Wednesday, 23 January 2013

Maternal C-reactive protein and autism

As per my previous blog entry on the possibility of some involvement of a skin-brain axis to cases of autism (no, seriously), one of the key themes seemingly increasing in importance in autism research is the possibility of some connection with inflammation and the inflammatory processes.

Whilst sounding completely at odds with how autism is commonly described - a developmental disorder variably manifesting specific behavioural and cognitive features - there is a surprisingly long and growing interest in how physiological processes like inflammation may overlap with cases of autism. I've covered a tiny, tiny portion of that research interest in a few posts on this blog previously (here and here for example) outside of the whole gastrointestinal inflammation side of things, which for some still remains a contentious area.
Karjalanpiirakka @ Wikipedia   

I wouldn't dream of trying to offer any consistent or reliable hypothesis for how inflammation might link into at least some cases of (the) autism(s) in either a correlative or causative way because it's way outside my area of competence. Instead I'll leave it to others looking at other, possibly related, conditions to speculate on one or two suspected mechanisms.

In this post however, I would like to talk some more about inflammation and autism following the publication of a study by Alan Brown and colleagues* reporting on the possibility that inflammation or rather one particular marker of inflammation - C-reactive protein (CRP) - in autism might have at least some of its roots and effects in the very earliest days of life. Prof. Brown by the way, seems to have some interest in how early life variables might link into later life psychiatry as per his name being on the recent Lehti paper on IVF covered in this post.

Before going further I will offer a caveat or two about the Brown paper and it's emphasis on looking at maternal CRP levels during early pregnancy. Although measuring maternal inflammation (via CRP) is the name of the game, this does not mean that autism or anything else is 'caused' by such inflammation based on the current bank of evidence. Everyone seems to be 'inflammed' to some degree and for lots of different reasons but not everyone has autism. Neither does it sound any return to the parental 'blame game' of times gone by in much the same way that de novo mutations and paternal age shouldn't either.

I could be wrong but Brown and colleagues seem to have based at least part of their collected data on a Finnish initiative detailed in this paper by Lampi and colleagues** that basically aimed to examine whether there were any interesting links between "prenatal serologic factors, mediating and moderating developmental antecedents, and risk of autism spectrum disorders (ASD)". In their recent paper they report a significant association between maternal CRP levels and risk of offspring autism; especially pronounced when comparing that fifth of the population where CRP levels were highest compared with the fifth where they were lowest.

With again all caveats in active play, this is not the first time that maternal inflammation related to risk of offspring autism has been discussed. My mind wanders back to my 'you give me fever' post based on some interesting observations from the CHARGE initiative on mum's [retrospectively] reporting fever during pregnancy and offspring autism risk. Also potentially important, and again CHARGE-related, is the whole air pollution exposure - inflammation link albeit slightly more speculative at this point. And of course there are the Paul Patterson mouse studies, which to regular readers probably require little introduction, but for everyone else implies some maternal immune activation to be potentially important to offspring autism, and in need of further investigation.

Outside of the autism risk bit, this is also not the first time that elevated maternal CRP levels have been reported in relation to autism and other developmental conditions. The possibility for example that CRP levels could be related to caring for a child with autism was discussed in this post and how the stress of raising a child with behavioural difficulties might take an inflammatory toll on parents. With all due respect to the Lovell findings***, the more recent Brown paper implies that the caring aspect might not necessarily be the root cause of elevated CRP given its measurement during pregnancy which, speaking from a bystander point of view, can be a stress in itself (also not ruling out caring duties enhancing any effect or being related to other physiological measures with a stress element).

I'm also drawn back to how the Brown findings might also relate to those studies which have actually looked at CRP in people with autism. I posted on the Khakzad study a while back and how they reported some very significant elevations in CRP in their cohort of participants with autism. On the basis of that study one might think that elevated CRP is a pretty consistent finding in autism. That being said there is still a relatively small body of CRP-autism research and in some studies, such elevations were not detected compared to controls (see this post). Such is the variable nature of the autism(s).

Brown and colleagues suggest that maternal CRP measures might potentially translate into "identifying preventive strategies and pathogenic mechanisms in autism". Personally I don't think we are quite there yet in terms of determining just how elevated CRP might translate into autism or anything else given that (a) we don't really know how far back CRP goes beyond mothers as per a family history of elevated CRP and whether any other comorbidity might be connected to it****, and (b) spot determinations of CRP levels (which I assume is what they did) don't necessarily translate into chronic elevations of CRP and says very little about other relationships such as those of the cytokines.

I am however sufficiently convinced from the cumulative data on inflammation (both maternal and first-person levels) and autism that this is an area worthy of much, much, much more investigation.


* Brown AS. et al. Elevated maternal C-reactive protein and autism in a national birth cohort. Molecular Psychiatry. January 2013.

** Lampi KM. et al. Finnish Prenatal Study of Autism and Autism Spectrum Disorders (FIPS-A): overview and design. J Autism Dev Disord. 2011; 41: 1090-1096.

*** Lovell B. et al. The psychosocial, endocrine and immune consequences of caring for a child with autism or ADHD. Psychoneuroendocrinology. 2012; 37: 534-542.

**** Ridker PM. et al. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000; 342: 836-843.

--------- Brown, A., Sourander, A., Hinkka-Yli-Salomäki, S., McKeague, I., Sundvall, J., & Surcel, H. (2013). Elevated maternal C-reactive protein and autism in a national birth cohort Molecular Psychiatry DOI: 10.1038/mp.2012.197