Hypertensive disorders of pregnancy (HDP) and offspring autism and/or ADHD meta-analysed

"Pooled estimates from this systematic review and meta-analysis of 61 studies suggest that exposure to hypertensive disorders of pregnancy is associated with a small yet statistically significant increase in the odds of autism spectrum disorder and attention-deficit/hyperactivity disorder in offspring compared with no exposure."

So concluded the review and meta-analysis published by Gillian Maher and colleagues [1] that collected and analysed the current peer-reviewed research literature (up to June 2017) looking at hypertensive disorders of pregnancy (HDP) and offspring developmental outcomes. Continuing an important research theme (see here), authors observed something around "a 35% increased odds of ASD [autism spectrum disorder] compared with nonexposure" and that children were "30% more likely to have ADHD compared with unexposed offspring."

HDP according to Maher et al, covers quite a bit of diagnostic ground: "chronic hypertension (essential/secondary), white-coat hypertension, masked hypertension, transient gestational hypertension, gestational hypertension, and preeclampsia (de novo or superimposed on chronic hypertension)." The primary characteristic is "high blood pressure that either precedes pregnancy, is diagnosed within the first 20 weeks of pregnancy, or does not resolve by the 12-week postpartum checkup" [2].

There's little more to say about this area of research aside from the idea that findings "highlight the need for greater pediatric surveillance of infants exposed to HDP to allow early intervention that may improve neurodevelopmental outcome" and that more work on possible mechanism(s) need to be undertaken. On that last point the authors opine that "placental dysfunction, associated with HDP, may result in reduced placental perfusion and oxidative stress" or that: "Maternal inflammation may also play a key role." Both worthy areas for future research. The implication also, is that yet again, there may be some form of 'foetal programming' going on with regards to offspring autism that *could* be sensitive to intervention at some point...

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[1] Maher GM. et al. Association of Hypertensive Disorders of Pregnancy With Risk of Neurodevelopmental Disorders in Offspring: A Systematic Review and Meta-analysis. JAMA Psychiatry. 2018 Jun 6.

[2] Mammaro A. et al. Hypertensive Disorders of Pregnancy. Journal of Prenatal Medicine. 2009;3(1):1-5.

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Pre-eclampsia increased the risk of ASD in offspring: meta-analysed

"The finding suggests a need for early screening for ASD [autism spectrum disorder] in offspring of women with pre-eclampsia."

That was the conclusion reached in the meta-analysis published by Berihun Assefa Dachew and colleagues [1] covering the literature on pre-clampsia and offspring risk of autism or ASD.

Pre-eclampsia refers to a condition/state typically occurring after about 20 weeks of pregnancy. It is characterised by a combination of symptoms including hypertension (raised blood pressure) and the presence of protein in the urine (proteinuria).

On the basis that pre-eclampsia has been mentioned as a *possible* risk factor for subsequent offspring autism diagnosis (see here), the authors set about meta-analysing the peer-reviewed research in this area covering the period up to the middle of March 2017. They eventually settled on 10 studies that suitably covered the topic; of which 5 were rated as 'good in methodological quality' and the rest, somewhere between fair and poor.

Results: most studies (7/10) reported a positive association between the presence of pre-eclampsia and offspring autism. Most studies included for meta-analysis had taken into account some potentially important confounding variables such as child gender, "maternal age and substance use during pregnancy." The overall enhanced risk of offspring autism - "pooled relative risk (RR)" - associated with intrauterine exposure to pre-eclampsia was 32% compared with non-exposed children. And with that, you can perhaps see why the authors make that call for preferential screening for autism in children exposed to pregnancy pre-eclampsia.

But one must also be a little careful with such results. Careful because studies were usually looking at one pregnancy variable and one offspring outcome. To quote the authors, studies typically "did not consistently adjust for important confounding factors such as maternal obesity, parity, gestational diabetes and infection during pregnancy" all of which have been mentioned with offspring autism risk in mind (see here and see here and see here and see here respectively). Lots of things go on during pregnancy (and indeed, before pregnancy) that *could* have a sizeable impact - alone or in combination with each other - on various offspring outcomes including risk of a diagnosis of autism.

Still the results are what they are. They invite further investigations in this area, including those relevant to the possible hows-and-whys of pre-eclampsia exposure potentially contributing to a developmental/behavioural diagnosis and what strategies might be useful to consider [2] more generally...

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[1] Dachew BA. et al. Pre-eclampsia and the risk of autism-spectrum disorder in offspring: meta-analysis. British Journal of Psychiatry. 2018. Jan 24.

