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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"parental asthma was associated with slightly elevated risk of ASD in offspring"

The paper by Tong Gong and colleagues [1] provides the blogging fodder today and the finding that "parental asthma was associated with slightly elevated risk of ASD [autism spectrum disorder] in offspring."

As unusual as it might sound to some people that a condition primarily affecting the lungs *might* show a connection to a developmental diagnosis in offspring, this is not the first time that asthma and autism has been talked about on this blog (see here and see here). Granted, much of that previous peer-reviewed research has been looking at the possible *connection* between asthma and autism diagnosed in the same person (albeit not necessarily always describing a link). But there is some research history connecting the two labels. Indeed, one of the primary comorbidities that can follow a diagnosis of autism - attention-deficit hyperactivity disorder (ADHD) - seems to have an even stronger *association* with asthma (see here).

Gong et al set out to investigate a few important issues: "the association between (a) maternal/paternal asthma and offspring ASD, and (b) prenatal exposures to β2-agonists, other asthma medications and offspring ASD." It would be difficult to describe the Gong study as 'underpowered' given that their use of those fabulous Scandinavian population registries - this time in Sweden - covering "all children (N=1,579,263) born in Sweden 1992-2007." From the total population, researchers identified some 22,000 children diagnosed with an ASD. They looked at their exposure to "parental asthma or prenatal asthma medications" and compared the data with other populations (not diagnosed with autism) including various degrees of siblings and extended family members.

As per the title of this post, a possible *association* was revealed between parental medical history of asthma and offspring risk of a diagnosis of ASD. Asthma in either parent seemed to show a connection, but maternal asthma showed the stronger connection. Also: "The risk of offspring ASD in mothers with asthma showed similar estimates when adjusting for shared familial factors among paternal half-siblings... full-cousins... and half-cousins." This suggests that familial factors were not 'confounding' factors. Another detail is important to mention: "Prenatal exposure to asthma medications among subjects whose mothers had asthma was not associated with subsequent ASD." This is an important detail. It mirrors the findings reported in the paper by Su and colleagues [2] looking at another Scandinavian cohort, and their conclusion: "children born to women who used β2AA [β2-adrenoreceptor agonist] during pregnancy have an increased risk of ASDs in later life" with the caveat that risk of offspring autism was "more likely due to underlying maternal diseases rather than the exposure to β2AA itself."

Implications? Well, several. Not least that more study is required looking at the biological and genetic links between autism and asthma. Y'know, something along the lines of the fact that 'autism genes are probably not just genes for autism' (see here) and how autism has been previously studied in the context of lung architecture too (see here).

What else? How about examining the possibility of some shared biological mechanisms also at work? Perhaps start with inflammation for example [3] and work through other potential immune-related issues as well (see here). And how about also thinking about the possibility of shared 'exposure' events being potentially important? Asthma is a condition affecting the lungs. Something like air pollution is therefore a prime suspect when it comes to the development and continuation of the condition. Likewise, air pollution is no stranger to the autism peer-reviewed research landscape (see here for example). Is it possible that air pollution might be implicated in asthma and autism?

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[1] Gong T. et al. Parental asthma and risk of autism spectrum disorder in offspring: a population and family based case-control study. Clin Exp Allergy. 2019 Feb 11.

[2] Su X. et al. Prenatal exposure to β2-adrenoreceptor agonists and the risk of autism spectrum disorders in offspring. Pharmacoepidemiol Drug Saf. 2017 Jul;26(7):812-818.

[3] Murdoch JR. & Lloyd CM. Chronic inflammation and asthma. Mutat Res. 2010;690(1-2):24-39.

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"two in five young people scoring above thresholds for emotional problems, conduct problems or hyperactivity"

The quote titling this post - "two in five young people scoring above thresholds for emotional problems, conduct problems or hyperactivity" - comes from the eye-opening findings published by Jessica Deighton and colleagues [1] (open-access available here).

