Childhood "neuropsychiatric morbidity" and prenatal exposure to pre-eclampsia (but not autism)

"Offspring exposed prenatally to preeclampsia have a significantly higher risk of developing a neuropsychiatric morbidity during childhood."

So said the findings reported by Kira Nahum Sacks and colleagues [1] following their analysis of a whopping "253,808 singletons... that were born between 1991 and 2014 in a single regional tertiary medical center" in Israel. Such work follows a research theme from this authorship group (see here).

Pre-eclampsia is no stranger to this blog (see here for example). It's a condition appearing during pregnancy that is characterised by "the onset of high blood pressure and often a significant amount of protein in the urine." Although most cases of pre-eclampsia are mild and some signs and symptoms treatable (see here), there are risks attached to the condition; one of the most notable being the possibility of eclampsia characterised by the onset of seizures to the mother. As you might imagine, such seizures present a risk to both mother and unborn child.

Nahum Sacks et al set out to "assess whether prenatal exposure to preeclampsia increases the risk of long-term neuropsychiatric morbidity" on the basis of "contradicting findings in the current literature." Including use of their large participant cohort, researchers took into account various other, potentially confounding factors, to look at what *might* happen in the longer term to those children who were exposed to pre-eclampsia during the nine months that made them. We are told that: "3.0% were born to mothers diagnosed with mild preeclampsia (n = 7660), 0.9% with severe preeclampsia (n = 2366) and 0.03% with eclampsia (n = 81)."

Results: it was a bit of a mixed bag of results if I'm honest. Researchers mention for example, how pre-eclampsia exposure was significantly associated with offspring obstructive sleep apnoea (OSA) and epilepsy. At least one of those outcomes - epilepsy - has previously been talked about in the peer-reviewed literature [2] as being associated with prenatal exposure to pre-eclampsia and eclampsia.

But then also there was something a little bit different in the Nahum Sacks paper: "Preeclampsia exposure [was] not associated with autism or eating disorders in offspring." This is intriguing in light of some fairly strong (and meta-analysed) links previously discussed between pre-eclampsia and autism (see here). The Dachew paper [3] that was previous fodder for this blog did caution that their meta-analysis on the topic of autism and pre-eclampsia saw evidence that many studies "did not consistently adjust for important confounding factors such as maternal obesity, parity, gestational diabetes and infection during pregnancy" and what this might mean for their overall findings. Indeed, it's a big issue for research looking at pregnancy factors as affecting offspring risk of this, that and t'other: various adverse pregnancy conditions tend to 'clump together'. This makes it all the more difficult to tie any one single factor down to any one specific risk (see here).

The Nahum Sacks findings are not to be taken lightly. The large participant group included for study add weight to the their findings. Yes, it was another observational study, and yes, there could be a 1001 other variables not controlled for that may influence the appearance of offspring neuropsychiatric morbidity. But the possibility of a link between exposure to pre-eclampsia in-utero and something like the appearance of epilepsy is something that could be worthy of a lot more study...

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[1] Nahum Sacks K. et al. Long-term neuropsychiatric morbidity in children exposed prenatally to preeclampsia. Early Hum Dev. 2019 Jan 31;130:96-100.

[2] Wu CS. et al. Preeclampsia and risk for epilepsy in offspring. Pediatrics. 2008 Nov;122(5):1072-8.

[3] Dachew BA. et al. Pre-eclampsia and the risk of autism-spectrum disorder in offspring: meta-analysis. Br J Psychiatry. 2018 Mar;212(3):142-147.

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"to [try and] advance the understanding of potential mechanisms underlying insomnia in adults with ASD"

The paper by Vanessa Hohn and colleagues [1] (open-access available here) provides the blogging fodder today and their findings in relation to the presence of insomnia as a "common source of distress in adults with autism spectrum disorder (ASD)."

Insomnia is essentially a regular problem in getting to sleep. It has a myriad of 'causes' ranging from uncomfortable sleeping conditions (bed, noise, temperature) to the influence of things like stress, depression and anxiety. Insomnia is no joke. Outside of the potential wide-ranging effects on physical and mental health [2] it puts a person at some heightened risk of all-manner of adverse outcomes [3].