[2] Nordqvist M. et al. Timing of probiotic milk consumption during pregnancy and effects on the incidence of preeclampsia and preterm delivery: a prospective observational cohort study in Norway. BMJ Open. 2018; 8: e018021.

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Pregnancy hypertension and offspring autism reloaded

"There is growing awareness that prenatal adversity may increase the risk of autism spectrum disorder (ASD)."

Go on.

"These findings indicate that HDP [hypertensive disorders of pregnancy] exposure may increase the risk of ASD in the offspring."

So said the findings reported by Eileen Curran and colleagues [1] whose results have previously appeared on this blog with hypertension in mind (see here). I'm not altogether sure if this latest publication from this group represents 'new data' or is the same as/similar to that previously published [2]. It doesn't really matter to be honest given that the latest publication also includes a research addition insofar as the examination of "cytokine expression in the serum of women with pre-eclampsia, which is the most common HDP, and whether exposure of foetal neurons to this serum could change patterns of neuronal growth."

Drawing on data from some 13,000 children whose details were included in the Millennium Cohort Study (MCS) researchers, after "adjusting for several potential confounders including maternal alcohol consumption, education, depression, age, and poverty status", observed "a significant association between HDP and a twofold increased risk of ASD." They also reported that: "exposure of foetal cortical neurons to 3% serum isolated from women with an established HDP increased neuronal growth and branching in vitro." The authors have reported similar things with attention-deficit/hyperactivity disorder (ADHD) in mind too [3]; something that might be particularly important in the context of autism and ADHD overlapping in quite a few people (see here).

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[1] Curran EA. et al. Exposure to Hypertensive Disorders of Pregnancy Increases the Risk of Autism Spectrum Disorder in Affected Offspring. Mol Neurobiol. 2017 Oct 3.

[2] Curran EA. et al. Hypertension in pregnancy and autism spectrum disorder in a British cohort: Long term consequences for mother and child. Pregnancy Hypertension: An International Journal of Women's Cardiovascular Health. 2016; 6: 153.

[3] Curran EA. et al. The effect of hypertensive disorders of pregnancy on the risk of attention-deficit/hyperactivity disorder in the offspring: Long term consequences for mother and child. Pregnancy Hypertension: An International Journal of Women's Cardiovascular Health. 2016; 6: 169–170.

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Pregnancy hypertension and offspring autism

"Hypertension in pregnancy was associated with ASD [autism spectrum disorder] in this population even after controlling for known confounders."

So said the findings reported by Eileen Curran and colleagues [1] who, once again (see here), relied on "data from the Millennium Cohort Study" to produce some potentially important information about how adverse pregnancy conditions may/may not impact on offspring behaviour and development.

Hypertension (a.k.a high blood pressure) during pregnancy is something to watch out for given the association with another condition: pre-eclampsia; something else that has been linked with various outcomes to offspring including autism as one possibility (see here). I might also point out that the evidence looking at pre-eclampsia and offspring autism risk is not however exactly all one-way traffic [2].

OK one needs to be a little careful with the Curran findings given that: "Mothers were asked if they experienced any illnesses during pregnancy for which they needed medical attention" where hypertension in pregnancy - "HIP" -  was one of the options. This alongside the fact that "ASD was parent-reported based on a diagnosis by a doctor or health care professional." It's not that science should disbelieve parental report (indeed, quite the contrary) but rather that when it comes to medical diagnoses such as HIP, access to medical records where facts are recorded rather than retrospectively recalled is always going to be more authoritative.

Anyhow, from the 13,000+ people who "responded to the question on health during pregnancy and ASD" researchers reported that there did seem to be something more to see when it came to the connection between HIP and autism. Such a relationship held over various different statistical models (adjusted - unadjusted, maternal age, etc.) Given also the effect of HIP on placental functions in particular, the authors suggest that their results "raises the possibility of using clinical data regarding the clinical course of pregnancy and the molecular characteristics of the placenta at birth to predict a child risk of future ASD." Big words, I'm sure you'll agree.

So, here we are again talking about 'the maternal body as environment' with autism in mind (see here). Here we are again talking about 'risk factors' for autism and particularly those linked into the nine months that made us. I know from some comments about some of my previous posts (this one for example) there is a degree of 'so what?' when it comes to this type of research and indeed, subtle shades of brow furrowing that such work is seemingly being done at all. I agree that autism research needs to broaden it's horizons quite a bit to focus more on what matters to people on the autism spectrum but I also see the value in this type of approach focused on pregnancy and even before. I say this on the basis that clues to some of the underlying biology of at least some autism may one day be gleaned from such data (indeed, some might argue it already has) and could potentially (somehow) translate into interventions supporting more traditional ones. Obviously one also needs to also bear in mind that not all autism is necessarily 'programmed' during pregnancy or before (see here).

