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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Can a 'disturbed gut microbiota' explain a cognitive performance dip in those born by C-section?

In answer to the question posed in the title of this post - Can a 'disturbed gut microbiota' explain a cognitive performance dip in those born by C-section? - I have to say that I don't know. I was however, rather intrigued by the findings reported by Cain Polidano and colleagues [1] (open-access) who observed that "cesarean-born children perform significantly below vaginally-born children, by up to a tenth of a standard deviation in national numeracy test scores at age 8–9" when allowing for "a large range of confounders."

Based on data derived from the Longitudinal Study of Australian Children (LSAC), a sort of Aussie equivalent to ALSPAC here in Blighty, researchers set about examining whether the growth in Caesarean sections might have some long-term implications for child cognitive development. The question of whether those trillions of wee beasties (bacteria and the like) that call our gastrointestinal (GI) tract home might be implicated in the cognitive findings stems from previous research talking about how, theoretically, said bacteria might be doing so much more than just helping us to digest our food or producing the odd nutrient here and there (see here for example). This also bearing in mind that those born by C-section have been suggested to show a different gut bacteria profile from those not. I say all that acknowledging that gut bacteria doing this, that and t'other is going through something of a period of reflection at the moment (see here).

It is the size of the Polidano participant sample (N=3,666) and the "internationally recognized and widely-used longitudinal" nature of the LSAC that interested me in these findings. The authors provide quite a bit of detail on how the initiative works and what measures have been put in place to potentially rule out mediating and/or confounding variables. Even missing data has been discussed and accounted for: "non-random attrition does not appear to be seriously biasing our results."

What is unfortunately missing from the Polidano paper is any measure of 'gut bacteria' to substantiate the possibility of a connection between C-section birth, gut bacteria and academic outcome(s). I say this bearing in mind that whilst there is extensive literature talking about *associations* between C-section birth and a variety of cognitive and developmental outcomes, the details are still a little scarce insofar as whether any association is tied to a specific family of bacteria or indeed, something like overall bacterial diversity. One also has to bear in mind that other factors also affect newborn gut bacterial make-up such as breastfeeding and seemingly specific components of breastfeeding [2]. I note that other authors are also not sold on the ideas generated from the Polidano paper (see here) and caution that C-sections are not somehow demonised as a result (not everyone is 'too posh to push').

"While the magnitude of our estimated difference in outcomes is not large, up to a tenth of a standard deviation in national test scores in numeracy, they are large enough to warrant action." The authors note that their observations might not seem to show a particularly large contribution to cognitive development, they are nonetheless still potentially important. Indeed: "A tenth of a standard deviation in national test scores is comparable in size to differences related to gender, class size and teacher quality that are the focus of policy effort." In other words, don't discount this potentially important area of investigation just yet...

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[1] Polidano C. et al. The relation between cesarean birth and child cognitive development. Scientific Reports. 2017; 7: 11483.

[2] Toscano M. et al. Impact of delivery mode on the colostrum microbiota composition. BMC Microbiology. 2017; 17: 205.

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Valproate use during pregnancy and/or breastfeeding and "greatest odds of adverse development"

As per other blogging occasions when I've talked about the antiepileptic drug (AED) valproate and its use specifically during pregnancy, I caution that no medical or clinical advice is given or intended on this blog. Anyone in any doubt or seeking an opinion on this other or any other AED should consult their prescribing physician. Don't mess with epilepsy. I repeat: don't mess with epilepsy.

The findings however reported by Areti Angeliki Veroniki and colleagues [1] (open-access) synthesising the available peer-reviewed evidence to compare "the safety of antiepileptic drugs (AEDs) on neurodevelopment of infants/children exposed in utero or during breast feeding" provides an all too familiar picture specifically in relation to valproate use during pregnancy. Namely: "Valproate alone or combined with another AED is associated with the greatest odds of adverse neurodevelopmental outcomes compared with control."

Utilising something called a Bayesian random-effects network meta-analysis (NMA), researchers set about synthesising and ranking various AEDs previously studied in terms of their safety when it comes to *association* with various childhood developmental diagnoses including autism and things like cognitive developmental delay. Based on the results from 29 studies reporting on AED use and 'neurological outcomes' including some 5000 patients, authors made some important observations.

Not to be alarmist but: "results suggest that AEDs generally pose a risk for infants and children exposed in utero or during breast feeding." The authors caution that their results whilst methodologically strong are not without limitations; not least that the studies in this area are observational only and therefore have "inherent biases because of confounding and shortcomings of these studies." That being said, the tide of such observational research cannot be readily ignored. If there is one or more confounding variables that is/are somehow being hidden behind something like valproate use during pregnancy and its potential risks of offspring developmental outcomes, they seem to be very well hidden indeed.

"Valproate was significantly associated with more children experiencing autism/dyspraxia, language, cognitive and psychomotor developmental delays versus children who were not exposed to AEDs." Valproate came 'top of the pops' when it came to those neurological outcomes. Other AEDs also showed associations with specific outcomes - "oxcarbazepine and lamotrigine were associated with increased occurrence of autism" - but the data pointed to valproate as potentially showing greatest risk to offspring. I should point out that there is a mouse model of autism that relies on offspring valproate exposure which, whilst subject to shortcomings (see here), kinda suggested that there may be an important association. Said animal research also reveals some potentially important avenues for perhaps mitigating any deleterious effects of valproate use on offspring too (see here) with the requirement for more experimental study.

"Future studies should assess the genetic contribution from the biological father, maternal seizures during pregnancy, exposure through breast feeding only, types of epilepsy and maternal family history." Of course the authors are right to talk about other factors that are probably important to various childhood developmental outcomes. But unlike a related area talking about medicines taken during pregnancy potentially affecting risk of something like autism and how one might tease apart medicine use from underlying health issue(s) (see here for example), I don't think it too likely that there is going to be a large bank of pregnant mums out there who present with epilepsy or other seizure disorder that is not going to be already managed via AEDs. Indeed, it would be rather unethical as well as unwise to leave epilepsy untreated under any conditions.