As part of a suite of sleeping-related problems, insomnia is also no stranger to diagnostic labels like autism. With autism in mind, sleep problems that begin in childhood are pretty likely to carry over to adulthood. Nobody knows the precise reason(s) why those on the autism spectrum are more likely to experience sleep problems including insomnia. Some have speculated that the presence of autistic traits may be a risk factor for such sleeping issues (see here) but there is currently little detail regarding the bridge from core autism features to sleep problems. Others have observed an *association* between the presence of other somatic issues occurring alongside autism and sleep problems (see here and see here) but again, further clarity is needed on the hows-and-whys of any relationship and, importantly, what can be done to alleviate such issues.

Hohn et al started with the premise that: "Two characteristics of ASD could be relevant to insomnia complaints by hampering the entrainment of a circadian sleep-wake rhythm." They specifically talk about examining the link between sensory responsiveness and social skills in the context of insomnia in adults with ASD.

"Data were obtained from the Netherlands Autism Register (NAR), which is a longitudinal register including approximately 2000 individuals with ASD." Some 630 participants with autism were included for study, where "individual responses given to three measures of interest during an online survey in 2015 were analyzed." Those 'measures' were the Insomnia Severity Index (ISI), the Sensory Perception Quotient and the Autism Spectrum Quotient-28. The combined data were analysed.

Results: bearing in mind that this was a study exclusively including self-report from participants with autism - with no non-autistic control group - and one that relied on a single temporal snapshot of insomnia symptoms, one has to be a little careful with the findings. So: "The mean ISI score in the present sample was 9.50 (SD = 6.01), which is indicative of subthreshold insomnia and higher than means reported for the general population ranging between 1 and 7... but lower than values obtained from insomnia patients ranging between 17 and 20." Further, about half of participants scored in the "absence of insomnia" category with only around 20% of the group recording either moderate or severe insomnia. This tells us that, again according to self-report (and not using actigraphy for example), insomnia was not necessarily a widespread issue in this cohort but present in a not-significant number: about 1 in 5 people.

Next: "Primary analyses revealed that each of the covariates had a significant impact on the ISI total score." What this means is that biological sex, gender and medication use potentially played a role in insomnia. Women participating in the study tended to score higher on the ISI than men, and those aged 45-65 also seemingly showed more of a tendency towards insomnia. I don't think anyone would be really surprised with the idea that age and insomnia might be connected [4].

Some further statistical analysis of their results led researchers to opine on: "positive associations of insomnia severity with general and visual sensory hyper-reactivity and with impairment of social skills." I'm not too au fait with the specifics of the statistical modelling technique used by the authors - hierarchical multiple linear regression analyses (HMLR) - but can see what they did and how they did it, including "controlling for confounding effects of covariates" such as "medication, biological sex, intelligence, and age" (as previously mentioned). That being said, I'll draw your attention to some other conclusions reached by the authors: "The rather small effect sizes reported in the present study suggest that other factors not assessed in this study contribute to the emergence and persistence of sleep problems in adults with ASD."

The Hohn study does add something to the literature on sleep difficulties being experienced by quite a few people (children and adults) on the autism spectrum. I'm not overly convinced that they've stumbled upon evidence that core autistic features such as social skills problems and sensory issues are necessarily central to insomnia in their cohort but am willing to concede that they might play a role. Personally, I'd be inclined to go back to that data on 'comorbid' issues like gastrointestinal (GI) problems (see here) or breathing issues like apnoea (see here) as being something to explore further; also with the assumption that such issues are potentially 'treatable' and could have an important knock-on effect for something like insomnia and other sleep issues with autism in mind...

Oh, and don't forget the molecular handyperson that is melatonin and it's potential role in all of this (see here and see here). That and other potential avenues of research/clinical interest (see here)...

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[1] Hohn VD. et al. Insomnia Severity in Adults with Autism Spectrum Disorder is Associated with sensory Hyper-Reactivity and Social Skill Impairment. J Autism Dev Disord. 2019 Feb 9.

[2] Fernandez-Mendoza J. & Vgontzas AN. Insomnia and its impact on physical and mental health. Curr Psychiatry Rep. 2013;15(12):418.

[3] Garbarino S. et al. Insomnia is associated with road accidents. Further evidence from a study on truck drivers. PLoS One. 2017;12(10):e0187256.

[4] Foley DJ. et al. Sleep complaints among elderly persons: an epidemiologic study of three communities. Sleep. 1995 Jul;18(6):425-32.

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Adenotonsillectomy for obstructive sleep apnea and autistic behaviours?