It's based on a study of over 28,000 adolescents here in Blighty: "51.2% of whom were in Year 7 (age 11–12) and 48.8% of whom were in Year 9 (age 13–14) in 97 state-maintained secondary schools across six geographical locations in England."

Said young people were given the "child self-report Strengths and Difficulties Questionnaire (SDQ)" to complete, and the received data were analysed alongside other information collected by the authors "from the National Pupil Database: SEN status; FSM eligibility; child in need status (CIN, this is a child who either (a) is unlikely to achieve/maintain a reasonable standard of health and development without local authority provision; (b) is likely to be impaired without local authority provision; or (c) is disabled); and ethnicity (Asian, Black, Chinese, Mixed, White or any other ethnic group)."

In more detail: "18.4% scored above the abnormal threshold for emotional symptoms, 18.5% for conduct problems, 25.3% for inattention/hyperactivity and 7.3% for peer-relationship problems." Going back to the title of this post, researchers mention how "around two in five young people scoring above ‘abnormal’ thresholds for three of the four problem areas measured (emotional problems, conduct problems and hyperactivity)." They also observed that:

• SEN - special educational needs - status played a role in those figures (those with SEN were consistently more likely to provide an above-threshold response to all the areas measured, particularly peer-relationship problems). 
• Entitlement to free school meals (FSM), a potential marker of deprivation, was also associated with an above-threshold response to all areas.
• "Being male significantly increased the odds of scoring above threshold for behavioural problems and inattention/hyperactivity, whereas being female significantly increased the odds of experiencing emotional symptoms."

There are caveats attached to the Deighton findings; not least the sole reliance on "child self-report data from a very brief assessment tool" without any accompanying further analysis on the presence (or not) of diagnosable psychopathology. But, in the context of the large participant number included for study and that most adolescents aren't likely to 'lie' about their positive responses to items such as "I get very angry and often lose my temper" or "I take things that are not mine from home, school or elsewhere" I'd be inclined to view the Deighton findings as a pretty accurate representation of their 'in the thousands' cohort.

So where next? Well, if we're talking about findings observing that "42.5% scored above threshold for any one of the first three problem scales (emotional symptoms, conduct problems or inattention/hyperactivity)" we have to talk about what services are in place (and should be in place) to support this large group. This, on the basis that, such 'problems' can potentially lead to various other 'adverse' outcomes both in later childhood and beyond. And when I talk about 'support', I mean both support and intervention to help those young adults to manage such issues. All of this set in the context of a continually squeezed financial and resource position (at least here in Blighty).

The other question has to be 'why'? Why have so many young people reported as they have? Deighton et al talk about various factors as potentially being important: "the impact of austerity, increasing experience of academic pressures, reduced rates of sleep and increased use of social media", to a large extent talking about the social environment as playing a significant role. I don't doubt that these external factors and other related variables will play a role in how young people are reporting, but I'm not convinced that the social environment is the only important factor to consider. It's not, for example, beyond the realms of possibility that other genetic and non-genetic variables (i.e. in the physical environment) could also play a role; something I say in the context of a 'growth' in the number of children and young adults being diagnosed with all-manner of different behavioural and/or psychiatric labels (see here and see here for examples).

Something important seems to be going on with our young people (see here and see here). We have to assume that such an issue is not going to resolve itself and may even increase in terms of numbers as time goes on. We really need to find out what factors are behind this and start taking action... like now.

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[1] Deighton J. et al. Prevalence of mental health problems in schools: poverty and other risk factors among 28 000 adolescents in England. Br J Psychiatry. 2019 Jan 30:1-3.

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ALSPAC says... frequency of depression during pregnancy has increased over time

Yes, it's yet another 'ALSPAC [Avon Longitudinal Study of Parents and Children] says...' post today, and the findings reported by Rebecca Pearson and colleagues [1] observing that "prenatal depression is on average 51% more common among young mothers in the current generation of the ALSPAC cohort than during their mothers’ generation 25 years ago."

