mothers took prenatal vitamins in the first month of pregnancy compared with 32.7% (37) in children whose mothers did not take prenatal vitamins during that time." As you can see, that is quite a stark [statistically significant] difference between the groups bearing in mind that around 25% of the total cohort were eventually diagnosed with autism (or at least met thresholds for a diagnosis based on the use of a gold-standard instrument). Authors also add that prenatal vitamin use did not seemingly impact on "other nontypical development" which included various other developmental 'outcomes'. They also reported that: "Children in the former maternal prenatal vitamin group also had statistically significantly lower autism symptom severity... and higher cognitive scores." This implies that even if such vitamin use did not 'halt' a/the pathway to an autism diagnosis in some, it might well have affected the presentation of their autism in terms of symptoms and intellectual functions (see here).

So an important question: what were the nutrients being supplemented that seemed to show such an effect? Well, as per that other previous research from Schmidt et al folic acid popped up again, as well as another important nutrient, iron (Fe) which she's also been previously interested in (see here).

As per some 'expert reaction' to the study (see here) there is a need for further research in this area before any sweeping generalisations are made. Ideally, I'd like to see Schmidt or others go further into the whole folate metabolism bit applied to autism (see here and see here) and what that means for supplementation levels in mums-to-be where offspring autism recurrence risk is potentially high. Indeed, whether folic acid is actually the ideal supplement for some pregnant mums (see here) is another potential route of investigation on the basis of what has previously turned up in 'some autism' (see here). By saying all that, I want to make it clear that I'm not giving anything that looks, sounds or smells like medical or clinical advice on this or any topic. The Schmidt findings also potentially tie into another area of autism research looking at the inter-pregnancy interval (IPI) with autism in mind (see here and see here). This, on the basis that words like 'depletion of micronutrients' have been banded around as being one possible explanation for the elevated risk of offspring autism correlating with a short IPI. Again, more study is indicated.

I try not to get too excited about new findings when it comes to autism because, inevitably, many end up falling by the wayside or being over-hyped. Given however the history of peer-reviewed science on the topic of pregnancy nutrition and risk of offspring autism, I'm inclined to think that there may be something quite special in the Schmidt findings and what directions they could eventually take with regards to both research and policy. Certainly when I read another study talking about siblings at 'high-risk' for autism, I'll be looking to see whether pregnancy nutrition has been considered as a potentially modifying variable...

28 February 2019: An addition. So, here I am talking about prenatal vitamin use and offspring autism risk and lo-and-behold, someone has just published a meta-analysis and systematic review of this topic [2]. The conclusion: "the likelihood of ASD in offspring whose mothers used multivitamin supplements during the prenatal period was significantly reduced compared with that in offspring of mothers without such supplementation."

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[1] Schmidt RJ. et al. Association of Maternal Prenatal Vitamin Use With Risk for Autism Spectrum Disorder Recurrence in Young Siblings. JAMA Psychiatry. 2019. Feb 27.

[2] Guo B-Q. et al. Maternal multivitamin supplementation is associated with a reduced risk of autism spectrum disorder in children: A systematic review and meta-analysis. Nutrition Research. 2019. Feb 24.

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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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Pregnancy depression (with or without antidepressant use) and offspring autism risk continued

"Women with depression during pregnancy have an increased risk of having a child with ASD [autism spectrum disorder], regardless of antidepressant use."

That was the conclusion reached by Katrina Wilcox Hagberg and colleagues [1] following their analysis of the UK Clinical Practice Research Datalink (CPRD). Their study was carried out as a result of the still-rumbling-on question of whether pregnancy depression or the pharmacological treatment of depression during pregnancy *might* be a risk factor for an offspring diagnosis of autism (see here and see here). As you might appreciate, it's difficult to pin down whether depression or the treatment of depression is the more important issue given that the two typically appear together.