To close, where we're up to when it comes to government (UK) advice on AEDS such as valproate and pregnancy use. Again, if it doubt, talk to your prescribing physician.

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[1] Vernoniki AA. et al. Comparative safety of antiepileptic drugs for neurological development in children exposed during pregnancy and breast feeding: a systematic review and network meta-analysis. BMJ Open. 2017; 7: e017248.

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Language and motor skills: preschool predictors of academic achievement in autism

A fairly quick post for your reading delight today as I bring the paper by Miller and colleagues [1] to your attention suggesting that: "Early intervention targeting language and motor skills may improve later achievement in this population."

'This population' referred to a small cohort (N=26) of children diagnosed with an autism spectrum disorder (ASD) who were examined "at the approximate ages of two, four, and ten" years with regards to their academic achievement and the variables that might be important to 'successful' achievements.

Including some familiar names when it comes to the concept of 'outcome' in relation to autism ('optimal outcome' that is), researchers determined a few potentially important relationships from their collected data: "Preschool verbal abilities significantly predicted school-age reading comprehension" and "early motor functioning predicted later math skills."

I'm not entirely surprised that infancy verbal (talking) abilities might play a role in later reading comprehension but I was rather more intrigued by the observation potentially linking motor skills to later maths abilities. Yes, I get that children learn to count on their fingers (and toes) and no doubt this and other scenarios might influence the connection between the two, but it strikes me that this connection requires quite a bit more study [2]. Indeed, welcoming the idea that motor skills are an important issue with regards to autism (see here) and that maths ability is 'as varied as the label of autism is itself' (see here) the idea that the archetypal all-rounder that is the occupational therapist (OT) might have a key role here is rather interesting (see here).

I'm also minded to suggest that a certain sport/discipline that I'm particularly fond of on this blog (the martial arts) might have some rather far-reaching 'mathematical' effects if one considers it's application to autism and motor functioning...

To close, Marvel are going full-strength with their next Wolverine film instalment titled 'Logan'...

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[1] Miller LE. et al. Preschool predictors of school-age academic achievement in autism spectrum disorder. Clin Neuropsychol. 2016 Oct 5:1-22.

[2] Pitchford NJ. et al. Fine Motor Skills Predict Maths Ability Better than They Predict Reading Ability in the Early Primary School Years. Front Psychol. 2016 May 30;7:783.

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Miller LE, Burke JD, Troyb E, Knoch K, Herlihy LE, & Fein DA (2016). Preschool predictors of school-age academic achievement in autism spectrum disorder. The Clinical neuropsychologist, 1-22 PMID: 27705180

Project TENDR and chemical exposures

Yes, I know I'm writing on a Sunday again, but it will be a short-ish post I promise you. The reason for the entry is this brief communication [1] reporting: "The TENDR [Targeting Environmental Neuro-Developmental Risks] authors agree that widespread exposures to toxic chemicals in our air, water, food, soil, and consumer products can increase the risks for cognitive, behavioral, or social impairment, as well as specific neurodevelopmental disorders such as autism and attention deficit hyperactivity disorder (ADHD)."

The press release accompanying the paper is here. Given the focus on neurodevelopmental disorders including autism it is perhaps not surprising that several of the signatories on the paper are stalwarts of the idea that 'environment' may play a not insignificant role when it comes to at least some autism. If you need examples, look no further than here and here.

I know there are still often heated discussions/arguments (delete as appropriate) about how environment - or non-genetic factors - might fit into the quite marked increase in the numbers of people being diagnosed with autism and various other developmental conditions. I think most people will appreciate that although there are clues in the current peer-reviewed literature to possible effects for some, a lot more science is needed to substantiate specific environmental risks and importantly, potential mode(s) of action when it comes to something like autism or ADHD as a clinical endpoint. There are however signs that science is starting to move in the right direction (see here)...

Set within changes to some of the regulatory affairs when it comes to how countries ensure 'chemicals' are safe (being careful about how one uses the word 'chemical') and perhaps because years of looking for the 'genetics of autism' has yielded only partial results (see here), it is starting to become better accepted that elements of our environment might also affect risk for many conditions, including those potentially affecting development.

To close, the news that Morrissey is returning to these hallowed shores naturally invites a song from the man driving a tractor...

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[1] Project TENDR: Targeting Environmental Neuro-Developmental Risks. The TENDR Consensus Statement. Environmental Health Perspectives. 2016.; 124: A118-A122.

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Bennett, D., Bellinger, D., Birnbaum, L., Bradman, A., Chen, A., Cory-Slechta, D., Engel, S., Fallin, M., Halladay, A., Hauser, R., Hertz-Picciotto, I., Kwiatkowski, C., Lanphear, B., Marquez, E., Marty, M., McPartland, J., Newschaffer, C., Payne-Sturges, D., Patisaul, H., Perera, F., Ritz, B., Sass, J., Schantz, S., Webster, T., Whyatt, R., Woodruff, T., Zoeller, R., Anderko, L., Campbell, C., Conry, J., DeNicola, N., Gould, R., Hirtz, D., Huffling, K., Landrigan, P., Lavin, A., Miller, M., Mitchell, M., Rubin, L., Schettler, T., Tran, H., Acosta, A., Brody, C., Miller, E., Miller, P., Swanson, M., Witherspoon, N., , ., , ., , ., , ., , ., , ., , ., , ., & , . (2016). Project TENDR: Targeting Environmental Neuro-Developmental Risks The TENDR Consensus Statement Environmental Health Perspectives, 124 (7) DOI: 10.1289/EHP358

Toy preference and parent-infant communication?

