Pregnancy diet and offspring "hyperactivity-inattention symptoms"?

I appreciate that the findings reported by Cédric Galera and colleagues [1] are potentially a little uncomfortable. Their examination of over 1200 mother-child pairs looking at data from food frequency questionnaires during pregnancy and subsequent offspring 'externalising' behaviours into childhood, could be construed as evidence that poor eating habits during the nine months that made us have the ability to translate into childhood issues. Because food choices are seen as just that - 'choices' - the Galera results *could* potentially fall into the same category as other 'choices' that also seemingly affect offspring development in this area (see here for example). I make no value judgements.

Having also bumped into the Galera paper at the same time as seeing a BBC media report observing that "We learn nothing about nutrition, claim medical students", one might further make an argument for the need for much greater education, guidance, support and potentially 'nudging', when it comes to issues such as 'what to eat during pregnancy'. That however, is another discussion for another day.

Anyhow, the science...

Galera et al report findings based on the EDEN mother-child cohort [2], an initiative set up to examine "the relations and potential interactions between maternal exposures and health status during pregnancy, fetal development, health status of the infant at birth and the child’s health and development." It's interesting that the opening words to the Heude [2] description of the initiative mention the name 'Barker', as in the late David Barker, a man who helped popularise the idea that nutrition in the womb (through maternal diet) might have some important *consequences* for offspring in the short- and long-term. Looking at some of the other research produced by the EDEN mother-child cohort (see here), Barker and others may have indeed been on to something.

As well as looking at offspring externalising symptoms such as conduct problems via use of "the Strength and Difficulties Questionnaire at ages 3, 5, and 8 years", authors also looked at "trajectories of hyperactivity-inattention symptoms." This, on the basis that the SDQ does pretty well at discriminating between ADHD and non-ADHD cases [3]. They concluded that, taking into account infant dietary patterns "at age 2 years" and various other potential influencing variables ("maternal stress and depression, gestational diabetes, and socioeconomic variables"), there was something to see with regards to use of a 'high Western diet' and 'low Healthy diet' during pregnancy in relation to offspring developmental outcome. Specifically: "Maternal diet during pregnancy was independently associated with children's hyperactivity-inattention symptoms."

Of course, one needs to be a little bit careful that *association* is not viewed as 'cause-and-effect' based on such observational studies. That also it is downright unethical to put mums-to-be on a 'healthy diet' vs. 'a non-healthy diet' is also a stumbling block to robust investigations in this area; similar to the fact that one wouldn't put mums-to-be on a tobacco smoking vs. a non-smoking intervention.

But the Galera results are not stand-alone in potentially implicating maternal diet as a factor in relation to offspring hyperactivity-inattention [4] and are therefore deserving of some further investigation. I've already mentioned that perhaps more guidance and 'nudges' need to be provided in the area of pregnancy nutrition, and that I assume, would include looking at the cost and convenience of a healthy diet vs. a not-so-healthy diet in the context of a possible *link* between diagnosed attention-deficit hyperactivity disorder (ADHD) and "socioeconomic deprivation" for example (see here). More than that however is the idea that David Barker and others who talked about 'foetal programming' during the pregnancy months as a result of what is in or perhaps not in a maternal diet may have been a lot more accurate than many people would have perhaps imagined...

And on the topic of 'foetal programming', diet might not be the only factor to consider [5]...

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[1] Galera C. et al. Prenatal diet and children's trajectories of hyperactivity-inattention and conduct problems from 3 to 8 years: the EDEN mother-child cohort. J Child Psychol Psychiatry. 2018 Mar 24.

[2] Heude B. et al. Cohort Profile: The EDEN mother-child cohort on the prenatal and early postnatal determinants of child health and development. Int J Epidemiol. 2016 Apr;45(2):353-63.

[3] Algorta GP. et al. Diagnostic efficiency of the SDQ for parents to identify ADHD in the UK: a ROC analysis. Eur Child Adolesc Psychiatry. 2016 Sep;25(9):949-57.

[4] Rijlaarsdam J. et al. Prenatal unhealthy diet, insulin-like growth factor 2 gene (IGF2) methylation, and attention deficit hyperactivity disorder symptoms in youth with early-onset conduct problems. J Child Psychol Psychiatry. 2017 Jan;58(1):19-27.

[5] Andersen SL. et al. Maternal Thyroid Function in Early Pregnancy and Child Neurodevelopmental Disorders: A Danish Nationwide Case-Cohort Study. Thyroid. 2018 Mar 27.

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Pregnancy multivitamins 'are a waste of money' (except when they're not)

Science headlines eh? Who would trust them and their sometimes inflated press releases?

