"Learning difficulties linked with winter conception"

Having recently mentioned the BBC headline that makes up the title of this entry in a related post (see here) I'm pleased to be finally able to bring the paper by Daniel Mackay and colleagues [1] (open-access) to your attention.

Observing that in Scotland at least, "that season of conception is strikingly associated with the subsequent risk of special educational needs in the offspring" there are various potential implications to come from such data covering both learning (intellectual) disability and also the autism spectrum.

So, take over 800,000 school children who attended a school in Scotland between 2006 and 2011 and whose data could be linked to maternity records (again, held in Scotland). Examine date of conception as per the formula "date of delivery minus gestational age at delivery plus 2 weeks" and plot "monthly incidence rates of children with special educational needs... by month of conception." Include "special educational needs attributed to intellectual disabilities, dyslexia, other specific learning difficulties, visual impairment, hearing impairment, deafness and blindness individually combined, physical or motor impairments, language or speech disorder, ASD [autism spectrum disorder], and social, emotional, and behavioral difficulties" for a more detailed breakdown of how month of conception might be linked to said labels.

Results: well, I've already mentioned about the 'striking association' that was made between season of conception for starters. The trends across various labels covered under special educational needs (SEN) were remarkably consistent where conception in quarter 1 (January–March) seemed to show a peak in terms of incidence compared with those conceived in quarter 3 (July–September). Even when researchers re-ran the data taking into account only children who were born at 40 weeks gestation (n=246,594), they got pretty much the same results coming back; "suggestive of an environmental exposure that occurs at a critical developmental stage before labor and delivery rather than secondary to seasonal variation in the gestational age at delivery."

So what might account for the possible link between winter conception and the presence of various labels headed under SEN? Well, it's not beyond the realms of possibility that winter, the season of coughs, colds and sneezes might imply some infective agent as potentially exerting an effect. There is a pretty sizeable volume of peer-reviewed literature suggesting that something like maternal influenza might influence offspring behaviour and development [2]. This line of research is all the more convincing given the continued drive to look at the [reprogrammed] maternal immune system during pregnancy and what effects infection might have on it. The maternal pregnancy body as 'environment' eh?

The authors also discuss another potentially equally important factor as also being something to look at: vitamin D. So: "In our study, the incidence of special educational needs peaked among children conceived in February whose mothers would have experienced low levels of ultraviolet B radiation and therefore produced low levels of vitamin D in early pregnancy and experienced higher levels in late pregnancy." Regular readers are probably pretty sick and tired of me going on (and on) about how vitamin D is potentially linked to so much more that just bone health. I was really happy to see that UK Government policy is starting to change when it comes to the 'sunshine' vitamin/hormone (see here) as it's importance is at last being recognised. Bearing in mind that because of their location, the people of Scotland are not exactly blessed with loads of solar radiation conducive to the synthesis of lots of year-round vitamin D, one can see how this stuff might be an important feature of the relationship observed by Mackay et al. But, as per recent headlines, one needs to be a little cautious when it comes to ideas about supplementation...

More research is however implied given that there could be other important factors potentially also at work, although I'd be minded to suggest we already have two important variables with infection and vitamin D.

To close, the UK Office of National Statistics (ONS) has some interesting data on how popular your birthday might be. Mine is rather less popular...

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[1] Mackay DF. et al. Month of Conception and Learning Disabilities: A Record-Linkage Study of 801,592 Children. Am J Epidemiol. 2016 Sep 20.

[2] Cai L. et al. Gestational Influenza Increases the Risk of Psychosis in Adults. Med Chem. 2015;11(7):676-82.

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Mackay DF, Smith GC, Cooper SA, Wood R, King A, Clark DN, & Pell JP (2016). Month of Conception and Learning Disabilities: A Record-Linkage Study of 801,592 Children. American journal of epidemiology PMID: 27651381

Autism and low vitamin D at birth

Discussions about vitamin D (the 'sunshine' vitamin/hormone) and autism are not unfamiliar to this blog. Just last year (2014) I covered research talking about the possibility of a connection between vitamin D and [some] autism at least three times (see here and see here and see here), possibly more.

..but in my game, I'm the bad guy,
and I live in the garbage.

I wouldn't say that I'm an advocate for everything implied by the correlations being made between vitamin D levels and autism given that vitamin D levels have also been linked to everything from depression (see here) to schizophrenia (see here), issues which might also show some passing connection for some people on the autism spectrum (see here for example). But I am interested in how this research area is evolving...

And evolving it is, as yet another study has been published on vitamin D and autism, this time from Elisabeth Fernell and colleagues [1] (open-access) based at the University of Gothenburg in Sweden. Examining 25-hydroxyvitamin D (25(OH)D) levels in dried blood spots "taken in the neonatal period for metabolic screening", researchers concluded that: "low prenatal vitamin D may act as a risk factor for ASD [autism spectrum disorder]."