I was intrigued to read the findings reported by Anna Sosa [1] who reported that "play with books and traditional toys was superior to play with electronic toys in promoting high-quality communication."

This was a study looking at communication between parents and their infants aged 10-16 months old as a function of toy type, where electronic toys - "3 battery-operated toys with buttons and switches that can be manipulated to produce lights, words, phrases, and songs" - were pitted against 'traditional' toys - "3 nonelectronic toys that also have the potential to teach animal names, colors, and shapes." Those electronic toys were also chosen on the premise that "they are marketed as educational toys that promote language development for children in this age range and are advertised as teaching animal names, colors, and shapes."

Describing results from 26 parent-infant dyads whereby pairs "engaged in 2 15-minute play sessions per toy set over a 3-day period" using electronic toys, non-electronic toys and also books (y'know those paper things), various outcomes were measured including child vocalisations, adult words and conversational turns. As per the opening sentence, toy type did seem to affect communication between parent and child. So: "Play with electronic toys is associated with decreased quantity and quality of language input compared with play with books or traditional toys." The author goes as far to say that set within other research in this area: "both play with traditional toys and book reading can be promoted as language-facilitating activities while play with electronic toys should be discouraged."

Being careful not to fall into any sweeping generalisations about how technology is 'all bad' for child development and beyond, bearing in mind where such discussions have previously led, I have to say that it there may be some important lessons to learn from the Sosa study results. That early years communication between parent and child is increasingly being realised to be pretty important is one part of discussions (see here for more information on the '30 million word gap' for example). That parents are also literally bombarded these days with various edu-toys and other gadgets often making some rather big claims is another aspect. The Sosa results hint that there might be a happy medium to strike between the old and the new when it comes to early play and communication (including reading) and that we should as parents, perhaps be mindful that electronic toys with their lights, sounds and various educational claims might not necessarily trump something a little less flashy. Similar sentiments might also apply to more pathological states too [2].

Music: William Shatner sings er... well, not for the easily offended.

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[1] Sosa AV. Association of the Type of Toy Used During Play With the Quantity and Quality of Parent-Infant Communication. JAMA Pediatrics. 2015. Dec 23.

[2] Christakis DA. Rethinking Attention-Deficit/Hyperactivity Disorder. JAMA Pediatr. 2016 Jan 4:1-2.

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Sosa AV (2015). Association of the Type of Toy Used During Play With the Quantity and Quality of Parent-Infant Communication JAMA Pediatrics : 10.1001/jamapediatrics.2015.3753

Nothing good comes from exposure to lead

"In this population of Mexican children, current blood lead level among children with low exposure (< 5µg/dL) was positively associated with hyperactive/impulsive behaviors, but not with inattentiveness. These results add to the existing evidence of lead-associated neurodevelopmental deficits at low levels of exposure."

That quote from the paper by Siying Huang and colleagues [1] (open-access available here) kinda says it all when it comes particularly to childhood exposure to lead (Pb) insofar as there really being no safe limit. Allied to other research in this area (see here) the message is coming through loud and clear that when it comes to this stuff: "Lead is a neurotoxin with no physiological functions in the human body, the ideal concentration of which in the blood is zero." [2]

Without pushing specific associations, I'd also suggest that where particular groups of children may be more prone to present with issues with lead (see here) (although not all [3]), science and clinical practice might be minded to think about minimising potential routes of exposure (see here) and perhaps strategies for removing any excess load [4]. Questions about whether there may be underlying biological or genetic 'issues' pertinent to the metabolism of such xenobiotics might also figure, specifically in light of where elements of autism research in particular, have already cast a spotlight (see here).

Nothing good comes from exposure to lead.

Tomorrow (30th December) I have my annual review of research on this blog so please come by and take a look. For now, I leave you with an idea for 2016... bring back Yub Nub (and original Anakin).

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[1] Huang S. et al. Childhood Blood Lead Levels and Symptoms of Attention Deficit Hyperactivity Disorder (ADHD): A Cross-Sectional Study of Mexican Children. Environ Health Perspect. 2015 Dec 8.

[2] Hou S. et al. A clinical study of the effects of lead poisoning on the intelligence and neurobehavioral abilities of children. Theor Biol Med Model. 2013 Feb 18;10:13.

[3] Fuentes-Albero M. et al. Lead excretion in spanish children with autism spectrum disorder. Brain Sci. 2015 Feb 16;5(1):58-68.

[4] Gracia RC. & Snodgrass WR. Lead toxicity and chelation therapy. Am J Health Syst Pharm. 2007 Jan 1;64(1):45-53.

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Huang S, Hu H, Sánchez BN, Peterson KE, Ettinger AS, Lamadrid-Figueroa H, Schnaas L, Mercado-García A, Wright RO, Basu N, Cantonwine DE, Hernández-Avila M, & Téllez-Rojo MM (2015). Childhood Blood Lead Levels and Symptoms of Attention Deficit Hyperactivity Disorder (ADHD): A Cross-Sectional Study of Mexican Children. Environmental health perspectives PMID: 26645203

Organic diet and urinary pesticide concentrations

"Eating Organic Lowers Pesticide Levels in Children" went the headline reporting on the small study by Asa Bradman and colleagues [1] (open-access available here). Detailing what happened to urinary pesticides levels following trials of combinations of conventionally grown food consumption vs. organic food consumption over 16 days, researchers reported some potentially interesting findings.

Measuring 23 metabolites "reflecting potential exposure to organophosphorous (OP), pyrethroid, and other pesticides used in homes and agriculture" via everyone's favourite analytical method (LC-MS) and specifically "tandem mass spectrometry", Bradman et al observed that: "An organic diet was significantly associated with reduced urinary concentrations of nonspecific dimethyl OP insecticide metabolites and the herbicide 2,4-D in children." If I had a beef with any part of the Bradman study outside of the fairly small participant group, it would be that the reliance of urinary excretion of pesticide residues might not necessarily show the whole story, as per what data one might get from the use of other biofluids such as blood samples too or even analysis of fat biposies (recognising how invasive these can be).

