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 obesity and offspring autism meta-analysed (yet again)

I think the findings reported by Sanchez and colleagues [1] make it at least the third time (see here and see here) that a meta-analysis has been conducted on the collected peer-reviewed research asking the question: does maternal weight before and/or during pregnancy affect offspring risk of being diagnosed with autism spectrum disorder (ASD)?

Granted the emphasis this time around was on "the association between maternal pre-pregnancy overweight/obesity status and child neurodevelopmental outcomes" (bold added by me), but the general question is similar to that looking at pregnancy overweight/obesity status, and whether such anthropometric variables might show an effect. The answer: according to the existing literature (see here for example) is yes; for whatever reason(s) "compared with children of normal weight mothers, children whose mothers were overweight or obese prior to pregnancy were at increased risk for compromised neurodevelopmental outcomes." A diagnosis of autism was but one outcome highlighted by the Sanchez results, as attention-deficit hyperactivity disorder (ADHD) also showed a potential *correlation* (see here).

"Of 1483 identified papers, 41 were included in the systematic review, and 32 articles representing 36 cohorts were included in the meta-analysis" indicating that there is some degree of confidence in a possible *correlation* between maternal weight and offspring outcomes.

What do the results mean? Well, being cautious that correlation is not necessarily the same as causation, and understanding that there may be a multitude of variables 'under' the issue of maternal obesity before and during pregnancy, there are a couple of potentially important implications arising from such findings. Pregnant mothers and potential mothers-to-be are already bombarded with quite a lot of information aimed at keeping themselves and their [potential] offspring 'healthy'. Part of that advice talks about how watching what you eat and maintaining a good physical activity schedule are key elements. Evidence like this from Sanchez et al perhaps add another dimension to any advice given; bearing in mind that pregnancy weight is probably not going to be an important factor for all autism or all ADHD. Indeed, the chances are that such findings are probably going to be part of a 'bigger picture' when it comes to risk profiles.

Mechanism(s) of effect? Potentially lots. Once again I'm going to zoom in on the idea that inflammation potentially generated by something like obesity [2] could be an important issue given all the previous chatter about maternal immune activation (MIA) and 'some' autism (see here). I don't doubt that there could be other factors to consider, but that's all I can [reliably] provide at the moment [3].

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[1] Sanchez CE. et al. (2017) Maternal pre-pregnancy obesity and child neurodevelopmental outcomes: a meta-analysis. Obesity Reviews. 2017. Nov 22.

[2] Lumeng CN. & Saltiel AR. Inflammatory links between obesity and metabolic disease. J Clin Invest. 2011 Jun;121(6):2111-7.

[3] van der Burg JW. et al. The role of systemic inflammation linking maternal BMI to neurodevelopment in children. Pediatr Res. 2016 Jan;79(1-1):3-12.

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