I start today with a science headline taken from the BBC website reading: "Pregnancy multivitamins 'are a waste of money'" based on the findings of a review article [1] published in the journal Drug and Therapeutics Bulletin.

In it we are told that complex multi-vitamin and mineral supplements are 'unlikely to be needed and are an unnecessary expense' during the nine months that made us. Further that certain vitamins are not indicated for supplementation during pregnancy including that contributory to excess vitamin A. All pregnant women have to do, we are told is "to have a healthy, varied diet including fresh fruit and vegetables" and avoid the old phrase 'eating for two'. What could be simpler?

The irony behind such findings and those BBC and other media headlines is that although one needs to be careful about one's vitamin and mineral intake (treat them as what they are, medicines) there is a long tradition of vitamin supplementation being indicated when it comes to that special time called pregnancy. Indeed, and I quote from the BBC article: "pregnant women should make sure they take folic acid and vitamin D, as well as eating a well-balanced diet, as per NHS guidelines, they add."

So let me get this straight: don't take a multi-vitamin supplement but makes sure that you take a (multi) supplement containing folic acid and vitamin D? You can perhaps see how confusing such headlines are and how grandiose ideas that every woman pre-conceptual and during pregnancy is feasting down on 5-a-day (or even 8-a-day if you actually believe it will make you happier!) are not necessarily based in reality. We would all love to think that important health messages about maternal fruit and vegetable consumption during pregnancy for example, are being heard loud and clear but the reality is that they aren't for everyone. The reality is that people are using vitamin and mineral supplements to supplement their dietary needs for whatever reasons and headlines further confusing the population about such supplementation being a 'waste of money' is only likely to put more people off using them without perhaps giving greater thought about the ways and means to help people alter their diet accordingly. The net result: more pregnant women potentially becoming deficient in certain core nutrients during pregnancy and more potential effects/risks for her and her offspring.

I do have a bee in my bonnet about this issue because time after time the research evidence points to how important pregnancy nutrition is for a variety of maternal and offspring outcomes [2]. Outside of folic acid and vitamin D, various other nutrients are also pretty important during pregnancy (i.e. iodine - 'good for baby, good for the economy') and the unfortunate reality is that most people can't or don't get enough of them from their diet alone. The late David Barker was a pioneer in the area of foetal programming including that related to pregnancy nutrition; one can only wonder what he would make of the suggestion that universally, supplementary multivitamin use during pregnancy is a 'waste of money'?

And finally, you want more people to eat fruit and vegetables? Don't focus too much on just price and positioning at the supermarket, focus on home economics (or just cookery!) classes at school [3] for starters and make fruit and vegetables interesting...

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[1] Vitamin supplementation in pregnancy. Drug & Therapeutics Bulletin. 2016. July 11.

[2] Harding JE. The nutritional basis of the fetal origins of adult disease. Int J Epidemiol. 2001 Feb;30(1):15-23.

[3] McMorrow L. et al. Perceived barriers towards healthy eating and their association with fruit and vegetable consumption. J Public Health (Oxf). 2016 May 24.

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Drug and Therapeutics Bulletin (2016). Vitamin supplementation in pregnancy Drug and Therapeutics Bulletin DOI: 10.1136/dtb.2016.7.0414

One more time... the interpregnancy interval and risk of offspring autism

"Children born after an IPI [interpregnancy interval] of <12 months or ≥72 months had a 2- to 3-fold increased ASD [autism spectrum disorder] risk compared with children born after an interval of 36 to 47 months."

So said the study results published by Ousseny Zerbo and colleagues [1] looking at the increasingly interesting area of the autism research landscape: the interpregnancy interval (the time from the birth of an index child to the next conception/pregnancy of a sibling).

Looking at data derived from children "born at Kaiser Permanente Northern California (KPNC) between 2000 and 2009", researchers examined the IPI to evaluate the risk of ASD in second-born children. Various hazard ratios (HRs) are reported based on the spacing between children: "<6 months, 3.0 (1.9–4.7); 6 to 8 months, 2.1 (1.4–3.3); 9 to 11 months, 1.9 (1.3–2.1); 12 to 23 months, 1.5 (1.1–2.1); and ≥72 months, 2.4 (1.5–3.7)." Following a sort of U-shaped response curve and taking into account various factors that may potentially impact on offspring autism risk, researchers concluded that: "Children born after interpregnancy intervals <2 years or >6 years may be at increased risk of ASD."

Whilst the Zerbo findings have attracted some media attention (see here and see here) it is not necessarily new news that the IPI might show some connection to offspring autism risk. I've covered the topic on at least two other occasions on this blog (see here and see here) outside of other research suggesting similar things [2]. The findings are fairly robust and importantly, seem to cross different geographies and different ethnicities, suggesting that the IPI might be something generalisable to autism across the globe.