These are interesting findings added to other similar research on this topic [2] looking at adults. Not only do they point to the idea that there is persistent low level exposure to pesticide residues in food but also that changes in food consumption patterns may affect such exposure events. That's not to say that food is the only way that pesticide exposure might occur, as per the findings of differences among children living in urban vs. agricultural communities (where those living in more agricultural areas generally had higher levels of some of the more frequently detected pesticide metabolites). But dietary change encompassing an organic diet did seem to lead to reductions in certain pesticide metabolite excretions irrespective of geography.

Accepting the often valuable reasons why pesticides are used in the first place, I don't think many people would argue with the idea that pesticide exposure should be limited, particularly in respect of children and their developing bodies and minds [3]. Allied to the idea that organic food might also confer other benefits in terms of nutritional quality (see here) and lower levels of fairly toxic metals such as cadmium [4], there seems to be common sense in rethinking some aspects of agriculture for certain groups. That the genetics of pesticide metabolism may also play a role [4] as per discussions about PON1 (paraoxonase/arylesterase 1), is also an important point and how childhood relates to PON1 activity among other factors [5]. Indeed, to answer the question posed in another paper [6] yes, there may indeed be some benefits from an organic diet for children...

Music: Adele - Rolling in the Deep.

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[1] Bradman A. et al. Effect of Organic Diet Intervention on Pesticide Exposures in Young Children Living in Low-Income Urban and Agricultural Communities. Environ Health Perspect. 2015 Oct;123(10):1086-93.

[2] Oates L. et al. Reduction in urinary organophosphate pesticide metabolites in adults after a week-long organic diet. Environ Res. 2014 Jul;132:105-11.

[3] Muñoz-Quezada MT. et al. Neurodevelopmental effects in children associated with exposure to organophosphate pesticides: a systematic review. Neurotoxicology. 2013 Dec;39:158-68.

[4] Barański M. et al. Higher antioxidant and lower cadmium concentrations and lower incidence of pesticide residues in organically grown crops: a systematic literature review and meta-analyses. Br J Nutr. 2014 Sep 14;112(5):794-811.

[5] Gonzalez V. et al. Cholinesterase and paraoxonase (PON1) enzyme activities in Mexican-American mothers and children from an agricultural community. J Expo Sci Environ Epidemiol. 2012 Nov;22(6):641-8.

[6] Vania A. et al. Is organic diet really necessary for children? Italian Journal of Pediatrics 2015, 41(Suppl 2):A75

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Bradman, A., Quirós-Alcalá, L., Castorina, R., Schall, R., Camacho, J., Holland, N., Barr, D., & Eskenazi, B. (2015). Effect of Organic Diet Intervention on Pesticide Exposures in Young Children Living in Low-Income Urban and Agricultural Communities Environmental Health Perspectives, 123 (10) DOI: 10.1289/ehp.1408660

Adult outcomes following childhood psychiatric problems

A long quote to begin:

"If the goal of public health efforts is to increase opportunity and optimal outcomes, and to reduce distress, then there may be no better target than the reduction of childhood psychiatric distress—at the clinical and subthreshold levels."

That was the bottom line reported by William Copeland and colleagues [1] (open-access) who set out to test whether psychiatric problems presenting in childhood can "adversely affect adult functioning even if the problems themselves do not persist." The Copeland study also has an accompanying editorial in the publishing journal [2].

Based on data derived from a prospective study of nearly 1500 participants "from 11 predominantly rural counties of North Carolina" researchers looked for the presence of "common psychiatric diagnoses and subthreshold psychiatric problems" by means of structured assessments during childhood (9-16 years of age). "The common childhood psychiatric disorders assessed included anxiety disorders (separation anxiety, generalized anxiety, social phobia, specific phobia, agoraphobia, panic disorder, obsessive-compulsive disorder, and posttraumatic stress disorder), mood disorders (major depression, dysthymia, mania, and hypomania), conduct disorder, oppositional defiant disorder, attention-deficit/hyperactivity disorder, and substance disorders."

Just over 1200 of these research participants were then followed into adulthood - young adulthood - and assessed "for adverse outcomes related to health, the legal system, personal finances, and social functioning." This included responses on the the Young Adult Psychiatric Assessment (YAPA) and accessing official criminal records.

Results: of the original childhood cohort, just over a quarter of children/young adults "met criteria for a common behavioral or emotional disorder at some point in childhood/adolescence (9-16 years of age)." Whilst this might sound a lot, other studies have reached similar conclusions (see here). Added to that, about a third of participants at this stage of development "displayed subthreshold psychiatric problems only."

For those followed into adulthood: "Participants with a childhood disorder had 6 times higher odds... of at least 1 adverse adult outcome (ie, indicator) compared with those with no history of psychiatric problems." In more detail: "41.5% of participants who were subthreshold cases only and 59.5% of participants who were psychiatric cases reported an adult outcome" where an 'adult outcome' was classified as one of those 'adverse outcomes' in the areas inspected. "Psychiatric and subthreshold cases made up close to 80% of participants with an adult indicator (42.3% of psychiatric cases, 35.7% of subthreshold cases, and 22.0% of noncases) and close to 90% of participants with 2 or more such indicators (48.2% of psychiatric cases, 39.4% of subthreshold cases, and 12.3% of noncases)."

Drilling down into the details of what diagnosis or subthreshold diagnosis specifically translated into adverse adult outcomes, the authors reported that "childhood depression and conduct disorder were associated with a higher likelihood of having an adverse outcome, and only conduct disorder predicted having 2 or more adverse outcomes." These results held true even when various covariates were taken into account such as low socio-economic status, unstable family structure and maltreatment.