The CPRD held here in Blighty is a mighty fine resource and has been used to examine all-manner of potentially important issues (see here and see here for some examples). Researchers looked at mums and offspring ("singleton infants") born between 1989 and 2011 totalling nearly 200,000 mother-baby pairs. They reported that: "Mothers were required to have at least 12 months of recorded history before the baby's delivery date, and the children were required to have at least 3 years follow-up after birth." Because antidepressants require a doctor's prescription in the UK, they were also able to identify those other important elements vital to this study: depression and it's antidepressant intervention or not, as well as "the timing of antidepressant use during the exposure period." Authors also report some additional analyses based on "a sibling case-control analysis of maternal pregnancy exposures in ASD cases compared to non-ASD siblings of the same mother."

Results: based on the examination of 'read codes', authors identified some 2100 children with a diagnosis of ASD. The old 4:1 male:female ratio yet again held true (see here). Taking into account being exposed to depression or not and whether exposure was treated or untreated, researchers formed their headline conclusion on pregnancy exposure to maternal depression being linked to an increased risk of offspring autism. Further: "The risk was slightly higher among women with treated depression... compared to untreated depression." The results of the sibling case-control part of their trial - "601 same-sex siblings who did not have an ASD diagnosis matched to 531 ASD cases" - also revealed that: "the risk of ASD in offspring of mothers with untreated depression was 1.18 (95% CI 0.64-2.20) and 1.53 (95% CI 0.89-2.62) for treated depression, compared to unexposed." Some further analysis looking at the timing of antidepressant exposure during pregnancy revealed that it didn't really matter when the exposure happened (i.e. which trimester).

Perhaps contrary to some of their findings, it's clear from some of the statements included in the Hagberg paper that the authors seem to have sided with the idea that "antidepressants are not themselves associated with the increased risk" of offspring autism. It's depression that is the important factor, and the "slight increase in risk with antidepressant use reflects differences in the underlying severity of depression." The other evidence they draw on to support their assertion is the "finding that the risk of ASD was not elevated in women who were prescribed antidepressants for other indications."

I'm not however so sure that we can be so certain about such a siding. I say that on the basis that researchers "did not evaluate the effect of antidepressant dose in this study" and: "Drug information in the CPRD covers written, but not dispensed prescriptions" so therefore they "cannot be sure that women used all the prescribed antidepressants." Their 'nested sibling case-control analysis' also revealed that: "the risk of ASD in offspring of mothers with untreated depression was 1.18 (95% CI 0.64-2.20) and 1.53 (95% CI 0.89-2.62) for treated depression, compared to unexposed." Not proof positive by any means, but interesting. I'm also inclined to direct you to other studies previously discussed on this blog, where the finger of suspicion has not rested entirely with maternal depression [2]. Indeed, where meta-analysed data [3] has been more partial to the idea that prenatal exposure to certain antidepressant formulations could still be on the menu with some offspring autism risk in mind.

Obviously one has to be very careful when talking about this area of autism research. Much like when another class of important medicines used during pregnancy are talked about with 'autism risk in mind' (see here), such medicines are not typically prescribed or dispensed willy-nilly without good reason. By saying that, I feel I must repeat my oft-said caveat on this blog: no medical or clinical advice is given or intended; if in doubt, talk to your prescribing physician.

But the weight of evidence produced so far has not let antidepressant use off the research hook just yet. And drawing on data suggesting that the frequency of depression during pregnancy might be on the increase (see here), one should perhaps also suspect that this could have something - a small part at least - to do with the ever-increasing rates of autism...

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[1] Hagberg KW. et al. Maternal depression and antidepressant use during pregnancy and the risk of autism spectrum disorder in offspring. Clinical Epidemiology. 2018; 10: 1599-1612.

[2] Raj D. et al. Antidepressants during pregnancy and autism in offspring: population based cohort study. BMJ. 2017; 358: j2811.

[3] Andalib S. et al. Maternal SSRI exposure increases the risk of autistic offspring: A meta-analysis and systematic review. Eur Psychiatry. 2017 Sep;45:161-166.