Aside from some happiness that the fantastic resource which is the neonatal blood spot is being put to good scientific use with autism in mind (see here), I was particularly interested to read about the findings from this research group given their previous foray in this area (see here) based on the paper from Kočovská and colleagues [2] (open-access). On that occasion they concluded that young adults diagnosed with an ASD were, as a group, quite a bit more likely to present with lower vitamin D levels than siblings, parents and an asymptomatic control group.

Back to the Fernell paper, and a few pointers might be in order:

• "The aim of the present study was to address the emerging hypothesis that low levels of vitamin D at birth increase the risk for ASD." OK.
• Sibling pairs were used, one child diagnosed with autism, the other "non-ASD affected". Participants were drawn from two samples, a Gothenburg catchment area sample and a "Stockholm Somali group" which have been previously used in a prevalence study of autism in Somali children in Sweden (see here). Those in the know about autism research will perhaps have heard about autism and Somali children a few times before (see here).
• Participants were coded according to ethnicity into one of three groups: Swedish, Miscellaneous (non-Scandinavian Europe, South America and East Asia) and African/Middle East. This was due to: "well-known ethnic disparity of vitamin D status."
• Results: "Children to parents of non-Scandinavian ethnicities had lower mean 25(OH)D levels than children to Swedish parents." See the previous point. 
• "The mean 25(OH)D level was lower in children with ASD... than in their siblings." This trend was significant in "the Swedish and Miscellaneous groups, but not in the African/Middle East group." The authors report that season of birth, a potentially important factor in birth vitamin D levels was likely not the primary variable to account for the ASD - non-ASD sibling differences but there were some disparities noted. I would also draw your attention to another comment from the authors: "Since we studied newborn children before diagnosis, our results are definitely unrelated to lifestyle and diet of the individual, although the mother’s lifestyle and other environmental factors cannot be ruled out."
• Author conclusion: their findings may support: "the hypothesis that developmental vitamin D deficiency during late pregnancy may carry an increased risk of ASD in the child." Alongside, that is, the requirement for further research with larger numbers of participants.

I would certainly echo the sentiments of the authors for the need for larger-scales studies of any connection between low pregnancy/birth vitamin D levels and risk of autism. This is however not the first time that this issue has been studied as per my commentary on the results from Whitehouse and colleagues [3] (see here) who based on the use of the Autism-Spectrum Quotient (AQ) (itself the topic of some recent inquiry) concluded that: "Maternal 25(OH)-vitamin D concentrations were unrelated to offspring scores on the majority of scales" bearing in mind their focus on mums not offspring when assaying for vitamin D.

A few further points before I let you go about your business.

"In this study we did not examine other possible causes for ASD, such as for instance infections during pregnancy." A very important point indeed if one looks at some of the research literature in this area (see here).

"Autoimmunity is another possible cause for ASD, which was not investigated. However, as low vitamin D is suggested to contribute to the pathogenesis of autoimmunity... our findings could be relevant in this context as well." Again, another potentially important point raised here on the basis of other research which has brought the issue of autoimmunity into the autism-vitamin D frame (see here). More generally, the issue of autoimmunity and autism is of increasing research interest.

Finally, the authors leave us with a tantalising question: "whether or not adequate supplementation of vitamin D to pregnant women might lower the risk for ASD in the offspring"? Before anyone get's ahead of themselves, I think we need quite a bit more discussion and study on this question specific to autism given that more generally vitamin D for pregnant women is seemingly being more frequently indicated.

Just one more thing (to coin a phrase)... although no-one really knows the specific hows, whys and wherefores of any vitamin D connection to autism, I'd be minded to suggest that physiological issues such as gut permeability (yes, it is a real thing) might also register on any future research endeavours given data like that from Assa and colleagues [4] adding to an already interesting area (see here). I'm not saying that this is the only potential factor but one among many.

Music: Do you feel lucky punk?

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[1] Fernell E. et al. Autism spectrum disorder and low vitamin D at birth: a sibling control study. Molecular Autism. 2015; 6: 3.

[2] Kočovská E. et al. Vitamin D in the General Population of Young Adults with Autism in the Faroe Islands. J Autism Dev Disord. 2014 Jun 14.

[3] Whitehouse AJ. et al. Maternal vitamin D levels and the autism phenotype among offspring. J Autism Dev Disord. 2013 Jul;43(7):1495-504.

[4] Assa A. et al. Vitamin D Deficiency Predisposes to Adherent-invasive Escherichia coli-induced Barrier Dysfunction and Experimental Colonic Injury. Inflamm Bowel Dis. 2015 Jan 14.