The accompanying editorial does make a case for not jumping to too many conclusions on the basis of the Copeland findings in terms of their meaning. "It is possible that some or all of the causes of psychopathology across the lifespan operate early in life" is one sentiment expressed. Being careful not to make any sweeping generalisations, I would tend to suggest that the evidence does seem to be pointing to early life psychopathology as expressing quite a effect when it comes to later life outcome. Taking for example the idea that a neurodevelopmental disorder might for example, influence the risk of psychosis in later life (see here) is one area where supporting peer-reviewed evidence has been produced. A possible link between the diagnosis of autism (Asperger syndrome) and an elevated risk of bipolar disorder (see here) in adult life is another.

Irrespective of the hows and whys, the data from Copeland adds to the idea that significantly more efforts are perhaps required to 'tackle' childhood psychopathology with the hope of reducing adverse adult outcomes and improving quality of life across the lifespan. Accepting that societal factors might also need some inspection alongside the idea that economics might enter into the equation at some point [3], questions remain about the best way to achieve this aim and how one goes about providing an evidence-based approach to analysing the success or not of any approach to this matter.

Music: LCD Soundsystem - Someone Great.

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[1] Copeland WE. et al. Adult Functional Outcomes of Common Childhood Psychiatric Problems: A Prospective, Longitudinal Study. JAMA Psychiatry. 2015. July 15.

[2] Lahey BB. Why Are Children Who Exhibit Psychopathology at High Risk for Psychopathology and Dysfunction in Adulthood? JAMA Psychiatry. 2015. July 15.

[3] Chorozoglou M. et al. Preschool hyperactivity is associated with long-term economic burden: evidence from a longitudinal health economic analysis of costs incurred across childhood, adolescence and young adulthood. Journal of Child Psychology and Psychiatry. 2015. June 13.

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Copeland WE, Wolke D, Shanahan L, & Costello EJ (2015). Adult Functional Outcomes of Common Childhood Psychiatric Problems: A Prospective, Longitudinal Study. JAMA psychiatry PMID: 26176785

Early sex differences are not autism-specific

The title of this post mirrors the title of the paper published by Daniel Messinger and colleagues [1] (open-access available here) that reported on "younger sibling sex differences and proband sex differences on the odds of ASD [autism spectrum disorder] in a large sample of prospectively followed high-risk siblings."

Researchers found that alongside "a three-to-one male:female odds ratio in ASD recurrence... the emergence of ASD symptoms in high-risk siblings—both with and without eventual ASD outcomes—occurs in the context of naturally occurring sex-related variability." Further that their results cast "doubt on a female protective effect among high-risk ASD siblings."

Based on participant data derived from the Baby Siblings Research Consortium (BSRC) [2], a collaborative initiative focused on identifying the earliest signs and symptoms of autism, researchers assessed cognitive functioning and autism symptom severity in over 1800 infants, over 1200 of whom were categorised as 'high risk' insofar as being a "younger sibling of a proband with an ASD diagnosis." Of those 1241 high-risk siblings "252 had ASD outcomes" on the basis of a clinical best estimate diagnosis derived from the various data sources available for each participant.

Results: well, there were quite a few of them as previously discussed but I'm going to pick out a few highlights:

• "The male rate of ASD recurrence in the high-risk siblings was approximately 1 in 4 (26.7 %) while the female rate was 1 in 10 (10.3 %)." Further: "The overall—combined male and female—ASD recurrence rate of 19.5 % yielded an ASD outcome for approximately one in five high-risk siblings." This is an important addition to the previous research done on sibling recurrence rates (see here) bearing in mind the potential effect of variables such as reproductive stoppage and multiplex status.
• "Challenging accounts of greater female affectedness, there was no evidence that girls exhibited lower levels of cognitive functioning or higher levels of symptom severity than boys." The idea that there may be a female phenotype of autism has gained significant research traction in recent times (see here) partially based on the idea that it may take 'more genetic issues to trigger autism in girls than boys'. Alongside the idea that females may somehow possess greater protection against autism is the suggestion that autism when it does appear in females, may show differences in terms of severity perhaps as a function of that larger genetic load required. Messinger et al however, report that things might not be so simple.
• "Boys across all groups exhibited slower growth trajectories and lower levels of cognitive performance than girls in fine motor, visual reception, receptive and expressive language functioning." Harking back to some previous musings on the 'fragile male' (see here) Messinger et al showed small but notable difference across the sexes and across ages suggesting female superiority of somewhere between "1.06 to 3.3 months on age-equivalent scores" compared to males. That's not to say males did not develop - everyone developed - rather that girls seemed to develop skills at a faster rate.
• "With respect to the ASD symptom severity indices, males exhibited higher levels of repetitive behaviors than females, but there were no sex differences in social affect severity scores." This finding tallies with other research in this area (see here). The indication being that aspects such as stereotyped language, hand and finger mannerisms or complex mannerisms may be quite a bit more prevalent in 'boy autism' compared to 'girl autism'. More than that however, such repetitive behaviours might be more present in boys over girls (taking out the variable of autism diagnosis) "consistent with a male focus on regularity in the behavior of non-social objects and events." 'Boys and their toys' is a phrase that springs to mind.

The authors conclude that their results "suggest that male:female ASD differences are not ASD-specific but instead reflect more general sex differences reflected through a prism of autism-linked symptoms."

These are interesting results that gain some scientific traction as a function of the large participant numbers included for study and the prospective nature of the study initiative. The authors have made quite a bit of the fact that their results provide "no overall evidence of a female protective effect" in their high-risk siblings group but acknowledge the need for further investigations in this area specifically where female autism is present and how "female probands in multiplex families (two or more female siblings) [may] confer greater risk for ASD in successive offspring." I wonder if this might include some further thought on how sex differences in brain plasticity [3] might potentially be linked to autism?