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"an association between maternal experience of childhood abuse and risk for ADHD in offspring"

As per the title of this post - "an association between maternal experience of childhood abuse and risk for ADHD [attention-deficit hyperactivity disorder] in offspring" - this is another entry about some uncomfortable but potentially important research [1]. Indeed, the findings reported by Andrea Roberts and colleagues continue a theme from this research group (see here and see here) on how maternal exposure to various forms of abuse both in childhood and adulthood *might* have some important repercussions for offspring psychological and developmental health and well being.

The authors begin with the premise that: "Children whose mothers experienced childhood abuse are more likely to suffer various neurodevelopmental deficits" based on quite a lot of their own previous findings [2]. Such abuse - which comes in many different forms - is, they observe, likely to impact various psychological and biological functions; some of those functions *could* also have an inter-generational effect.

So: "We examined the association of maternal experience of childhood abuse with ADHD in offspring, assessed by maternal report of diagnosis and validated with the ADHD Rating Scale-IV in a subsample, in the Nurses' Health Study II (n = 49,497 mothers, N offspring cases = 7,607, N offspring controls = 102,151)." The Nurses' Health Study II seems to be a favourite resource for these researchers, and continues to contribute to many areas of health science and research (see here). Alongside looking at maternal experience of abuse and ADHD diagnosis in offspring, researchers also looked for the presence of various other 'adverse circumstances' that might be important to any enhanced risk of offspring ADHD being diagnosed. This included exposure to tobacco smoking (see here) which has some pretty strong 'observational' evidence on a possible effect.

Results: "Exposure to abuse was associated with greater prevalence of ADHD in offspring." Although important, the nature of the relationship between abuse exposure and offspring ADHD was not exclusive, i.e. ADHD was present in both offspring of mums exposed to abuse and those not exposed to abuse. The percentage difference between abuse exposure vs. no exposure was statistically significant however, and importantly, remained significant even after adjustment for those other adverse circumstances mentioned previously. Ergo, maternal exposure to childhood abuse *might* have an important impact on offspring enhanced risk of a diagnosis of ADHD.

Although requiring further study, these are important findings. A case is made for further inspection of how such a relationship comes about covering important areas such as the effects of childhood abuse on maternal state and behaviour(s) [3] and indeed, whether adverse pregnancy factors such as tobacco smoking may also actually be related to such previous experiences of abuse [4]. I daresay that things are going to be complicated and not straight-forward when it comes to any relationship(s) and so no sweeping generalisations are required from me or anyone else.

The possibility of an 'inter-generational' aspect to the experience of childhood abuse and subsequent offspring ADHD risk is important. It provides evidence that the expression of some childhood developmental disorders may not necessarily be 'hard-wired' in a genetic sense (assuming that is, that exposure to childhood abuse is not able to 'modify' the structure/functioning of the genome [5] for example). It provides evidence for the idea that adverse life experiences may be able to manifest as physical issues (being careful how I use the term 'biopsychosocial' for example). It also might suggest that alongside the continuously important stress on preventing any form of childhood abuse, there may interventions that could eventually be put in place to 'undo' any biological effects that it causes to offspring... Eventually.

I do want to end by reiterating that whilst the experience of childhood abuse may be *associated* with a heightened risk of offspring ADHD, such a relationship does need to be treated with some caution. I'm particularly keen to 'nip in the bud' any idea that every diagnosis of ADHD is somehow an intergenerational product of abuse: it's not.

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[1] Roberts AL. et al. Association of Maternal Exposure to Childhood Abuse With Elevated Risk for Attention Deficit Hyperactivity Disorder in Offspring. Am J Epidemiol. 2018 May 14.

[2] Roberts AL. et al. Maternal exposure to intimate partner abuse before birth is associated with autism spectrum disorder in offspring. Autism. 2016 Jan;20(1):26-36.

[3] Chronis AM. et al. Maternal depression and early positive parenting predict future conduct problems in young children with attention-deficit/hyperactivity disorder. Dev Psychol. 2007 Jan;43(1):70-82.

