Nicotine exposure and offspring ADHD (yet again)

The study findings reported by Andre Sourander and colleagues [1] talking about "an association with and a dose-response relationship between nicotine exposure during pregnancy and offspring ADHD [attention-deficit hyperactivity disorder]" continue an important research theme (see here and see here).

What was different about the Sourander results compared with some of the other studies in this area was their focus on the measurement of cotinine levels - cotinine being a biomarker for exposure to tobacco smoke - in mums-to-be as "measured by using quantitative immunoassays from maternal serum specimens collected during the first and second trimesters of pregnancy and archived in the national biobank." Indeed, such a biological marker measurement protocol mimics other research from members of this authorship group when looking at maternal nicotine exposure and offspring risk of schizophrenia for example (see here).

Based on the analyses of samples from over a thousand participants born in the late 1990s and diagnosed with ADHD compared with samples from a similar number of non-ADHD control participants, researchers came to their possible *link* observation. They mention how the relationship between maternal cotinine levels and offspring ADHD diagnosis was statistically significant even when other important, potentially confounding, variables were taken into account. When categorising their maternal cotinine results into bands approximating light to heavy nicotine exposure and the possibility of a link with offspring ADHD diagnosis, researchers also reported something that looked like a dose-response relationship. Ergo, a biomarker of nicotine exposure during pregnancy *looked* to be potentially linked to offspring risk of ADHD.

Although important work, my first thought when reading this research was about how these results are 'set' within the context that historically, smoking rates or tobacco exposure rates during pregnancy were so much larger decades ago than they are now (see here), but ADHD is seemingly showing only quite a recent rise in numbers (see here). Although no expert on pregnancy tobacco consumption during the 20th century, I'm assuming that all those adverts about smoking being 'healthy' in the 1940s and beyond (see here) probably meant that quite a few women smoked during their pregnancy in the belief that it was 'healthy'. At the very least, it probably meant that they were exposed to a lot more second-hand tobacco smoke as a result of smoking being allowed in various public places and also more likely to be observed in the home environment. Surely then we would have seen an explosion of ADHD diagnoses at that point in time if the link was so simple? That is, assuming that the tobacco of today is the same as the tobacco of yesteryear.

I'm also intrigued that within the various potentially confounding variables which Sourander and colleagues adjusted for - "maternal socioeconomic status, maternal age, maternal psychopathology, paternal age, paternal psychopathology, and child’s birth weight for gestational age" - there's another variable that could exert an effect on ADHD risk: relative age (see here and see here). Relative age refers to the observation that the youngest children in the school classroom compared to their older classmates, are more likely to be diagnosed with ADHD. It strikes me that alongside something like tobacco or nicotine exposure, so age and other effects could be important.

I'm not trying to poo-poo the link that Sourander and various other research teams have independently observed. I'm also not trying to downplay the harms that tobacco (nicotine) exposure can have for the unborn child. I merely suggest that with typically falling rates of (reported) tobacco exposure during pregnancy in many countries (see here) and increasing levels of childhood (and adulthood) ADHD being reported, there must be other factors at work in any such relationship (see here for example).

----------

[1] Sourander A. et al. Prenatal Cotinine Levels and ADHD Among Offspring. Pediatrics. 2019. Feb 25.

----------

Maternal prenatal acetaminophen use and the risk of ADHD in offspring (again)

By discussing the findings - meta-analysis findings - published by Xiaoyun Gou and colleagues [1] I once again approach the topic of whether some medicines use during pregnancy might have some important implications for offspring development. And yet again we're talking about the use of acetaminophen a.k.a paracetamol, during pregnancy and how it *might* have some important implications when it comes to offspring development (see here and see here and see here for other blogging examples on this subject).

The Gou study focused on the risk of an offspring diagnosis of attention-deficit hyperactivity disorder (ADHD) following maternal exposure to paracetamol during pregnancy. And whether timing of said exposure and/or duration of exposure showed any *association* to risk of offspring ADHD.

As per the opening sentence to this post, the Gou study was a meta-analysis, meaning that it was a synthesis of the available peer-reviewed research literature. Indeed, authors identified 8 studies published up to November 2018 that included data on nearly a quarter of a million participants in total.