Finally, the question of how HIP or other related pregnancy factors might impact on offspring behaviour and development still needs answering. Yes, there is the concept of 'inflammation' creeping into this question [3], made all the more plausible by the fact that mothers body has to alter during pregnancy to accommodate that foreign body known as a foetus together with its placenta. Combined with the already known about idea that HIP can seemingly impact on the flow of nutrients through the placenta (made all the more convincing as a consequence of findings linking the inter-pregnancy interval to autism) and there are a few research avenues potentially ripe for further investigation.

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[1] Curran EA. et al. Hypertension in pregnancy and autism spectrum disorder in a British cohort: Long term consequences for mother and child. Pregnancy Hypertension: An International Journal of Women's Cardiovascular Health. 2016; 6: 153.

[2] Gardener H. et al. Prenatal risk factors for autism: comprehensive meta-analysis. Br J Psychiatry. 2009 Jul;195(1):7-14.

[3] LaMarca BD. et al. Inflammatory cytokines in the pathophysiology of hypertension during preeclampsia. Curr Hypertens Rep. 2007 Dec;9(6):480-5.

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Eileen A. Curran, Ali S. Khashan, Gerard W. O’Keeffe, & Louise C. Kenny (2016). 35 Hypertension in pregnancy and autism spectrum disorder in a British cohort regnancy Hypertension: An International Journal of Women's Cardiovascular Health., 6

Maternal diagnosis of PCOS increases the risk of offspring autism?

"We found that maternal diagnosis of PCOS [polycystic ovary syndrome] increased the risk of ASD [autism spectrum disorder], even after adjusting for potential confounders. Obesity among women with PCOS appeared to further increase the risk of ASD in the offspring. The risk associated with PCOS was similar in males and females."

Those were some of the main findings reported in the paper by Kyriaki (Sunday) Kosidou and colleagues [1] (open-access) who conducted a case-control study in Sweden looking at "23 748 ASD cases and 208 796 controls, matched by birth month and year, sex and region of birth." PCOS - an endocrine disorder characterised by polycystic ovaries, irregular periods and elevated levels of male hormones (androgens) - "was classified according to any lifetime recorded diagnosis (ICD-8: 256.90, ICD-9: 256E and ICD-10: E28.2)." The frequency of maternal PCOS alongside various other potentially confounding variables were analysed across the groups. Some media about the study can be seen here.

As per the opening paragraph, there did appear to be something to see when looking at rates of maternal PCOS where offspring autism was mentioned. One hundred and sixty-nine mothers of children with autism were found to have had a diagnosis of PCOS (0.7%) compared with 837 control mothers (0.4%). The difference (0.7% vs 0.4%) was deemed statistically significant (<0.001). That being said, and as with many factors when it comes to autism, differences were also noted across quite a few other parameters too such that 'maternal essential hypertension' was more frequently reported in mothers of children with autism compared with controls (1% vs. 0.8% respectively). Rates of diabetes mellitus were also significantly elevated (autism: 1.2% vs. controls: 0.8%). I'll come back to these findings shortly.

A few more details might also be useful to mention including: "The odds of offspring ASD were further increased among mothers with both PCOS and obesity, a condition common to PCOS that is related to more severe hyperandrogenemia." That and that fact that: "Risk estimates did not differ between sexes" and we have some potentially important results that "awaits confirmation, and exploration of potentially underlying mechanisms."

This is not the first time that the words 'PCOS' and 'autism' have graced this blog in the same entry (see here). That post from a few years back did quite a bit of speculating in terms of how mention of androgens and autism might link back to various discussions down the years talking about 'extreme male brains' and the like (bearing in mind that sweeping generalisations are not required [2]). It certainly appears that the Kosidou findings might tap into research chatter about things like testosterone and autism albeit with some provisos (see here and see here for example) and taking into account other recent findings [3].

Going back to the data on maternal hypertension and/or maternal diabetes as also showing some possible 'connection' to offspring autism, I've covered these variables before based on other independent peer-reviewed findings (see here and see here respectively). Maternal diabetes, specifically gestational diabetes, is something where the research evidence is increasingly converging in terms of an elevated risk of offspring autism. Mechanisms of effect are however, a little in short supply outside of talk about more autoimmune mediated diabetes (type 1 diabetes) and autism (see here). Maternal obesity and offspring autism has similarly figured in the peer-reviewed literature (see here).