[4] Pear VA. et al. The Role of Maternal Adverse Childhood Experiences and Race in Intergenerational High-Risk Smoking Behaviors. Nicotine Tob Res. 2017 May 1;19(5):623-630.

[5] Cecil CA. et al. Epigenetic signatures of childhood abuse and neglect: Implications for psychiatric vulnerability. J Psychiatr Res. 2016 Dec;83:184-194.

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SEED says... opioid prescription before or in early pregnancy may impact on 'child neurodevelopment'

One has to be a little careful with a few things associated with the findings reported by Eric Rubenstein and colleagues [1] but they are interesting.

In it, researchers talk about analysing for various opioid based medicines prescribed over the period 3 months before conception up to the point of childbirth and onward any subsequent correlation with "child’s risk of ASD [autism spectrum disorder], developmental delay/disorder (DD) with no ASD features, or ASD/DD with autism features." Readers may have already heard about this study as a function of its inclusion in the 2018 INSAR (IMFAR) meeting (see here).

Outside of the old tenet 'correlation is not the same as causation', the authors specific focus was on 'opioid prescription', referring to a range of opiate-based medicines that are typically indicated for pain relief and supplied under medical consultation/supervision. This was not a study looking at other types of opioid 'drug' use that seem to be making a lot of news headlines in recent times (see here), despite the inclusion of methadone and buprenorphine in their list of watched-for prescriptions in maternal medical records. Authors do however mention that opioid use among pregnant women is increasing for various different reasons...

The use of the SEED - Study to Explore Early Development - initiative was the starting point for the Rubenstein study. As per the title of this post - 'SEED says' - it's yet another research venture (see here and see here for other examples) that seems to be producing some important data covering various aspects of autism and related developmental disorders (see here). At first glance, I was a little confused about the categorisation of 'ASD/DD with autism features' included in the study but readily accepted that this was a grouping distinct from another categorisation: 'developmental delay/disorder without features of ASD'. The authors were specifically looking at autistic features with such a division of the groups.

Taking into account the various medicines that are listed as opiates (including medicines containing codeine and fentanyl), authors scoured maternal medical records looking for opioid prescriptions. The also looked at time of use covering pregnancy trimesters, their use 3 months prior to conception and 'peri-pregnancy', all as a function of those diagnostic bandings.

Results: "Preconception opioid prescription was associated with 2.43 times the odds of ASD [95% confidence interval (CI) 0.99, 6.02] and 2.64 times the odds of ASD/DD with autism features (95% CI 1.10, 6.31) compared to mothers without prescriptions." CI refers to confidence interval and although I'm no statistics expert, I noted that the first finding on preconceptual opioid prescription being *associated with* an increased odds of offspring ASD (as in a diagnosis of ASD) did cross the magical '1' number: "95% confidence interval (CI) 0.99, 6.02." Combined with quite a large CI interval, and some might say that the 'precision' of that finding was less than convincing in a statistical sense. The other 'autistic traits' finding is a little more robust but there's still a need for further investigations in this area, including the use of some biological testing parameters perhaps?

I'm not saying that medicines taken during pregnancy can't have a possible impact on offspring neurodevelopment. The still-emerging data for example, on paracetamol (see here) or valproate (see here) seem to underline that point; albeit with a scheme of work to follow in those areas too. I'm also not saying that opioid-based medicines might not have some effect on offspring development [2], quite a few effects by all accounts [3], bearing in mind the pressing need to look at this issue in the context of the opioid crisis seemingly affecting many nations these days. But, at the present time, we have to be a little careful with the still-emerging-picture in this area so as not to make big claims or unduly tarnish what is an important class of prescription medicines when it comes to pain relief and beyond. And I say that as someone who has done his fair share of using the words 'opioid' and 'autism' down the [research] years [4]...

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[1] Rubenstein E. et al. Brief Report: Maternal Opioid Prescription from Preconception Through Pregnancy and the Odds of Autism Spectrum Disorder and Autism Features in Children. J Autism Dev Disord. 2018. Aug 21.