Given the quite consistent consensus already seen in the science on this topic (see here for example) it's probably not unexpected that that authors concluded that: "Maternal exposure to acetaminophen during pregnancy increased the risk of attention deficit/hyperactivity disorder in offspring with a pooled adjusted risk ratio of 1.25." Further: "Children exposed prenatally to acetaminophen in the third trimester seemed to have the greatest risk of developing attention deficit/hyperactivity disorder" and "a longer duration of maternal acetaminophen use during pregnancy was correlated with a higher risk ratio."

Of course such findings, even such meta-analysis findings, come with cautions about correlation not necessarily being the same as causation given the observational nature of the studies included for review. There are also a myriad of other potential factors that seemingly impact on offspring risk for ADHD (see here and see here for some other possible examples) which perhaps require consideration at the same time.

But... this is a topic that requires a lot more investigation. Investigations into whether (a) the association is indeed a real one and not just epiphenomenal, (b) the reasons leading to paracetamol use during pregnancy which may also exert an effect on offspring risk, and (c) which biological mechanisms may be pertinent to any connection (see here and see here), are all indicated. As for where medical opinion stands on this topic at the moment, well, minus any medical or clinical advice from me, I go with the research literature on this topic [2] and would suggest that if you're in doubt, talk to your medical professional...

----------

[1] Gou X. et al. Association of maternal prenatal acetaminophen use with the risk of attention deficit/hyperactivity disorder in offspring: A meta-analysis. Aust N Z J Psychiatry. 2019 Jan 17:4867418823276.

[2] Andrade C. et al. Use of acetaminophen (paracetamol) during pregnancy and the risk of attention-deficit/hyperactivity disorder in the offspring. J Clin Psychiatry. 2016 Mar;77(3):e312-4.

----------

Vitamin D supplementation and autism: more work needed on the biochemistry of vitamin D metabolism

The findings reported by Conor Kerley and colleagues [1] provide the brief blogging fodder today. Researchers, who are no stranger to the research area that is vitamin D and autism (see here), decided to conduct a 'post-hoc analysis' of data from two controlled trials where vitamin D supplementation was experimentally tested for children with autism and children with asthma. They were specifically looking at the "serum response to vitamin D supplementation" rather that the amount of vitamin D supplemented as potentially being important to the clinical results obtained. They concluded that "children with ASD [autism spectrum disorder] had a lower increase in 25(OH)D levels with supplementation." Further: "Potential mechanisms include altered absorption/metabolism as well as well genetic factors."

Bearing in mind the relatively small participant group numbers used and comparisons between kids with autism and kids with asthma without any other 'asymptomatic' group involvement, I was really rather interested in the Kerley findings. This was a research group who previously concluded that vitamin D supplementation did little for their cohort of autistic children under experimental conditions [2]. Now they're perhaps suggesting that there may have been valid biological reasons behind such results with respect to the biochemistry/metabolism behind vitamin D with such issues potentially affecting how much vitamin D supplementation is required to suitably raise vitamin D levels.

Of course this is not necessarily a new finding. Science has already started to look at the genetics/biology of vitamin D metabolism in relation to autism (see here and see here) and continues to do so [3]. It also converges with the idea that a deficiency/insufficiency of vitamin D is an important clinical finding but does not necessarily mean that a universal dose of vitamin D supplementation will 'fix anything' (see here for another example in another label).

"Clinical and research work relating to vitamin D is ASD should measure 25(OHO)D response to supplementation to assess therapeutic doses." I can't argue with such sentiments on the basis of the results observed. Working back from sayings such as 'the dose makes the poison', it appears that for some on the autism spectrum, that dose may not be the same as everyone else...

----------

[1] Kerley CP. et al. Blunted serum 25(OH)D response to vitamin D3 supplementation in children with autism. Nutr Neurosci. 2018 Oct 10:1-6.

[2] Kerley CP. et al. Lack of effect of vitamin D3 supplementation in autism: a 20-week, placebo-controlled RCT. Arch Dis Child. 2017 Nov;102(11):1030-1036.

[3] Biswas S. et al. Fok-I, Bsm-I, and Taq-I Variants of Vitamin D Receptor Polymorphism in the Development of Autism Spectrum Disorder: A Literature Review. Cureus. 2018 Aug 29;10(8):e3228.

----------