Reiterating that there is more to do in this area of autism research, I do find the Kosidou results to be interesting. That preferential screening of offspring autism might be offered to women diagnosed with PCOS could be one consideration from such results; another might be for further research to focus on how PCOS and "elevated steroidopathic symptoms" might also feature among some people with an autism diagnosis or autistic traits in mind [4]. That being said, I must re-state that the overall numbers of diagnosed cases of PCOS in mums to children with autism was quite small...

Music: Steve - Emergency Art Rate.

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[1] Kosidou K. et al. Maternal polycystic ovary syndrome and the risk of autism spectrum disorders in the offspring: a population-based nationwide study in Sweden. Molecular Psychiatry. 2015. 8 December.

[2] Joel D. et al. Sex beyond the genitalia: The human brain mosaic. Proc Natl Acad Sci U S A. 2015 Nov 30. pii: 201509654.

[3] Bilgiç A. et al. Autistic Trait, Empathy, and Attention-Deficit/Hyperactivity Symptoms in Women with Idiopathic Hirsutism. Int J Trichology. 2015 Jul-Sep;7(3):113-118.

[4] Pohl A. et al. Uncovering steroidopathy in women with autism: a latent class analysis. Mol Autism. 2014 Apr 9;5:27.

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Kosidou, K., Dalman, C., Widman, L., Arver, S., Lee, B., Magnusson, C., & Gardner, R. (2015). Maternal polycystic ovary syndrome and the risk of autism spectrum disorders in the offspring: a population-based nationwide study in Sweden Molecular Psychiatry DOI: 10.1038/mp.2015.183

Maternal recall vs. medical records: implications for autism research

I don't want to dwell too much on the findings reported by Paula Krakowiak and colleagues [1] talking about the accuracy of "maternally-reported diabetes and hypertensive disorders, and reliability of BMI [body mass index] measurements during periconception and pregnancy compared with medical records when mothers are interviewed 2-5 years after delivery" but they are potentially important.

With authors such as Krakowiak and Irva Hertz-Picciotto on the paper in question, those who follow the autism research scene might have already made the connection back to the CHARGE (CHildhood Autism Risks from Genetics and the Environment) study (beincharge!) as the source of the current data. Indeed from CHARGE, findings such as a link between maternal obesity and offspring autism risk (see here) and maternal diabetes and autism (see here) have been previously discussed on this blog. For the most part, examination of such factors linked to subsequent offspring autism diagnosis has been through self-report and post-event questioning which potentially opens up such studies to various forms of bias.

The results from Krakowiak et al seemed to suggest when questioned about such issues: "self-reported diabetes and hypertensive disorders during periconception and pregnancy show high validity among mothers." Further: "Recall of pre-pregnancy BMI is reliable compared with self-reported values in medical records." In other words, still with some caution, families involved in initiatives such as CHARGE can and do quite accurately communicate their medical history. Of course this is not the first time that science has shown parentally-derived medical information to be pretty accurate when it comes to autism as per the Gorrindo findings [2]: "sensitive to the existence, although not necessarily the nature of" gastrointestinal issues related to autism (see here). That being said, developmental history recall is still subject to some forms of bias (see here).

There's little more for me to say about this topic aside from highlighting how: "Multiparity was associated with higher discrepancies in BMI and misreporting of hypertensive disorders" suggestive that 'the state of having borne a number of children' might interfere with recall in these areas. Still, when it comes to asking parents about their health and wellbeing before, during and after the birth of their children with autism research in mind and without over-generalising, one might be a little less critical of the value of the information received.

Music to close: The Flaming Lips and Race For The Prize. Scientists... don't race for the prize!

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[1] Krakowiak P. et al. Maternal Recall Versus Medical Records of Metabolic Conditions from the Prenatal Period: A Validation Study. Matern Child Health J. 2015 Feb 6.

[2] Gorrindo P. et al. Gastrointestinal dysfunction in autism: parental report, clinical evaluation, and associated factors. Autism Res. 2012 Apr;5(2):101-8.

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Krakowiak P, Walker CK, Tancredi DJ, & Hertz-Picciotto I (2015). Maternal Recall Versus Medical Records of Metabolic Conditions from the Prenatal Period: A Validation Study. Maternal and child health journal PMID: 25656730

Increased risk of chronic kidney disease in schizophrenia

"After adjusting for demographic characteristics, select comorbid medical disorders and NSAIDs [non-steroid anti-inflammatory drugs] usage, the current results reveal that patients with schizophrenia have an increased risk of nearly 40% (HR=1.36; 95% CI 1.13 to 1.63; p<0.001) of developing CKD [chronic kidney disease] within a 3-year follow-up period after their schizophrenia diagnosis."