[2] Hans SL. & Jeremy RJ. Postneonatal mental and motor development of infants exposed in utero to opioid drugs. Infant Mental Health Journal. 2001. May 9.

[3] Fill M-MA. et al. Educational Disabilities Among Children Born With Neonatal Abstinence Syndrome. Pediatrics. 2018. Aug 30.

[4] Shattock P. & Whiteley P. Biochemical aspects in autism spectrum disorders: updating the opioid-excess theory and presenting new opportunities for biomedical intervention. Expert Opin Ther Targets. 2002 Apr;6(2):175-83.

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Maternal tobacco smoking and offspring ADHD risk again

"ADHD [attention-deficit hyperactivity disorder] and movement disorders were found to be more common in hospitalized children of smoking mothers."

That was one of the details recorded in the research findings published by Gil Gutvirtz and colleagues [1] adding to a growing research 'trend' suggesting that maternal tobacco smoking during pregnancy seemingly does little for mum's health and also probably not a great deal for her offspring's health and wellbeing either (see here).

Based on results analysing "all deliveries of mothers who reported smoking during pregnancy and non-smoking mothers between 1991 and 2014 at a single tertiary medical center" researchers included almost 250,000 children in their study. Quite a small proportion - "2861 (1.2%)" - were children of mothers who smoked during pregnancy. When researchers looked at these children they noted "higher rates of movement, eating and developmental disorders as well as attention deficit hyperactive disorder" as compared with the larger non-smoking group. "Maternal smoking during pregnancy is an independent risk factor for long-term neurological morbidity of the offspring" was the conclusion.

Allowing for the fact that observational studies, even population-based ones, aren't great for 'proving' cause-and-effect, the volume of such studies independently reaching the conclusion that maternal smoking during pregnancy *might* have an important connection to risk of offspring ADHD is growing. Indeed, alongside all the other adverse outcomes seemingly connected to smoking during pregnancy (see here) I don't think it would be out of place for regulators and health-related agencies to start informing the population at large that ADHD or ADHD-related behaviours as an outcome is at least possible; as some agencies seem to be doing (see here)...

Another research step could be some further investigations actually looking at something like cotinine levels (and important marker of tobacco smoke exposure) in both mums and offspring to see whether 'the dose makes the poison' as other recent studies have hinted at [2].

Tobacco smoking ain't good for anyone it seems, and children seem to be particularly vulnerable to its effects.

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[1] Gutvirtz G. et al. Maternal smoking during pregnancy and long-term neurological morbidity of the offspring. Addictive Behaviors. 2018. Aug 16.

[2] Kim KM. et al. Associations between urinary cotinine and symptoms of attention deficit/hyperactivity disorder and autism spectrum disorder. Environ Res. 2018 Jun 26;166:481-486.

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Maternal and child immune disease and autism or other developmental disorder

The paper by Lisa Croen and colleagues [1] provides the brief blogging fodder today and some further results from the Study to Explore Early Development (SEED) initiative based in the United States. Whilst SEED has already produced quite a bit of peer-reviewed research data (see here), this time around the focus was on "the role of family history of autoimmune diseases, asthma, and allergies in autism spectrum disorder (ASD) as well as other developmental disorders (DD)." Yep, immune function yet again (see here).

Researchers mention how following their analysis of some 660 children with ASD, nearly a thousand children with DD and over 900 not-autism, not-DD population (POP) controls, they turned up some potentially important *associations* pertinent to immune system related conditions potentially elevating the risk of autism and/or DD. So: "Maternal history of eczema/psoriasis and asthma was associated with a 20%-40% increased odds of both ASD and DD" and "children with ASD were more likely to have a history of psoriasis/eczema or allergies than POP controls." Conversely, they did not detect any statistically significant associations between "paternal history or family history of these immune conditions for either ASD or DD."

I'm gonna leave things there for now on this topic. The immune system seems to be related to at least 'some' autism. There's nothing particularly new or novel about that sentiment but it does cover an awful lot of ground. A lot more research is required on the 'hows-and-whys' (see here for one example research route) and whether intervening on various immune system related conditions, one *might* also impact on the presentation of behaviour too...

