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

Schizophrenia, coeliac disease and cerebral blood flow

Weather @ Paul Whiteley

Day: Sunday 19th February 2012. Weather: cold, bright. Mood: upbeat. Dear Diary, exactly a year since I began my blogging odyssey and I'm still enjoying the experience.

Speaking of the past, let's set the way-back machine a little further back to 1997. The UK swayed to the tune of 'Things can only get better' alongside a rare win at Eurovision. Bill Clinton also started his second term in office. An interesting paper also appeared by De Santis and colleagues* detailing some surprising findings in a case of comorbid schizophrenia and coeliac (celiac) disease. In some quarters, this single person study has taken on almost cult status. My opinion: it is interesting and I'll attempt to try and explain why.

I discuss this paper because despite being a case study, there are potentially some important facts which have never really been followed up with more rigorous study. I apologise that I can't link to a full-text of the paper so you will have to take my word for it or visit your nearest academic library to get a full-text copy.

The person at the centre of this report was a 33 year old woman admitted to hospital with weight loss and severe diarrhoea. She had a previous history of schizophrenia (diagnosed by DSM-III-R) progressively becoming more severe with accompanying "autistic disorder, social/occupational dysfunction, affective flattening and inferential thinking".

Upon admission, schizophrenia was again confirmed (by DSM-IV) alongside various other laboratory findings including low iron levels without anaemia. Coeliac disease (CD) was diagnosed on the basis of anti-endomysial antibodies and villous atrophy following jejunal biopsy. A brain SPECT scan -  (99mTc)HMPAO SPECT - was performed following some irregular activity in the fronto-temporal left hemisphere picked up on EEG. The scan showed an area of hypoperfusion in the left frontal cortex.

What this all basically means was that verifiable diagnostic accounts of schizophrenia and CD were picked up in this patient alongside some noticeable restriction in blood flow to a part of the brain thought to be involved in integrating various perceptual information and other executive functions.

Implementation of a gluten-free diet is reported to have quickly improved both physical and psychiatric symptoms "within a few days". Alongside expected gains in body weight, a repeat SPECT scan was undertaken after 6 months using as similar procedures as possible to the first scan to allow a reliable slice by slice analysis. The results were surprising in that there was a "complete normalization of the brain perfusion". The woman remained symptom-free and medication-free for at least a year at follow-up obviously maintaining her gluten-free diet.

The authors were obviously quite taken aback by these findings although I suspect not totally surprised by them. Inevitably discussions are filled with excerpts from the late Kurt Dohan and his ideas on schizophrenia and wheat intake as well as one of the modern day champions of research into the neurological effects of untreated CD, Dr Marios Hadjivassiliou. One phrase in particular stands out from the paper: ".. that schizophrenic symptoms may be the expression of organic disease, such as coeliac disease, rather than primary psychiatric illness".

I said that there were quite a few aspects of this study which have never really been followed up. Not being a neurologist or anything related, I don't know enough about SPECT scans as to be able to offer an informed opinion on their accuracy or not. Certainly with the advances that have been made in the intervening 15 years, I would imagine that technologies like fMRI might be slightly more descriptive in terms of the results produced. Scanning on just two occasions might also be subject to some bias.

Accepting that use of a gluten-free diet for schizophrenia, autism, ADHD or any other behaviourally-defined condition that you might care to mention is not exactly mainstream, I would be inclined to suggest that there is a study or two waiting to happen here. So, monitoring things like cerebral blood flow and related brain-based markers before and after use of a gluten-free diet alongside various behavioural indices. SPECT scans still mark the autism research landscape as per articles like this one. Indeed I am quite surprised that many more intervention studies in psychiatry don't look at things like cerebral blood flow when it comes to outcome measures, even as per models such as that described in this study on primates. Monitoring such parameters where schizophrenia and CD are comorbid or how about where autism and CD are comorbid? Too much perhaps..?

I don't want to get too carried away with this single-case report because for all we know, this might be a one in seven billion event. Having said that, every theory has to start somewhere, and at the moment, no-one appears to be producing contrary evidence to the report from De Santis et al.

To finish, more memories of 1997 courtesy of Hanson.

* De Santis. et al. Schizophrenic symptoms and SPECT abnormalities in a coeliac patient: regression after a gluten-free diet. Journal of Internal Medicine. 1997; 242: 421-423.