That was the rather surprising finding reported by Nian-Sheng Tzeng and colleagues [1] (open-access) following their interrogation of the national research database which continues to give based in Taiwan. I've talked about the very, very useful data emerging from the Taiwanese National Health Insurance Research Database (NHIRD) before on this blog quite a few times (see here for example) and it's world-leading role in various research areas. I'm particularly impressed with the use of this resource when it comes to the intersection between psychiatry and physical health as per the evidence that something like asthma might for example have a connection to autism or ADHD [attention deficit hyperactivity disorder] (see here and see here respectively). Yes, I know correlation is not the same as causation, but the prospective design of some of  this research and the sheer numbers of participants involved should really be stimulating quite a bit more interest in such associations.

Anyhow, back to the recent Tzeng paper:

• Chronic kidney disease (CKD) is all about the kidneys "not working as well as they once did." The kidneys serve quite a few important functions including getting rid of our waste products and aiding the reabsorption of various nutrients. The kidneys also help regulate blood pressure. CKD - which has various stages - has several potential causes, notably diabetes and high blood pressure (hypertension).
• Researchers located some 2300 people diagnosed with schizophrenia from the NHIRD and matched them 3:1 with over 7000 people not diagnosed with schizophrenia. Age, gender and level of urbanisation were some of the matching factors.
• Results: "A comparison with controls revealed that patients with schizophrenia were more likely to have the comorbidities of diabetes mellitus..., hypertension... and hyperlipidaemia. Patients with schizophrenia were more likely to take NSAIDs..." NSAIDs also have a connection to CKD as per data such as that from Gooch and colleagues [2]. What this all means is that participants with schizophrenia were already more likely to present with some of the risk factors for CKD over and above controls.
• Over the course of 3-years of follow-up "528 (3.21%) of the 9352 study patients experienced CKD" which in proportional terms was weighted towards more participants with schizophrenia presenting with CKD over controls. "The incidence rate (per 1000 person-years) of CKD for patients with schizophrenia (25.13) was higher than that for non-schizophrenic controls (18.60)."
• The authors conclude: "we found a significant association, a 25% increased risk, between schizophrenia and subsequent CKD in a 3-year follow-up period, especially in those older ages, those with DM [diabetes mellitus] and those using NSAIDs." And with that comes the important idea that further research on the merit of preferential screening for CKD in cases of schizophrenia might be indicated.

I have little more to say about this study and the important conclusions reached. The idea that physical / somatic health issues perhaps don't receive the research or clinical interest they deserve where and when a psychiatric or behavioural diagnosis is received is becoming an all-too frequent theme on this blog. Be it heart health and schizophrenia (see here) or something like medical comorbidity and autism (see here), there remains something of a disjoin between psychological health and physical health and the acceptance that people with diagnoses such as schizophrenia are people first and so at least as likely as every else to present with physical health issues. Added to the idea that a label such as schizophrenia might predispose a person to be more likely to partake in activities such as tobacco smoking [3] and/or be overweight / obese [4] as a function of lifestyle or medication (see here), the focus on improving psychiatric outcome in cases of schizophrenia should really be going hand-in-hand with ensuring physical health is also catered for and the risk of chronic disease, even early mortality [5] is kept to a minimum.

Music to close: Morrissey with Suedehead.

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[1] Tzeng N-S. et al. Is schizophrenia associated with an increased risk of chronic kidney disease? A nationwide matched-cohort study. BMJ Open 2015; 5: e006777.

[2] Gooch K. et al. NSAID Use and Progression of Chronic Kidney Disease. American Journal of Medicine. 2007; 120: 280.e1–280.e7.

[3] Kelly C. & McCreadie R. Cigarette smoking and schizophrenia. Advances in Psychiatric Treatment. 2000; 6: 327-331.

[4] Hjorth P. et al. A systematic review of controlled interventions to reduce overweight and obesity in people with schizophrenia. Acta Psychiatr Scand. 2014 Oct;130(4):279-89.

[5] Hsu WY. et al. A population-based cohort study on deep vein thrombosis and pulmonary embolism among schizophrenia patients. Schizophr Res. 2015 Jan 23. pii: S0920-9964(15)00016-X.