And on the topic of intervention, may I also draw your attention to the mammoth paper by Marchezan and colleagues [2] reviewing the many and varied (evidence-based) intervention methods that are available as and when immune system issues crop up in the context of autism?

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[1] Croen LA. et al. Family history of immune conditions and autism spectrum and developmental disorders: Findings from the study to explore early development. Autism Res. 2018 Aug 10.

[2] Marchezan J. et al. Immunological Dysfunction in Autism Spectrum Disorder: A Potential Target for Therapy. Neuroimmunomodulation. 2018. Sept 5.

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The continuing legacy of DDT? Maternal insecticide levels and risk of offspring autism

I see that the paper published by Alan Brown and colleagues [1] reporting on "the first biomarker-based evidence that maternal exposure to insecticides is associated with autism among offspring" has been garnering headlines and ruffling feathers in equal measure.

It's seemingly guaranteed that whenever a study mentions words like 'toxins' and 'environment' in the context of (some) autism, some brows become furrowed, decrying any possibility of a *connection*. In equal measure, it has to be said, opposite views on such evidence being proof positive that 'autism is all environmental' and 'man-made' also emerge. To quote from an imaginary character: "Darkness rises and light to meet it!" (I'll leave you to decide which side is which).

DDT - dichlorodiphenyltrichloroethane - mentioned in the title of this post, is an insecticide categorised as a persistent organic pollutant (POP). Like many such products, it started off being used with noble intentions, to control important diseases like malaria and typhus, and even earned someone a Nobel prize as a result. It's also credited with saving millions of lives during the period of its use; as one WL Churchill apparently said: "The excellent DDT powder has been found to yield astonishing results against insects of all kinds, from lice to mosquitoes."

But things did not remain so rosy for DDT as data (see here) and a book subsequently emerged suggesting a link between exposure to DDT and various adverse animal and human outcomes. Restrictions on use and banning eventually came into effect and the glory days of DDT started to wane, albeit not with everyone being totally supportive of an outright ban. As per the POP status of DDT however, restrictions and banning did not mean that this stuff magically disappeared from the environment overnight. Coupled to a less than universal ban on the use of DDT, and residues of DDT can still be found in the environment today, albeit in lower levels than when it was at peak production and usage. And science is able to test for them fairly accurately...

Set in this context, the Brown paper did just that; the DDT 'connection' stems from researchers noting that levels of a specific metabolite of DDT - p,p'-dichlorodiphenyl dichloroethylene (p,p'-DDE) - measured in "maternal serum specimens from early pregnancy" seemed to show a 'threshold' *association* with offspring developmental outcomes such as autism (with and without intellectual disability). This, in the context that there is also some evidence of 'transplacental transfer' of such compounds [2], and where other studies have talked about the possible effects of in-utero exposure to DDT and offspring neurodevelopment [3] as part of a wider appreciation that infants and children may be uniquely sensitive to such pesticide exposures (see here). Brown et al report such results as part of the Finnish Prenatal Study of Autism (FIPS-A), an initiative that has already yielded quite a few important peer-reviewed findings (see here), some of which have been previously covered on this blog (see here for example). Study organisation and participant numbers are pretty good in the FIPS-A initiative, albeit with some methodological caveats (i.e. the use of observational study not able to prove cause-and-effect).

The finding of a 'dose-related' (threshold-related) relationship between p,p'-DDE and offspring autism risk noted by Brown is also interesting. Add in the observation that autism accompanied by intellectual (learning) disability also seemed to show an apparent relationship to p,p'-DDE levels and there is a scheme of additional work to be followed. Not least with regards to mechanism(s) - preterm birth risk has been mentioned which could 'overlap' with some autism-related data [4] - and whether for example, other risk 'compounds' might also be important. Indeed, I understand that the possibility of 'synergistic' interactions might be on the cards in future study for this group in light of previous results [5]. And going back to those findings from Eskenazi et al [3] who noted that "breastfeeding was found to be beneficial even among women with high levels of [DDT] exposure", I do wonder if this variable might also require further examination in the context of the Brown findings too [6].