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Elisabeth Fernell, Susanne Bejerot, Joakim Westerlund, Carmela Miniscalco, Henry Simila, Darryl Eyles, Christopher Gillberg, & Mats B Humble (2015). Autism spectrum disorder and low vitamin D at birth: a sibling control study. Molecular Autism : 10.1186/2040-2392-6-3

Summarising birth risk factors for autism

Hot on the heels of the various evidence published last week on the rise and rise of variable gene-environment interactions in relation to autism aetiology, an entry on the Autism Speaks blog directed me to a study published in the Pediatrics today which takes an overview look at the collected data on birth factors in relation to risk of developing autism. The abstract to the paper can be found here.

Based on a meta-analysis of several studies looking at various perinatal and neonatal risk factors analysed in connection to autism, several issues are suggested to be potentially related by Gardener and colleagues, although like many things about autism, no one factor or pattern of factors seems to show a universal connection.

So, issues such as umbilical cord 'complications' (I assume this means things like knots and/or being wrapped around baby's head), low birth weight and small for dates are a few of the risks which seem to show some possible connection. Others which have already come up on this blog in one shape or form include: hyperbilirubinemia, neonatal anaemia, feeding difficulties, and being a summer birth. I note also a possible connection with blood or rhesus incompatibility which is something I perhaps will go into in a future entry. There were a few other conditions not found to be associated with any increased risk including head circumference and prematurity. I was a bit taken aback by prematurity not showing association when the data were joined. Having said that, studies like this one have perhaps indicated that such issues might be more related to any co-morbid cognitive problems attached to the autism diagnosis. The head circumference factor is something that is due to be discussed in a separate post in the coming weeks.

I don't want to jump on to any bandwagon with these findings because, as the authors note, they were often comparing oranges and apples with the array of research reviewed. I do however think that this paper provides some important data when starting to look at both 'risk' factors in developing autism and possibly mechanisms; building on what is known about some of the birth factors listed and the risk of other physical and behavioural developmental conditions outside of autism.

Risk, season of birth and autism

Risk is a strange thing. We are told by many different sources about the risk of this happening, or that happening, normally accompanied by some smart figure. This page offers quite a good example of risk in action based on the UK mortality figures. What the statistics tell me is that, as a man, I am at greater risk than a woman of death at every stage of my life, from my first breath to my last, and without giving my age to you, I am currently on the borderline of a low-to-moderate risk of dying anytime soon. Great (he says reaching for the Smiths CD).

I was in two minds whether or not to make this post relating to possible seasonal influences and risk of receiving a diagnosis of an autism spectrum condition. Two minds because you could give me almost any reasonably well-known condition and I could probably provide some evidence that season or month of birth is potentially connected in some way. For example, the risk of brain tumor is greater for those born in the Winter according to this study. Interesting yes? But consider how many factors might be involved in developing a brain tumor - not least your subsequent exposure events to lots of things - and then such statistics begin to mean less and less.

I am not disputing that there may be a connection between some conditions and season of birth. There are perhaps some important connections to be made in respect to things like maternal risk of exposure to viral or other infectious agents, whether pollen counts are high, sunlight exposure, and even depending on where you live, whether or not there is increased exposure to environmental pollutants such as car fumes or pesticides.
I merely suggest that when we start to say that heterogeneous conditions like autism are 'related' to this month or that month of birth or conception, we start to enter some pretty shaky territory.

The paper which attracted my interest was this one published in Epidemiology from the MIND Institute. It has been followed by quite a few headlines like this one. Their findings: based on an analysis of quite a large participant base of people with autism (n=19,238), there was an increased 'risk' of autism where conception occurred in December through to March.

I say an increased risk but the odds ratios (OR) ranged between 1.08 - 1.16). Assuming that 1 implies the likelihood of something occurring in equal measure across 2 groups, you can see that the stats are not exactly jumping out at us (even with the confidence interval data presented). Consider as a comparator the OR of developing autism and living close to a motorway (freeway) by some of the same author group (OR = 1.86, CI: 1.04-3.45). See what I mean?

The MIND paper is not the first (and no doubt won't be the last) to suggest such a correlation to onset of autism. Last year we had this paper which suggested that in a UK cohort, conception during the summer months was associated with an increased risk of autism. Yes, I know that the participant group was far, far less (n=86) but importantly this was a prospective study based on the ALSPAC initiative.

I could go on with other studies, all seemingly suggesting different things. There are of course various factors to consider: where the study was conducted, how many people were included, etc. All of which can (and do) impact on the results obtained. There may very well be some sub-groups of autism with a seasonality factor attached, but at the moment we can't say for sure.

Importantly also some studies have reported no seasonality effect. This paper from Fred Volkmar and colleagues says it all in their title - even showing no association when sub-categorising participants based on language ability.

I will close with our contribution to this issue published in 2009. We did a slightly different kind of analysis, looking at the various sub-diagnoses of pervasive developmental disorder according to season of birth compared with population data (from the ONS) and found... absolutely nothing - no differences across the different cohorts and no differences overall. I would not presume to say that this issue is closed but I am inclined to say whilst an interesting area of research there is probably no overall relationship with autism.