Adenotonsillectomy refers to the surgical removal of the tonsils and adenoids and is typically indicated for a variety of reasons, not least in cases of obstructive sleep apnoea (OSA) (where breathing is interrupted during sleep). It's not an unfamiliar operation and is generally categorised as low-risk surgery. The positive outcomes following surgery have been described as 'dramatic' both in clinical terms and also related to quality of life [1].

A recent study published by Emi Murata and colleagues [2] (open-access available here) adds a further dimension to the use of adenotonsillectomy (AT) for obstructive sleep apnoea specifically with the autism spectrum in mind. They concluded that: "Behavioral problems were significantly improved following AT in ASD [autism spectrum disorder] children with OSA."

First off, I'll direct you to a previous post that I wrote about sleep apnoea and autism (see here) based on the findings reported by Hirata and colleagues [3]. They concluded that within their research cohort: "sleep problems, especially obstructive sleep apnea, are more common in ASD preschoolers than in community preschoolers." Then there are the study results by Malow and colleagues [4] who detailed a case report of treating sleep apnoea in a child with autism via use of AT. Bearing in mind this was an N=1, they observed that treatment coincided with "improvements in sleep, social communication, attention, repetitive behaviors, and hypersensitivity" based on use of the ADOS among other measures.

Set within this context, the Murata paper detailed the results of a study including some 54 children diagnosed with ASD. Their aims were two-fold: "to determine whether AT for the treatment of OSA improves the behavior of Japanese children with ASD using the Child Behavior Checklist (CBCL)" and "to identify characteristics for behavioral improvement following the treatment of OSA in these children with ASD." Thirty of the study participants were diagnosed with OSA and all underwent surgery for AT. I must also stress that said surgery was a clinical decision: "Because hypertrophy of the adenoids and/or palatine tonsils was observed." The rest of the cohort served as a control group used "to establish whether observed changes in CBCL scores were due to the natural course or a result of the experimental intervention."

The results are pretty interesting: "After AT, T-scores of the CBCL scales were significantly improved in the OSA group, but no change was observed in the control." This was based on before and after inspection at 0 months (before surgery) and 6 months after surgery. The sorts of things seemingly improved in the AT group were aspects of behaviour and functioning linked to being withdrawn, social problems. attention issues and aggressive behaviour. Authors noted that: "The domain of “thought problems” showed the largest decrease... in the OSA group."

When it came to the 'characteristics for behavioural improvement' side of their study, authors noted that: "the improved group show[ed] significantly higher scores on the CBCL at pre-AT than the unchanged/deteriorated group in ASD children with OSA after OSA treatment". This implies that baseline presentation might be important when it comes to behavioural outcomes following the use of AT and also that not every child with ASD and sleep apnoea undergoing AT will show the same pattern of behavioural changes.

I find these results to be fascinating. Not least because they offer a roadmap for (a) screening for sleep apnoea in cases of autism and (b) details of how a treatment for one cause of sleep apnoea in such cases might have effects well beyond just related to breathing patterns. Then also, there is the question of why such surgery might impact on presented behaviour? I'm afraid I don't know enough about such issues to offer any definitive explanations. I might refer you back to some other discussions on this blog about middle ear infections and autism (see here) in the context of ear, nose and throat being linked on several levels but further investigations are very much required on the biological parameters potentially important to findings such as those described by Murata et al. That being said [5] there may already be some clues in the peer-reviewed science literature...

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[1] Mitchell RB. Adenotonsillectomy for obstructive sleep apnea in children: outcome evaluated by pre- and postoperative polysomnography. Laryngoscope. 2007 Oct;117(10):1844-54.

[2] Murata E. et al. Evaluation of behavioral change after adenotonsillectomy for obstructive sleep apnea in children with autism spectrum disorder. Res Dev Disabil. 2017 May 14;65:127-139.

[3] Hirata I. et al. Sleep problems are more frequent and associated with problematic behaviors in preschoolers with autism spectrum disorder. Research in Developmental Disabilities. 2016; 49-50: 86-99.

[4] Malow BA. et al. Impact of treating sleep apnea in a child with autism spectrum disorder. Pediatr Neurol. 2006 Apr;34(4):325-8.

[5] Mitchell RB. & Kelly J. Behavioral changes in children with mild sleep-disordered breathing or obstructive sleep apnea after adenotonsillectomy. Laryngoscope. 2007 Sep;117(9):1685-8.

