Sunday, 3 February 2013

Antiepileptic exposure and offspring autism risk

The great autism research spotlight continues to focus its gazerbeam on the very earliest days of being for any clues governing why some children might go on to develop autism. I've kinda lost count of how many times I've talked about maternal exposure for this or that having been linked to an elevated risk of offspring autism; ranging from maternal inflammation to parental occupational exposure to the possibility that maternal medication history during pregnancy might singularly or cumulatively exert some potential effect on risk.

Baby @ Wikipedia  
Indeed this last factor on medication during pregnancy has once again been the source of some speculation following the publication of a paper by Bromley and colleagues* suggesting an increased risk of offspring autism in cases of exposure to various antiepileptic drugs in-utero.

A quick search of PubMed reveals that Dr Bromley has some history in looking at foetal antiepileptic exposure on developmental outcomes as per papers like this one and this one (open-access). There were a few clues in these papers that autism and other developmental disorders might well have been next on the list for investigation for this research group.

Press attention for the current study? Er, yes, it goes without saying particularly in light of headlines like: Epilepsy drug linked to tenfold increase in autism (complete with picture of pregnant mums holding their tummy) and Epilepsy drug link to brain damage in 17,500 babies. Aside from thinking that there is probably lots of money to be made in stock photos of pregnant women and their bumps, if I were a pregnant mum with epilepsy taking such meds, I would probably be straight on the phone to my doctor/midwife to ask about these findings.

So what did Bromley et al actually find and report:

  • Based on an analysis of children born to 528 pregnant mums based here in Blighty, physical and cognitive abilities were assessed at various point during early infancy and childhood.
  • Of the total cohort, data across various testing points were available for 415 children; of which 19 had been diagnosed with a "neurodevelopmental disorder" by the age of 6 years.
  • Some of these neurodevelopmental disorders included autism (n=12); others had diagnoses of conditions like ADHD and dyspraxia (developmental coordination disorder, DCD).
  • Looking through the kind of meds being taken by mum's during pregnancy, the authors reported a connection between greater offspring neurodevelopmental issues in those mothers who were taking anti-epileptic medication compared to those who weren't (7.4% vs. 1.8% respectively) as per the rate of epilepsy in mums-to-be (243/528; 46%).
  • Sodium valproate was in particular singled out as part of the study as per the text: "children exposed to valproate alone in the womb were six times more likely to be diagnosed with a neurodevelopmental disorder". Indeed an even greater risk if a cocktail of other meds were also used during pregnancy.

As one would expect, the authors have cautioned that pregnant women with epilepsy taking these medications does not automatically translate into offspring autism and on no account should pregnant women just stop taking the drug without appropriate medical advice. Risk, as I have discussed before, is risk not certainty and epilepsy can be a life-threatening condition.

Valproate has already some history with regards to its possible effects on the developing infant as per the description of foetal valproate syndrome** (open-access) highlighting its potential teratogenicity. With autism in mind, this is also not the first time that valproate has appeared in the research texts. I note for example papers like this one from Bristot Silvestrin and colleagues*** which talked about an "animal model of autism induced by prenatal exposure to valproate", also bringing in words like 'glutamate' which has also seen its fair share of scientific inquiry in recent times (see this post). There are several other papers I could cite with a valproate-autism connection but I don't want to bore you.

Valproate is also a compound I've become quite interested in recently as a result of being part of some very brief forays into the science writing domain and in particular on the topic of epigenetics (see here but now for PJ members only). Since doing a little bit of research in that area I've for example, read quite a bit on how valproate is now considered to be quite a potent HDAC inhibitor**** (open-access) with some potentially useful effects in cancer therapy. This HDAC inhibition quality - leading on to histone hyperacetylation - has also been questioned as a possible route towards some of the autism-like findings. To quote from the paper by Kataoka and colleagues***** "findings suggest that VPA-induced histone hyperacetylation plays a key role in cortical pathology and abnormal autism-like behaviours in mice". Bearing in mind mice are mice and not humans.

The Bromley paper is an interesting paper and certainly invites a lot more study into how prenatal valproate exposure *might* show some connection to offspring risk of autism and other developmental conditions. Not trying to be anti-medication or anything, the study also highlights how little we actually know about the medicines we take and in particular their potential for things like trans-generational effects...


* Bromley RL. et al. The prevalence of neurodevelopmental disorders in children prenatally exposed to antiepileptic drugs. J Neurol Neurosurg Psychiatry. January 2013.

** Kini U. Fetal valproate syndrome: a review. Pediatric & Perinatal Drug Therapy. 2006; 7: 123-130.

*** Bristot Silvestrin R. et al. Animal model of autism induced by prenatal exposure to valproate: Altered glutamate metabolism in the hippocampus. Brain Res. 2013; 1495: 52-60.

**** Göttlicher M. et al. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J. 2001;20:6969–6978.

***** Kataoka S. et al. Autism-like behaviours with transient histone hyperacetylation in mice treated prenatally with valproic acid. Int J Neuropsychopharmacol. 2013; 16: 91-103.

---------- Bromley, R., Mawer, G., Briggs, M., Cheyne, C., Clayton-Smith, J., Garcia-Finana, M., Kneen, R., Lucas, S., Shallcross, R., Baker, G., & , . (2013). The prevalence of neurodevelopmental disorders in children prenatally exposed to antiepileptic drugs Journal of Neurology, Neurosurgery & Psychiatry DOI: 10.1136/jnnp-2012-304270