Once again, autism reveals just how complicated a condition it is...

Music: The Slits - Typical Girls.

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[1] Messinger DS. et al. Early sex differences are not autism-specific: A Baby Siblings Research Consortium (BSRC) study. Mol Autism. 2015 Jun 4;6:32.

[2] Messinger D. et al. Beyond autism: a baby siblings research consortium study of high-risk children at three years of age. J Am Acad Child Adolesc Psychiatry. 2013 Mar;52(3):300-308.

[3] Mottron L. et al. Sex differences in brain plasticity: a new hypothesis for sex ratio bias in autism. Molecular Autism. 2015. 6; 33.

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Messinger DS, Young GS, Webb SJ, Ozonoff S, Bryson SE, Carter A, Carver L, Charman T, Chawarska K, Curtin S, Dobkins K, Hertz-Picciotto I, Hutman T, Iverson JM, Landa R, Nelson CA, Stone WL, Tager-Flusberg H, & Zwaigenbaum L (2015). Early sex differences are not autism-specific: A Baby Siblings Research Consortium (BSRC) study. Molecular autism, 6 PMID: 26045943

Gut bacteria and toddler temperament

The 'terrible twos'. Y'know, that special time in a child's development when the words 'mine' and 'no' are much more than a daily occurrence and visions of supermarket / restaurant meltdowns complete with scathing looks from strangers still linger in the rose-tinted memories of parenting.

There's still quite a bit of debate about the hows and whys of the terrible twos but new research by Lisa Christian and colleagues [1] implicates a hitherto unappreciated system potentially at work: our gut bacteria. Examining the possibility that "the community structure of the gut microbiome" might correlate with maternal measures of offspring temperament for 77 children aged between 18-27 months of age, researchers reported preliminary results looking at bacterial diversity and bacterial composition in relation to reported child behaviour across three scales of emotional reactivity according to media reports of the study (see here).

"Among both boys and girls, greater Surgency/Extraversion was associated [with] greater phylogenetic diversity." In other words, a more varied gut bacterial population seemed to correlate with scores more pertinent to an 'out-going' temperament "related with positive mood, curiosity, sociability and impulsivity." This is also the temperament style that seems to be potentially linked to later attentional issues such as ADHD (attention-deficit hyperactivity disorder) [2].

"Additional sex-specific associations between temperament and the gut microbiome were observed." So, taking into account gender/sex and temperament, certain types of gut bacteria were more commonly observed; specifically: "In boys only, researchers reported that extroverted personality traits were associated with the abundances of microbes from the Rikenellaceae and Ruminococcaceae families and Dialister and Parabacteroides genera." The exact meaning of these findings is unknown at present.

Importantly: "Some differences in dietary patterns were observed in relation to temperament, but these did not account for the observed differences in the microbiome." As anyone who has followed the recent 'Spector diet experiment' might know, there is a growing acceptance that what we eat (and drink) might have repercussions for the balance of the trillions of beasties that reside in our gut. The jury is however still out about the long-term effects of diet on the gut microbiota and indeed, what this might mean in relation to modifying risk of disease through diet affecting gut bacteria.

Assuming that the Christian results hold out following independent replication and the link between behaviour and gut bacteria keeps heading the direction it's heading (see here) there are some pretty important implications from this line of scientific thought. Minus the hype, one might reasonably ask: 'Is it possible to alter temperament by altering the gut microbiome?' as a primary question. The authors make some effort to answer this in the accompanying press about their findings: "Both researchers say that parents shouldn't try to change their child's gut microbiome just yet. Scientists still don't know what a healthy combination looks like, or what might influence its development." I agree that we don't yet know what it means to have a 'surgency/extraversion gut microbiome' but we do know that supplementation with probiotics for example, can seemingly affect aspects of behaviour and thought [3] (see my take here). Again, if we assume that diet affects gut bacterial composition, one might also acknowledge that what a young child eats is already affecting their gut bacteria populations, something that might have implications for our modern eating habits and various other issues. And then there are variable such as the issue of stool consistency to potentially take into account [4]...

Psychology textbooks perhaps might need rewriting in future eh?

Music: Hate to Say I Told You So - The Hives.

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[1] Christian LM. et al. Gut microbiome composition is associated with temperament during early childhood. Brain, Behavior, and Immunity. 2015; 45: 118-127.

[2] Bussing R. et al. Child temperament, ADHD, and caregiver strain: exploring relationships in an epidemiological sample. J Am Acad Child Adolesc Psychiatry. 2003 Feb;42(2):184-92.

[3] Steenbergen L. et al. A randomized controlled trial to test the effect of multispecies probiotics on cognitive reactivity to sad mood. Brain Behav Immun. 2015 Apr 7. pii: S0889-1591(15)00088-4.

[4] Vandeputte D. et al. Stool consistency is strongly associated with gut microbiota richness and composition, enterotypes and bacterial growth rates. Gut. 2015 Jun 11. pii: gutjnl-2015-309618.

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Christian LM, Galley JD, Hade EM, Schoppe-Sullivan S, Kamp Dush C, & Bailey MT (2015). Gut microbiome composition is associated with temperament during early childhood. Brain, behavior, and immunity, 45, 118-27 PMID: 25449582

Social anxiety affecting autism intervention outcome?

"Anxiety is an unpleasant state of inner turmoil" according to one definition. In other descriptions, words such as 'worry' and 'dread' are used (see here) describing how beyond the typical feelings of apprehension about a new situation for example, anxiety can turn into something altogether more serious and life-disrupting for some.

There are various types of anxiety disorder (see here) to consider, but for the purposes of this post I'm going to focus on social anxiety disorder in the context of autism and how the results from Melanie Pellecchia and colleagues [1] suggest we should be dedicating quite a few more resources to studying and ameliorating this important issue.