Having already attracted some media attention (see here), the aim of the current study was to "compare prenatal depression prevalence in young women across time." Because ALSPAC is a longitudinal study (following participants across some quite long periods of time) also involving several generations of the same families, it was ideally placed to compare depressive symptoms during pregnancy across different temporal cohorts.

And compare it did, as responses to the Edinburgh Postnatal Depression Scale (EPDS) were analysed from those in the original ALSPAC cohort participating in the early 1990s (N=2390) compared with those second-generation ALSPAC participants (G1: 2012-2016, N=180), including "66 mother-offspring pairs." All participants were aged between 19-24 years of age at the time of pregnancy assessment and, to reiterate, all "had the same measure of prenatal depression assessed at approximately the same time in pregnancy."

Results: well, alongside some potentially important differences between the two cohorts - "ALSPAC-G1 women were more likely to have achieved A-Levels and were less likely to smoke, but were more likely to take antidepressants" - the study suggested that reaching cut-off scores on the EPDS (≥13) was about 50% more likely in the G1 (younger) cohort. The strength of this 'association' actually increased when researchers took into account other variables potentially likely to affect the study results such as "age, BMI, smoking, parity, and education." They also noted that: "Restricting the analyses to the 66 mother-offspring pairs and accounting for clustering of pairs, we found a virtually identical association, but with wider a confidence interval."

Caveats? Well, one needs to remember that this was a study based on one self-report questionnaire which includes 10 questions answered on a scale from 'not at all' to 'most of the time' (or something similar). It's useful in the context of depression over the course of pregnancy but, as per the instructions for completion, only provides a snapshot (over the past 7 days), so please keep that in mind. The authors are also quite specific in their discussion about the applicability of their results, bearing in mind the age of their cohort(s) and the fact that: "The ALSPAC population largely consists of white European individuals."

That all being said, the findings are interesting and certainly worthy of further inspection and study. The authors go through the possible hows-and-whys of their findings; heading down the path that something(s) in the environment has changed over the decades and could be related to mechanisms. So: "This [younger] generation of young women has also experienced rapid change in technology, internet, and social media use, which has been associated with increased feelings of depression and social isolation and changes to social relationships." They also mention words like 'chronic stress' and 'sedentary lifestyle' as perhaps influencing the wider increase in depression that seems to be present these days. Whilst important (see here for example), I'm not totally convinced that the rise in depression or depressive symptoms is necessarily just a product of such modern living. Take 'chronic stress' for example; are we saying that young mothers-to-be are more stressed now than during the 1990s? I'm also minded to point out that the physical environment has also changed somewhat in the intervening years, as per the comment by the authors about G1 women being "more likely to take antidepressants." I don't doubt that there have been other 'chemical' changes too; some of which might be important.

Oh, there's another possibility too: I've talked about research using the EPDS before on this blog (see here). On that particular research occasion [2] an observation was made suggesting that "pregnant women with broader autism phenotype (BAP) showed an increased risk for developing postpartum depression (PPD)." Not to try and make connections where none may exist, but I'm wondering whether Pearson et al or someone else from ALSPAC might want to have a look-see whether this could be relevant to their current findings. Well, it's not as if ALSPAC don't have data on autistic traits for example (see here) and set against more recent ALSPAC research findings (see here), there's another hypothesis to be tested.

And as if to prove a point, the findings reported by Hirokawa and colleagues [3] observing that the BAP and postpartum depression might be *linked* should also be [carefully] introduced as part of the research conversation...

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[1] Pearson MR. et al. Prevalence of Prenatal Depression Symptoms Among 2 Generations of Pregnant Mothers. JAMA Network Open. 2018; 1: e180725.

[2] Asano R. et al. Broader autism phenotype as a risk factor for postpartum depression: Hamamatsu Birth Cohort (HBC) Study. Research in Autism Spectrum Disorders. 2014; 8: 1672-1678.

[3] Hirokawa K. et al. Associations between broader autism phenotype (BAP) and maternal attachment are moderated by maternal postpartum depression when infants are one month old: A prospective study of the Japan environment & children's study. J Affect Disord. 2018 Sep 19;243:485-493.

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