As per my other musings on this topic, there are several possibilities as to how a short (or long) IPI might impact on offspring autism risk, mainly associated with more general research on how IPI might influence various birth outcomes (albeit with caveats [3]). Having watched the recent BBC series called 'Countdown to Life' documenting the nine months that made us, I'm particularly interested in the idea that there may be more than one mechanism at work depending on the IPI. Specifically, whether a short IPI where the greatest HR was reported by Zerbo, might be related to a depletion of maternal stores of various micronutrients (the authors have talked about folate although I'd be careful there, indeed very careful there [4]) that comes with pregnancy and David Barker style (see here) whether intrauterine health might be a factor in the elevated risk?

Music, and something a little 'cool' today: The Specials And Fun Boy Three - Our Lips Are Sealed (complete with a sample of the Go-Go's).

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[1] Zerbo O. et al. Interpregnancy Interval and Risk of Autism Spectrum Disorders. Pediatrics. 2015. Sept 14.

[2] Coo H. et al. The association between the interpregnancy interval and autism spectrum disorder in a Canadian cohort. Can J Public Health. 2015 Feb 3;106(2):e36-42.

[3] Ball SJ. et al. Re-evaluation of link between interpregnancy interval and adverse birth outcomes: retrospective cohort study matching two intervals per mother. BMJ. 2014; 349: g4333.

[4] Virk J. et al. Preconceptional and prenatal supplementary folic acid and multivitamin intake and autism spectrum disorders. Autism. 2015 Sep 25. pii: 1362361315604076.

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Zerbo, O., Yoshida, C., Gunderson, E., Dorward, K., & Croen, L. (2015). Interpregnancy Interval and Risk of Autism Spectrum Disorders PEDIATRICS DOI: 10.1542/peds.2015-1099

Maternal obesity and offspring autism meta-analysed

So: "The meta-analysis results support an increased risk of autism spectrum disorder in children of women who were obese during pregnancy. However, further study is warranted to confirm these results."

That was the conclusion reached by Ya-Min Li and colleagues [1] looking at the collected peer-reviewed data currently available on how maternal weight might impact on offspring neurodevelopmental outcomes. Without wishing to blame or stigmatise (this is a blog based on the examination of cold, objective, peer-reviewed science) such results are not altogether unexpected based on instances where maternal weight might impact on offspring autism risk have been discussed (see here).

There are caveats to ideas of such an association. Not least that observational studies for example, often provide little information on 'cause and effect'. That not every child born to a mum who is overweight and/or obese develops autism should also be kept firmly in mind, as should the idea that overweight and/or obesity can sometimes sit with other comorbidity as part of the 'metabolic syndrome' so potentially introducing other variables into any association (see here). I might add that an array of other factors cross obesity and autism risk areas, not least mothers' nutritional status before and during pregnancy for example (see here).

That all being said, there is more science to do in this area. Thinking back to other discussions on data about how father's weight might also influence offspring autism risk (see here) and the idea of foetal programming [2] based to a large extent on the writings of the late David Barker, one gets some ideas of where science might want to start heading in continuing this line of inquiry.

Music: Keane - Everybody's Changing.

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[1] Li YM. et al. Association Between Maternal Obesity and Autism Spectrum Disorder in Offspring: A Meta-analysis. J Autism Dev Disord. 2015 Aug 9.

[2] Lau C. & Rogers JM. Embryonic and fetal programming of physiological disorders in adulthood. Birth Defects Res C Embryo Today. 2004 Dec;72(4):300-12.

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Li YM, Ou JJ, Liu L, Zhang D, Zhao JP, & Tang SY (2015). Association Between Maternal Obesity and Autism Spectrum Disorder in Offspring: A Meta-analysis. Journal of autism and developmental disorders PMID: 26254893

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

Maternal iron intake and offspring autism risk

Much like the discussions around the paper by Rogers and colleagues (see here) on treating autism in the first year of life, the media scrum around the findings from Rebecca Schmidt and colleagues [1] talking about maternal iron supplements and offspring autism spectrum disorder (ASD) risk preceded the publication of the paper by a few days. It's getting to be a pet-hate of mine that big headlines are being generated sometimes days before your average Jane or Joe can see the data upon which they're based...

