Questioning Answers: Soy infant formula and seizures in autism

Spring @ Wikipedia

'Association' is a word I'm sure many people with a connection to autism will have heard a lot about. Y'know gene X or compound Y is the plat du jour when it comes to autism aetiology; more often than not carrying the caveat 'requires further investigation'. As to whether such investigations are ever truly carried out would perhaps be an interesting piece of research on autism research.

Today I'm talking about another association, another variable to throw into the statistical risk mix derived from the paper by Cara Westmark [1] (open-access here) suggesting that where seizures or epilepsy present alongside (or as part of) autism, there may be a curious correlation to be had with the use of soy infant formula.

I'll readily admit that when first reading the title to this study I was more than a little reluctant to blog about it. I can't really explain why - whether it was yet another study of 'association' or something about what appears to be quite a well-used feeding strategy for infants where traditional methods are not indicated - there wasn't the initial appetite to talk about it. Following some light reading around the topic and what looks to be some quite strongly held views on the use of infant soy formula (see this BBC report) including mention of a possible relationship with ADHD (see here) I eventually decided that this might be something to cover. The press release covering the study also helped (see here and see here) in making my decision.

A few details:

The hypothesis: "the use of soy-based infant formulas could be contributing to seizure incidence in autism and other neurodevelopmental disorders" came about apparently on the basis of some earlier work by the authors [2] (open-access here) which suggested that a component of soy-feed (daidzein) given to rats might have the ability to induce seizures after a few days consumption. More discussion about this earlier trial can be found here.
So, based on an analysis of data derived from the Simons Foundation Autism Research Initiative (SFARI), Westmark and colleagues looked at the occurrence of seizures and if available, the types of seizures reported, alongside the frequency of soy infant formula use, using sex as a differentiating variable in cases of autism.
Results: "There was a 2.6-fold higher rate of febrile seizures in the soy-fed cohort (4.2% seizures with soy and 1.6% seizures without soy)". That being said, the results only passed significance for females who were fed soy formula; males were more likely to present with seizures after soy feeding "but [results] were not statistically significant".
Also: "A comorbid diagnosis of autism and epilepsy was more prevalent in males fed soy-based formula (odds ratio = 2.4, 95% confidence interval 1.1–5.2; P = 0.02) than females (odds ratio = 1.4, 95% confidence interval 0.056–14; P = 0.8)". This does sound a little counter-intuitive given what the last sentence said about febrile seizures and gender but I would draw your attention to the use of the diagnostic term 'epilepsy' as opposed to 'febrile seizure'.

I'm pretty sure that you can see from the collected data included in this paper there are some potentially interesting details which require further analysis. I'm for example interested in seeing more about the proposed mechanism to account for the correlation reported between soy formula use and an elevated frequency of seizures/epilepsy in relation to autism. The authors suggest "the effects of an underlying genetic mutation that lowers seizure threshold may be exacerbated, for example, by dietary exposure to high concentrations of phytoestrogens". Yes, possibly; although with various other autism-related research areas in mind, I'd be interested to see whether there may other effects from for example, the gut microbiota [3] and how they might also play their part.

Perhaps another question would be whether the underlying reason why soy infant formula was used in the first place might also have played some role in the results. The authors do approach this topic as per the sentences: "A possible criticism is that subjects, who were fed soy-based infant formula because they were allergic to cow's milk, had allergies that made them vulnerable to illnesses associated with fever-induced convulsions. Though the retrospective nature of the data does not allow us to make definitive conclusions regarding this point, we found that 2.7% of females and 1.7% of males in the study population reported allergies, but no subjects reported both allergies and febrile seizures suggesting that this criticism may not be valid". I'd perhaps chime in here and suggest that 'allergy' might be a bit of a red herring here as per the research looking at something like lactose intolerance in relation to autism (see here) and the still quite speculative role of milk peptides (see here). There is also the potential issue of something like those folate receptor autoantibodies to consider (see here) which also seem to be affected by old fashioned milk although I am speculating here. There is the odd study (case report) talking about something like lactose intolerance and epilepsy for example [4] but still a lot more scope for further investigation in this area.

As per my introduction to this post on the role of 'association' when it comes to autism research, one always needs to be a little careful when interpreting such data and drawing too many conclusions. I'm not saying that seizures or epilepsy in autism may not be linked to something like early infant feeding choice, but with the same logic, I'd be hard pressed to say there is conclusive evidence of any association yet. And remember, the plural condition of autisms are a very complicated set of conditions indeed.

Finally, quite by coincidence, just yesterday I received an email invite to submit to a Frontiers journal topic headed by Dr Westmark on a favourite topic of mine (diet and the brain) which reminded me of an equally interesting research area on the use of ketogenic diets with autism and epilepsy in mind... more food for thought? (without any medical or clinical advice given or intended)

Music to close. Bowie and Jagger and a great video with some contrasting dancing styles. Condolences also to Sir Mick and the family of L'Wren Scott.

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[1] Westmark CJ. Soy infant formula and seizures in children with autism: a retrospective study. PLoS One. 2014 Mar 12;9(3):e80488.

[2] Westmark CJ. et al. Soy-based diet exacerbates seizures in mouse models of neurological disease. J Alzheimers Dis. 2013;33(3):797-805.

[3] Atkinson C. et al. Gut bacterial metabolism of the soy isoflavone daidzein: exploring the relevance to human health. Exp Biol Med (Maywood). 2005 Mar;230(3):155-70.

[4] Yaman H. et al. Epileptic seizures associated with lactose intolerance in a child: A causal relationship? J Pediatr Neurology. 2012; 10: 151-154.

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