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Tzeng, N., Hsu, Y., Ho, S., Kuo, Y., Lee, H., Yin, Y., Chen, H., Chen, W., Chu, W., & Huang, H. (2015). Is schizophrenia associated with an increased risk of chronic kidney disease? A nationwide matched-cohort study BMJ Open, 5 (1) DOI: 10.1136/bmjopen-2014-006777

Pre-eclampsia exposure and autism

A few weeks back, the paper from Cheryl Walker and colleagues [1] reporting that: "Children with ASD [autism spectrum disorder] were twice as likely to have been exposed in utero to preeclampsia as controls with TD [typical development]" provided some column inches in certain media quarters.

How dare you insult Hero's Duty, you little guttersnipe!

Although not the first time that pre-eclampsia - a hypertensive state characterised by proteinuria occurring during pregnancy and potentially affected by/affecting the placenta - has been mentioned in the autism research literature [2] (open-access), the value-added bit to the Walker paper was the use of participants/data included in the CHARGE study. As an aside, CHARGE has been mentioned a few times on this blog (see here for example).

The Walker study looked at maternal self-reports and details "abstracted from medical records" of "Preeclampsia and placental insufficiency" in their cohort comprising some 500 children diagnosed with an ASD and nearly 200 diagnosed with developmental delay (DD) compared against 350 asymptomatic controls. Compared against those TD children, those with autism were more frequently reported to have been exposed to pre-eclampsia during gestation. Further, some relationship between pre-eclampsia severity and autism risk was also observed. The authors also noted: "Placental insufficiency appeared responsible for the increase in DD risk associated with severe preeclampsia."

Whilst appreciating that not nearly a week goes by without scientific research linking something or other to a higher risk of autism and the subsequent possibility of 'correlation burnout', these are interesting results. Pregnancy hypertension - high blood pressure - as part of pre-eclampsia is an important factor driving various adverse effects/events which can impact on both developing foetus and mother (e.g. placental abruption). Maternal hypertension as part of the condition called metabolic syndrome has previously been linked to an increased risk of offspring autism [3] (see here for my take on the study) as well as being a potential stand-alone factor [4].

The link between pre-eclampsia and placental insufficiency (where the placenta does not deliver the optimal amount of oxygen or nutrients to the baby) is also a potentially intriguing point with autism in mind. Regular readers might remember some of my previous discussions on the Barker (foetal programming) hypothesis proposed by the late David Barker, and the idea that nutrition in-utero might have some pretty profound consequences for offspring later life health. Although hesitant to say that issues mediated by placental function are directly linked to autism, there is a growing appreciation that the placenta may be a further point of inquiry when it comes to offspring neurodevelopmental functions. Take for example other work by Walker and colleagues related to trophoblast inclusions in relation to autism [5] (see here for my previous discussion on this research) as one example. Perhaps more speculatively is the suggestion that a short interpregnancy interval (IPI) might also increase the risk of offspring autism [6] and what this could also mean from a 'depletion of micronutrients' point of view potentially similar to a placental insufficiency scenario.

What is becoming clearer from this and other research on the 'nine months that made us' in relation to autism or other neurodevelopmental diagnoses, is that further efforts are required to tease apart various factors. So:

(a) What are the process by which adverse pregnancy conditions impact on offspring outcomes? Do we already have research precedents as per the paper by van Gelder and colleagues [7] talking about "physiological changes early in pregnancy that manifest in gestational hypertension and pre-eclampsia may play a role in the aetiology of major birth defects, including congenital heart defects and hypospadias". Both congential heart defects and hypospadias have been previously mentioned in the autism research literature (see here and see here respectively).

 and

(b) Linked to the previous question(s), who is more likely to be at risk of such issues, and what intervention(s) might mean for offspring and mother alike?

Music: Dolly sings Jolene at Glastonbury 2014.

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[1] Walker CK. et al. Preeclampsia, Placental Insufficiency, and Autism Spectrum Disorder or Developmental Delay. JAMA Pediatrics. 2014. 8 December.

[2] Gardener H. et al. Prenatal risk factors for autism: comprehensive meta-analysis. Br J Psychiatry. 2009 Jul;195(1):7-14.

[3] Krakowiak P. et al. Maternal metabolic conditions and risk for autism and other neurodevelopmental disorders. Pediatrics. 2012 May;129(5):e1121-8.

[4] Polo-Kantola P. et al. Obstetric risk factors and autism spectrum disorders in Finland. J Pediatr. 2014 Feb;164(2):358-65.

[5] Walker CK. et al. Trophoblast Inclusions Are Significantly Increased in the Placentas of Children in Families at Risk for Autism. Biological Psychiatry. 2013; 74: 204-211.