"This study examined the extent to which clinical and demographic characteristics predicted outcome for children with autism spectrum disorder." That was the starting point for the Pellecchia study looking at how child characteristics including the presentation of autism and other comorbidities might affect outcome following a school-based behavioural intervention. Drawing on data from an initial sample of over 150 pupils with autism, authors concluded that: "age and the presence of symptoms associated with social anxiety, such as social avoidance and social fearfulness, as measured through the Child Symptom Inventory-4, were associated with differences in outcome." Further: "The findings regarding the role of social anxiety are new and have important implications for treatment."

I'll chime in here and say that social anxiety in relation to autism is by no means a 'new ' concept as per other mentions on this blog (see here and see here for example). Indeed, anxiety appearing in the context of autism or autistic traits (see here) is something that many people have recognised as being potentially central to the more disabling features for quite a few on those on the autism spectrum. That and an 'intolerance of uncertainty' to borrow an important phrase [2]. The novelty from the Pellecchia data comes from the idea that the presentation of social anxiety alongside paediatric autism might well have some important effects on intervention outcome.

It's an interesting idea that when it comes to intervention for autism, the presentation of core autism symptoms might not be the major hurdle to 'treatment' success or positive outcome. I'm not sure how relevant it might be to this discussion, but I have talked previously on this blog about how one or two intervention ideas put forward for autism are probably not affecting core symptoms but rather peripheral or comorbid presentations. It strikes me that a question requiring some answers is whether targeting issues like social or other forms of anxiety when comorbid, might similarly affect the core presentation of autism? How about targeting other potential manifestations of anxiety presenting as more somatic features too?

And just in case you needed telling, issues such as anxiety are not some 'flash in the pan' thing when it comes to quite a few cases of autism [3]. Indeed, the implication being that even into adulthood, moves to curb anxiety-related issues might potentially have some very positive effects on the presentation of autism and onwards improvements in quality of life. The flip-side to all that being that anxiety, when unremitting, might have some far-reaching implications [4]...

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[1] Pellecchia M. et al. Child characteristics associated with outcome for children with autism in a school-based behavioral intervention. Autism. 2015. April 24.

[2] Boulter C. et al. Intolerance of uncertainty as a framework for understanding anxiety in children and adolescents with autism spectrum disorders. J Autism Dev Disord. 2014 Jun;44(6):1391-402.

[3] Gotham K. et al. Depressive and anxiety symptom trajectories from school age through young adulthood in samples with autism spectrum disorder and developmental delay. J Am Acad Child Adolesc Psychiatry. 2015 May;54(5):369-376.e3.

[4] Verhoeven JE. et al. Anxiety disorders and accelerated cellular ageing. Br J Psychiatry. 2015. May 1.

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Pellecchia, M., Connell, J., Kerns, C., Xie, M., Marcus, S., & Mandell, D. (2015). Child characteristics associated with outcome for children with autism in a school-based behavioral intervention Autism DOI: 10.1177/1362361315577518

Childhood inattention and later academic outcome

"Across the full range of scores at a population level, each 1-point increase in inattention at age 7 years is associated with worse academic outcomes at age 16."

That was one of the conclusions reached in the study by Kapil Sayal and colleagues [1] (open-access) drawing on data derived from the Avon Longitudinal Study of Parents and Children or ALSPAC to those in the know. This initiative has also recently produced some other intriguing results on the potential long-term effects of bullying for example (see here).

"Matching of the ALSPAC database with the administrative National Pupil Database (NPD, the central repository in England for pupil-level educational data) provided details of the children's results in the General Certificate of Secondary Education (GCSE) examinations at age 16 years." For those resident in England, Wales and Northern Ireland, GCSEs are probably a familiar concept (they were the starting point for my own academic achievement record). For everyone else, GCSEs are normally sat at the end of the school journey (16 years) and form the start of the typical educational achievement hierarchy leading into A-levels, university degree and beyond. "In total, GCSE attainment data were available for 11,640 children (83% of the core ALSPAC sample)."

The Development and Well-Being Assessment (DAWBA) was completed by parents and teachers of participating children when aged 7 years old. Similar to other discussions on this blog mentioning the DAWBA (see here) it relates "closely to DSM-IV items and focus on current problems and associated impairment." For the purposes of the Sayal study "the key variables of interest relate to inattention, hyperactivity/impulsivity, and oppositional/defiant behaviors." Various other potential confounders such as child cognitive abilities and parental social class were also measured and taken into account when it came to the final analyses.

Following some number-crunching the authors concluded that their results potentially "highlights the adverse effects of early childhood behavioral difficulties on educational outcomes in adolescence" specifically based on inattention symptoms: "inattention, particularly if noticeable to a parent or teacher, is a stronger predictor than hyperactivity/impulsivity of later academic difficulties." Disruptive behaviour disorder (DBD) and oppositional/defiant symptoms were also independently linked to worse academic outcomes in boys.

I know that such findings are probably not totally unexpected in terms of issues such as inattention potentially impacting on learning ability/capacity/enthusiasm subsequently also being reflected in exam results, but the results do put a peer-reviewed, evidence-based perspective on things. Authors also note that: "teachers and parents should be aware of the academic impact of early behavioral difficulties, and, in particular, the risk associated with subthreshold difficulties." I might add that such results do not rule out other factors as playing a role in academic outcome as per other recent data [2].

Insofar as what can be potentially done to mitigate such symptoms and their potential impact on academic performance, the authors offer a few suggestions including: "strategies that might help to optimize examination performance during teenage years include time management and organization skills (throughout the course of study), prioritization of key work, minimizing distractions, examination revision, and within-examination strategy." All well and good (and discussed by other authors [3]) I say but perhaps one might also look to 'tackling' issues such as inattention in other ways too. Take for example the recent paper from Bos and colleagues [4] (see this post) discussing their results based on supplementation with omega-3 fatty acids specifically on inattention symptoms. Probably not suitable or useful for every child with attentional issues, but certainly worth quite a bit more investigation looking for potential best responders based on the idea that good nutrition might be an important part of good mental health. Oh, and how about looking at sleep and even chess? [5]

Music: Cannonball - The Breeders.