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Murata E, Mohri I, Kato-Nishimura K, Iimura J, Ogawa M, Tachibana M, Ohno Y, & Taniike M (2017). Evaluation of behavioral change after adenotonsillectomy for obstructive sleep apnea in children with autism spectrum disorder. Research in developmental disabilities, 65, 127-139 PMID: 28514706

Sleep apnoea and autism

Sleep apnoea defined as "a condition where the walls of the throat relax and narrow during sleep, interrupting normal breathing" is not natural fodder for this blog. When however it is mentioned in the context of autism as it was in the paper by Ikuko Hirata and colleagues [1] it becomes a little more relevant; more so when one realises that sleep issues and autism might actually be quite an important topic (see here).

Hirata et al describe the assessment of sleep problems in "965 community and 193 ASD [autism spectrum disorder] preschoolers using the Japanese Sleep Questionnaire for Preschoolers." They noted how various sleep problems were more frequently reported in the the group with autism compared with asymptomatic (not-autism) controls including "obstructive sleep apnea and parasomnias." Further: "ASD preschoolers with sleep problems exhibited more behavioral problems than those without sleep problems"; something perhaps not entirely unexpected.

The comment about obstructive sleep apnoea being more frequently reported in those with autism got me looking into some of the other peer-reviewed material with this 'association' in mind. Not surprisingly, among the vast number of papers making up with the autism research landscape, sleep apnoea receives attention. The case report detailed by Malow and colleagues [2] provides one of the early accounts of sleep apnoea occurring alongside autism. Describing "a 5-year-old female with an autism spectrum disorder" the authors report "improvements in sleep, social communication, attention, repetitive behaviors, and hypersensitivity after adenotonsillectomy for obstructive sleep apnea." Some of the same authors followed up this finding [3] with more general guidance on how "suspected obstructive sleep apnea, should be referred to a sleep specialist" with autism in mind.

When it comes to the question of what factors might be influential in the development of sleep apnoea with autism in mind, there is some science here too. Outside of the typically defined causes of sleep apnoea (see here) papers such as the one by Bowers and colleagues [4] hinted at other potentially important correlates including gestational factors allied to gender. Youssef and colleagues [5] reported a possible connection between serum ferritin levels linked to iron levels and sleep apnoea and autism. Ferritin and iron levels have some history with [some] autism in mind (see here) although I'm a little unsure about the direct connection between this nutrient and sleep apnoea outside of the whole 'periodic limb movement' bit.

Accepting that screening for sleep apnoea is probably not commonplace when it comes to autism, I do believe that there is more science to do on this topic. Without hopefully displaying too much 'lack of knowledge' and making connections where none might exist, I do wonder whether the focus on airways and sleep apnoea might tie into some interesting findings reported a while back on 'bronchoscopic airway anatomy' and autism (see here). That also nasal congestion might be a risk factor for sleep apnoea is potentially relevant to some autism also, specifically where allergy might also be present [6] (see here for my take on this). I don't doubt there will be other factors requiring further investigation too, as once again the idea is to screen not to assume...

Music: Buddy Holly - Everyday.

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[1] Hirata I. et al. Sleep problems are more frequent and associated with problematic behaviors in preschoolers with autism spectrum disorder. Research in Developmental Disabilities.  2016; 49-50: 86-99.

[2] Malow BA. et al. Impact of treating sleep apnea in a child with autism spectrum disorder. Pediatr Neurol. 2006 Apr;34(4):325-8.

[3] Johnson KP. & Malow BA. Sleep in children with autism spectrum disorders. Curr Treat Options Neurol. 2008 Sep;10(5):350-9.

[4] Bowers K. et al. Phenotypic differences in individuals with autism spectrum disorder born preterm and at term gestation. Autism. 2015 Aug;19(6):758-63.

[5] Youssef J. et al. Relationship of serum ferritin levels to sleep fragmentation and periodic limb movements of sleep on polysomnography in autism spectrum disorders. Pediatr Neurol. 2013 Oct;49(4):274-8.

[6] Jyonouchi H. Marked improvement of neuropsychiatric symptoms following control of allergy symptoms with the use of humanized murine anti-IgE antibody (omalizumab) in 2 patients with severely limited expressive language. Allergy Asthma Clin Immunol. 2015 Dec 9;11:38.

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Hirata, I., Mohri, I., Kato-Nishimura, K., Tachibana, M., Kuwada, A., Kagitani-Shimono, K., Ohno, Y., Ozono, K., & Taniike, M. (2016). Sleep problems are more frequent and associated with problematic behaviors in preschoolers with autism spectrum disorder Research in Developmental Disabilities, 49-50, 86-99 DOI: 10.1016/j.ridd.2015.11.002