[6] Gunnes N. et al. Interpregnancy interval and risk of autistic disorder. Epidemiology. 2013 Nov;24(6):906-12.

[7] van Gelder M. et al. Maternal hypertensive disorders, antihypertensive medication use, and the risk of birth defects: a case-control study. BJOG. 2014 Nov 14. doi: 10.1111/1471-0528.13138.

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Walker CK, Krakowiak P, Baker A, Hansen RL, Ozonoff S, & Hertz-Picciotto I (2014). Preeclampsia, Placental Insufficiency, and Autism Spectrum Disorder or Developmental Delay. JAMA pediatrics PMID: 25485869

Autism and ID: Born again?

The recent papers published by Amanda Langridge and colleagues* (open-access) and Venla Lehti and colleagues** set some cogs running in my grey/pink matter recently with their research focus on our very earliest days and what (if any) risk for the autism spectrum disorders (ASDs) there may be when things don't go as smoothly as expected during that magical nine months and just before/after.

A new child is Björn @ Wikipedia  

I've previously talked about factors during pregnancy and parturition (child birth) in relation to autism as per posts like this one from quite a while back and all that newer stuff from initiatives like CHARGE. Combined with investigations examining everything from season of birth to birth weight to birth order, there is quite a bit of peer-reviewed literature on this area with autism in mind.

Having said all that, I don't want to give any false impression that there are any hard and fast rules about in-utero or birth factors being linked to autism, because there aren't. Indeed, it's all even further complicated by lots of other conditions potentially being linked also to pregnancy and birth and a flurry of speculation.

Nevertheless, there are some interesting points raised by each of the articles presented today which are worthy of discussion. So in turn:

The Langridge paper:

• Open-access so please do have a look at it for yourself. A huge data mining study examining the "total population data sets of children diagnosed with ID and ASD in Western Australia (WA)" between 1984 and 1999 (included among N=383,153) to see if there were any links between "maternal conditions and perinatal factors for all WA children subsequently diagnosed with ASD, with or without ID, and children with varying severity of ID, and compare findings to the rest of the birth cohort of unaffected children". Lots of description of the population and how autism and intellectual disability (ID) were ascertained. Also how this huge dataset were analysed.
• Results: yes, quite a few depending on how the data were modelled and what background characteristics were controlled for. Notably suggesting that those diagnosed with an ID were more likely to have experienced some episode or event in their earliest days when compared with those diagnosed with an ASD. I'll leave you to pick out the associations but there were some interesting findings related to gestational diabetes, threatened abortion before 20 weeks and pregnancy hypertension.
• Soundbite: "small head circumference was associated with reduced risk of ASD" bearing in mind head size and autism is a complicated area.
• Another soundbite: "These findings support the concept that ID and ASD may lie on a continuum, as opposed to being different clinical entities, and may explain why there are various ID subtypes of ASD (i.e. ASD with and without ID)". I can't fault their logic. Perhaps another addition to the spectral model of behaviour and psychiatry since that is the direction things seem to be heading these days.

The Lehti paper examined IVF (In vitro fertilisation) and...

• A very organised paper which bluntly asked: "Does IVF increase the risk of autism spectrum disorders (ASDs)?"
• Another very big participant group (autism: n=4164, matched controls: n=16,582); all born in Finland.
• Result: "This study showed no increased risk of ASDs in children born after IVF" as per other studies in this general area.
• But...  and it is a but, the connection in particular between IVF and boys with Asperger syndrome (AS) might need to be looked at with greater assiduity. Having said that, any study had better be done sooner rather than later since AS as an independent diagnostic entity is due to be phased into ASD in the latest DSM revision in May (2013). Please note: this does not mean that people will lose their AS diagnosis though.

Combined, these papers add quite a bit to the literature on birth factors in relation to autism bearing in mind risk is risk and not proof. Although events in-utero and during childbirth have always been on the autism research radar, I am noting a renewed interest in all things early development with autism in mind in recent years as per areas like maternal immune activation and autism risk (think Paul Patterson and mice) and some continued interest in the environment (think pollution and correlation for a start). The suggestion that the placenta for example may play a "potent role in autism risk" represents quite an exciting research opportunity, mirroring research on other health-related conditions. Thin-fat body anyone?  

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* Langridge A. et al. Maternal conditions and perinatal characteristics associated with autism spectrum disorder and intellectual disability. PLoS ONE. 2013; 8: e50963.

** Lehti V. et al. Autism spectrum disorders in IVF children: a national case-control study in Finland. Hum Reprod. 2013 Jan 4.