Obviously one has to be slightly careful with any sweeping generalisations made as a result of the Brown findings. This research did not say that all autism was 'caused' by DDT exposure or any other insecticide or related compound, and neither was it designed to do so. The authors also mentioning that their study "has implications for the prevention of autism" is perhaps more than a little premature and seemingly at odds with some (recent) opinions.

But the Brown study did make a point of testing for DDT metabolites in mums-to-be and, set within other independent research findings *highlighting* various other pollutant exposures as potentially being relevant to the developing brain and important offspring outcomes like autism (see here and see here and see here for examples), one cannot simply brush off the Brown results and their important implications. Further research is implied minus hype.

Coincidentally, a 'roadmap' for incorporating the 'exposome' into psychiatry research was recently published [7] and could prove quite useful in the context of further research in this area...

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[1] Brown AS. et al. Association of Maternal Insecticide Levels With Autism in Offspring From a National Birth Cohort. Am J Psychiatry. 2018 Aug 16:appiajp201817101129.

[2] Zhang X. et al. Transplacental transfer characteristics of organochlorine pesticides in paired maternal and cord sera, and placentas and possible influencing factors. Environ Pollut. 2018 Feb;233:446-454.

[3] Eskenazi B. et al. In utero exposure to dichlorodiphenyltrichloroethane (DDT) and dichlorodiphenyldichloroethylene (DDE) and neurodevelopment among young Mexican American children. Pediatrics. 2006 Jul;118(1):233-41.

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

[5] Cheslack-Postava K. et al. Maternal serum persistent organic pollutants in the Finnish Prenatal Study of Autism: A pilot study. Neurotoxicol Teratol. 2013 Jul-Aug;38:1-5.

[6] Tseng PT. et al. Maternal breastfeeding and autism spectrum disorder in children: A systematic review and meta-analysis. Nutr Neurosci. 2017 Oct 18:1-9.

[7] Guloksuz S. et al. The Exposome Paradigm and the Complexities of Environmental Research in Psychiatry. JAMA Psychiatry. 2018 Jun 6.

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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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Pregnancy diet and offspring "hyperactivity-inattention symptoms"?

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

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

Anyhow, the science...

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

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

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

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

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

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

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

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

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

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

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Effects of pregnancy vitamin D deficiency on social behaviours of offspring rats

I note the findings reported by Nathanael Yates and colleagues [1] have garnered a few lay and science media headlines recently (see here) as authors concluded that "early life levels of vitamin D are an important consideration for maternal behavioural adaptations as well as offspring neuropsychiatry." Further coverage of their findings is provided in a helpful article for The Conversation (see here), where some authors - including the autism research powerhouse that is Andrew Whitehouse - provide a little more interpretation of their findings. I might also add that Whitehouse is no stranger to the vitamin D - autism research story (see here).

So, what's all the current discussion about?

Well, vitamin D - the 'sunshine' vitamin/hormone - is front and centre of this latest research, and some investigation into "how early life vitamin D deficiency during rat pregnancy and lactation alters maternal care and influences neurodevelopment and affective, cognitive and social behaviours in male adult offspring." This is set within the context that vitamin D seems to be doing a lot more than just contributing to bone health (see here). You'll of course note the use of the word 'rat' in the above text, and in particular what happened to offspring baby rats in terms of "offspring neurodevelopmental markers, ultrasonic vocalisations and adult behavioural outcomes including social, cognitive and affective-like behaviours" when mummy rat diets are loaded up with enough vitamin D as opposed to those mummy rats who were provided with a vitamin D deficient diet. The theory behind those vitamin D loaded vs. vitamin D deficient mummy rat diets is that: "In both humans and rats, a baby developing in the womb is completely reliant on the mother’s vitamin D stores." Probably something to do with the lack of sunlight exposure in the womb(!)...