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[1] Sayal K. et al. Childhood behavior problems and academic outcomes in adolescence: longitudinal population-based study. J Am Acad Child Adolesc Psychiatry. 2015 May;54(5):360-368.e2.

[2] Peyrot WJ. et al. The association between lower educational attainment and depression owing to shared genetic effects? Results in ~25 000 subjects. Molecular Psychiatry. 2015. April 28.

[3] Ciesielski HA. et al. Academic Skills Groups for Middle School Children With ADHD in the Outpatient Mental Health Setting: An Open Trial. J Atten Disord. 2015 Apr 29. pii: 1087054715584055.

[4] Bos DJ. et al. Reduced Symptoms of Inattention after Dietary Omega-3 Fatty Acid Supplementation in Boys with and without Attention Deficit/Hyperactivity Disorder. Neuropsychopharmacology. 2015 Mar 19.

[5] Blasco-Fontecilla H. et al. Efficacy of chess training for the treatment of ADHD: A prospective, open label study. Rev Psiquiatr Salud Ment. 2015 Apr 21. pii: S1888-9891(15)00048-8.

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Sayal K, Washbrook E, & Propper C (2015). Childhood behavior problems and academic outcomes in adolescence: longitudinal population-based study. Journal of the American Academy of Child and Adolescent Psychiatry, 54 (5), 360-36800 PMID: 25901772

Responding to parental concerns about possible offspring autism

"In conclusion, despite early parental concerns, children with ASD [autism spectrum disorder] receive less proactive provider responses to these concerns than children with ID/DD [intellectual disability/developmental delay]. Less proactive/more passive provider responses are associated with delays in diagnosing ASD."

So said the paper from Katharine Zuckerman and colleagues [1] (open-access) who using "nationally representative data from the 2011 Survey of Pathways to Diagnosis and Treatment" tried to answer the following questions: "(1) Did child age at first parental concern and first parental conversation with provider differ among children eventually diagnosed with ASD compared with those diagnosed with DD or ID?; (2) Did provider response to concerns differ among these conditions?; and (3) Among children with ASD, was a more proactive/less reassuring provider response to parental concerns associated with earlier ASD diagnosis?"

What they found has been reported by various media (see here for example) and indicated that when it comes to early parental concerns about the behaviour and development of their offspring: "compared with parents of children with ID/DD, parents of children with ASD reported concerns earlier and had earlier provider conversations about these concerns, but were more likely than to receive reassuring/passive provider responses to those concerns." Indeed, the authors implied that healthcare provider behaviour might be an important factor in 'delayed autism identification'.

As it is in many areas of autism research, we've been here before. In a previous post titled ''You know what boys are like' and the autism pre-diagnostic experience' (see here) I discussed the paper by Sara Ryan & Helen Salisbury [2] (open-access). How for example, the UK experience of autism diagnosis might not be so different from the US experiences talked about by Zuckerman et al specifically with the idea that for some parents, premature reassurance by health professionals about their concerns about their child's behaviour/development may not sit too well with parents and may result in delays in assessment/diagnosis for the child. By saying this, I'm not trying to tarnish medical reputations. Children do not uniformly develop in the same way with lots of stopping and starting in skills learned in the early years which does not necessarily mean 'autism' or any other label. But Zuckerman et al are right to highlight this issue.

From the collected peer-reviewed evidence currently available, we know that there are many variables potentially affecting age of diagnosis when it comes to autism (see here). We also know that autism assessment/diagnosis is one part science and one part of art in terms of the skills of those charged with such tasks and the path does not always run as smoothly as we would wish (see here). Late, delayed or mis-diagnosis however, can be a source of significant stress to both families and children/adults alike (see here) particularly when parental views and opinions have been shown to be pretty accurate when it comes to the appearance of something like autism (see here). I might also direct you to the paper by Sacrey and colleagues at this point [3].

The best way forward? Accepting that resources are being stretched for many different reasons and that assessments cost both in terms of finance and human resources, perhaps give parents/significant others the benefit of the doubt when they say they think there might be 'issues' for someone. Dedicate greater resources towards how screening and assessment could be done more cost-effectively and reliably in the digital age (remember that YouTube work?) and focus on how early diagnosis might offer so much to a person (see here). Oh, and consider that "screening for ASD may need to be repeated multiple times in the first years of life" [4].

As is customary on this day: May the 4th be with you...

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[1] Zuckerman KE. et al. Parental Concerns, Provider Response, and Timeliness of Autism Spectrum Disorder Diagnosis. The Journal of Pediatrics. 2015. 14 April.

[2] Ryan S. & Salisbury H. 'You know what boys are like': pre-diagnosis experiences of parents of children with autism spectrum conditions. Br J Gen Pract. 2012 May;62(598):e378-83.

[3] Sacrey L-A R. et al. Can Parents’ Concerns Predict Autism Spectrum Disorder? A Prospective Study of High-Risk Siblings From 6 to 36 Months of Age. JAACAP. 2015. March 27.

[4] Ozonoff S. et al. Diagnostic stability in young children at risk for autism spectrum disorder: a baby siblings research consortium study. J Child Psychol Psychiatry. 2015 Apr 29.

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Katharine Elizabeth Zuckerman, Olivia Jasmine Lindly, & Brianna Kathleen Sinche (2015). Parental Concerns, Provider Response, and Timeliness of Autism Spectrum Disorder Diagnosis The Journal of Pediatrics : 10.1016/j.jpeds.2015.03.007