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Amanda T. Langridge, Emma J. Glasson, Natasha Nassar, Peter Jacoby, Craig Pennell, Ronald Hagan, Jenny Bourke, Helen Leonard, & Fiona J. Stanley (2013). Maternal Conditions and Perinatal Characteristics Associated with Autism Spectrum Disorder and Intellectual Disability PLoS ONE : 10.1371/journal.pone.0050963

Bumetanide for autism?

The paper by Lemonnier and colleagues* (open-access) reporting results from a randomised, placebo-controlled trial of the diuretic drug bumetanide in cases of autism has received quite a bit of publicity over the past few days. As with other big autism research news, the study was accompanied by quite a good write-up in Nature (see here) which very conveniently allows me to skip over the ins and outs of the study and pick out a few notable points in this brief post.

As always with the 'no medical advice given' caveat in full working order:

• This was a gold-standard trial insofar as similar to other research discussed on this blog it was randomised and also incorporated a placebo into the methodology which meant that participants were randomly assigned to treatment or not and the 'not' consisted of something that I assume, looked, smelled and tasted the same as bumetanide. Indeed the study lists 'lactose' as being the placebo which is fine as long as participants with autism did not have a lactose intolerance as per other autism research findings.
• Bumetanide as well as being a diuretic (increasing urine excretion) is a loop diuretic acting on a specific part of the kidney. Its uses are varied but mainly focus on reducing swelling and fluid retention following problems with the heart and other organs. It's also apparently quite good for treating hypertension (high blood pressure) too** and potentially useful for certain types of epilepsy*** (although I'd like to see more data on this effect). 
• Quite a lot of the focus on why the drug seemed to affect autistic behaviours has been on the GABA side of things and how "disruption of GABA is due to increased levels of chloride ions in the brain cells" in case of autism. The theory goes that bumetanide has an effect of decreasing levels of chloride in neuronal cells, which theoretically should positively alter that GABA disruption. In particular is the proposed action of bumetanide on NKCC1 an importer of chloride, where if I understand it correctly, bumetanide blocks NKCC1 from doing its duties. Indeed I might be confusing myself even further but NKCC1 also has something of a relationship with hypertension****.
• Why am I focusing on the hypertension side of things? Well, with all that we think we know about autism in terms of stress responses and comorbidity potentially focused on things like hypertension***** as part of the whole metabolic syndrome side of things, one might also be minded to look at whether this might have been part and parcel of any effect noted. Of course, I'm just speculating, bearing in mind that no measure of blood pressure for example, was seemingly reported during the trial. 
• As per this review by Ward & Heel****** (open-access), there are several other physiological changes/effects associated with taking bumetanide, all of which should remain at the back of one's mind when thinking about potential mechanisms of effect.  

I've not got too much more to say about this work aside from it being quite an interesting study and indeed (a) providing further support for how the myriad of pharmaceutical compounds we use might have many more uses than those cited on the patient information leaflet, and (b) how some of the effects of such medicines in cases of autism might be more evidence for the 'whole-body' nature of the condition, or at least some cases of the condition.

'Nuff said.

[Update: February 2014. Well it wasn't exactly 'nuff said as indeed, more was subsequently said on this topic... see this post on bumetanide, GABA, oxytocin and mouse models of autism].

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* Lemonnier E. et al. A randomised controlled trial of bumetanide in the treatment of autism in children. Translational Psychiatry. 2012: e202.

** van der Heijden et al. A randomized, placebo-controlled study of loop diuretics in patients with essential hypertension: the bumetanide and furosemide on lipid profile (BUFUL) clinical study report. J Clin Pharmacol. 1998; 38: 630-635.

*** Eftekhari S. et al. Bumetanide reduces seizure frequency in patients with temporal lobe epilepsy. Epilepsia. October 2012.

**** Ye ZY. et al. NKCC1 upregulation disrupts chloride homeostasis in the hypothalamus and increases neuronal activity-sympathetic drive in hypertension. J Neurosci. 2012; 32: 8560-8568.

***** Tyler CV. et al. Chronic disease risks in young adults with autism spectrum disorder: forewarned is forearmed. Am J Intellect Dev Disabil. 2011; 116: 371-380.

****** Ward A. & Heel RC. Bumetanide: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic use. Drugs. 1984; 28: 426-464.

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Lemonnier, E., Degrez, C., Phelep, M., Tyzio, R., Josse, F., Grandgeorge, M., Hadjikhani, N., & Ben-Ari, Y. (2012). A randomised controlled trial of bumetanide in the treatment of autism in children Translational Psychiatry, 2 (12) DOI: 10.1038/tp.2012.124