Results: there did seem to be some difference across various 'test a rat / test an offspring rat' measures as a function of vitamin D status, looking across behaviour, brain scans (yes, rats did meet some MRI equipment) and also "plasma corticosterone levels and neural expression of genes associated with language, dopamine and glucocorticoid exposure." So for example, authors describe how "males that had been exposed to vitamin D deficiency in early life exhibited decreased social behaviour, impaired learning and memory outcomes and increased grooming behaviour, but unaltered affective behaviours." It's not difficult to see the 'decreased social behaviour' links that *could* be made with a condition / label / diagnosis like autism; particularly when vitamin D has quite the peer-reviewed research history with autism in mind (see here).

Interestingly too, but not made too much of in the chatter about this study for obvious reasons, were the observations made around maternal care as a function of vitamin D status, bearing in mind that vitamin D deficiency will probably impact both mummy rat and baby rat. So: "the quality of maternal care was decreased in dams consuming a vitamin D-deficient diet." Mmm...

Whilst this is important work, and adds to our understanding that appropriate nutrition throughout the lifespan is important to various aspects of functioning, I'll reiterate that this was research using rats. Rats not humans. It is perhaps timely that at around the same time that the Yates paper was published, I also chanced upon some discussion over at Spectrum on how we all need to be a little bit careful when talking about modelling autism in various animals (see here) and their relevance to real, often much more complicated, people (see here) and their [multiple] labels (see here).

I note that in their piece for the The Conversation, authors caution that their findings don't mean everyone who is pregnant (or could become pregnant) should rush out and load up on vitamin D so as to potentially influence offspring developmental course. I would second that view; but would also direct your attention to some Government advice quite recently (at least here in Blighty) that we should perhaps all be thinking about vitamin D supplementation (see here) and the many and varied ways that this vitamin/hormone *might* impact on our physiology and beyond (see here).

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[1] Yates NJ. et al. Vitamin D is crucial for maternal care and offspring social behaviour in rats. J Endocrinol. 2018 May;237(2):73-85.

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" a parental history of T1D was associated with a 29% increased risk of being diagnosed with ADHD"

T1D mentioned in the title of this post - "a parental history of T1D was associated with a 29% increased risk of being diagnosed with ADHD [attention-deficit hyperactivity disorder]" - refers to type 1 diabetes. This is an autoimmune condition where the body's own immune system attacks 'self' and, in this case, leads to serious problems with the production of insulin with onward effects on blood sugar (glucose) levels.

The findings reported by Jianguang Ji and colleagues [1] observed something of a *correlation* between parental history of type 1 diabetes and offspring risk for ADHD. Based on the analysis of one of some of those splendid Scandinavian population registries - this time based in Sweden - researchers found upwards of 15,000 children "born after their parents were diagnosed with T1D." Bearing in mind previous research had hinted that a parental medical history of various autoimmune conditions might elevate the risk of offspring ADHD (see here), they looked-see whether "a family history of type 1 diabetes (T1D) is associated with an increased incidence of attention deficit hyperactivity disorder (ADHD) in offspring." It appeared to be so.

When taking into account various other potentially confounding variables, authors noted an overall increased risk (hazard ratio) to offspring which also appeared to fluctuate depending on whether mum or dad was diagnosed with T1D, albeit not statistically significantly so. Having said all that, this study is still one of correlation and not necessarily causation...

'Why?' is the question still to be answered. Why would an autoimmune condition with seemingly little neurodevelopmental 'connection' in terms of behavioural symptoms, raise the risk of something like ADHD in offspring? I might add that a similar question is being asked across quite a few other developmental diagnoses (see here for example). I have some ideas (see here) outside the obvious focus on blood glucose, but some solid research and science really needs to follow.

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[1] Ji J. et al. Type 1 Diabetes in Parents and Risk of Attention Deficit Hyperactivity Disorder in Offspring: A Population-Based Study in Sweden. Diabetes Care. 2018 Jan 26. pii: dc170592.

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