Grumbling aside, here are a few factoids from the now published Schmidt paper:

• CHARGE was the source initiative for participants, as it has been for various studies, and following on from other research on nutrition during pregnancy potentially affecting offspring autism risk from this group (see here), the idea was to look at pre- and pregnancy maternal iron intake in relation to autism risk.
• Data for mothers of children with autism (n=520) were compared against mothers with children who did not have autism (n=346) and "maternal daily iron intake was quantified on the basis of frequency, dose, and brands of supplements and cereals consumed each month from 3 months before pregnancy through the end of pregnancy and during breastfeeding (the index period), as reported in parental interviews". You'll note the words 'parental interviews' there.
• Results: well, the mothers of children with autism were less likely to report taking 'iron-specific supplements' than control mothers and overall, a "lower mean daily iron intake" in the order of 5-6 mg/day less than controls was observed.
• "Low iron intake significantly interacted with advanced maternal age and metabolic conditions; combined exposures were associated with a 5-fold increased ASD risk". Advanced maternal age by the way, refers to women who were 35 or older at the time of their child's birth, and metabolic conditions means obesity, diabetes or hypertension (in line with other evidence).

These are interesting findings which add to the growing literature on how maternal nutrition before and during the nine months that made us potentially impacts on offspring development and outcome. Certainly, there are hints of the foetal programming hypothesis in there, for which the late David Barker receives quite a bit of credit. I was also wondering whether other issues potentially affecting foetal nutrition such as the inter-pregnancy interval (see here) might also tie into these findings too?

But there are some obvious cautions to take on board when it comes to these findings. First is the continued reliance on self-report, which even under the most controlled of situations, is always going to be an estimate at best. Next, and I might be completely wrong about this, but even with the report of a mean daily intake of ~51 mg/day, the mothers with children with autism group were still quite a bit above the daily recommendations in the United States (see here) for pregnant or lactating women. Finally, I'm wondering whether the idea of "combined exposures" when it comes to maternal age and the presence of metabolic syndrome might actually be the more important issue raised in this paper...

Iron and autism is a topic which has been discussed a few times on this blog (see here). The data is slightly mixed when it comes to looking at iron levels in children with autism as per my discussions on the Reynolds paper [2] versus the Hergüner findings [3]. Dr Schmidt and colleagues did not directly assay for iron or ferritin levels in their current paper so we can't really say much more at this point on how actual maternal iron levels translated into offspring iron levels and what effect(s) this may have had on offspring autism or other risks. That and whether other factors might also have played some role as per the rodent findings from Harvey & Boksa [4] talking about an additive effect from iron deficiency and prenatal immune activation (a topic that has cropped up a few times with autism in mind). These are perhaps the next studies that need to be done alongside what biological effects supplementation may have [5].

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[1] Schmidt RJ. et al. Maternal Intake of Supplemental Iron and Risk of Autism Spectrum Disorder. Am J Epidemiol. 2014. 22 September.

[2] Reynolds A. et al. Iron status in children with autism spectrum disorder. Pediatrics. 2012; 130 Suppl 2:S154-S159.

[3] Hergüner S. et al. Ferritin and iron levels in children with autistic disorder. Eur J Pediatr. 2012; 171: 143-146.

[4] Harvey L. & Boksa P. Additive effects of maternal iron deficiency and prenatal immune activation on adult behaviors in rat offspring. Brain Behav Immun. 2014 Aug;40:27-37.

[5] Dosman CF. et al. Children with autism: effect of iron supplementation on sleep and ferritin. Pediatr Neurol. 2007 Mar;36(3):152-8.

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Rebecca J. Schmidt, Daniel J. Tancredi, Paula Krakowiak, Robin L. Hansen, & Sally Ozonoff (2014). Maternal Intake of Supplemental Iron and Risk of Autism Spectrum Disorder American Journal of Epidemiology : doi: 10.1093/aje/kwu208

Dad's obesity and risk of offspring autism

In this post I'm talking about the paper by Pål Surén and colleagues [1] (open-access here) and their suggestion that "paternal obesity is an independent risk factor for ASDs [autism spectrum disorders] in children". I do so not with the intent of stigmatising parents and specifically parents with weight issues, which tend to be present for many more reasons than just food and exercise (see here), but merely to highlight how parental physical health may show some relationship to offspring cognitive and developmental progress. Indeed, the findings from Surén et al are to viewed in the context of some other related research in this area (see here).

By the water @ Renoir @ Wikipedia 

Quite a nice summary of the Surén work can be found here and here. The basics are: MoBa (see here), questioning parents particularly fathers about their physical health while their partner was pregnant, following up offspring and their subsequent development - specifically whether they had received a diagnosis of "autistic disorder", Asperger syndrome or pervasive developmental disorder not otherwise specified (PDD-NOS).

The results: well, the rate of autism reported (0.45%) was interesting. Certainly compared to other prevalence estimates we've been hearing about recently, quite a different figure was noted altogether (see here) allowing for age differences in case ascertainment. Then to the primary findings: "The risk of autistic disorder was 0.27% (25 of 9267) in children of obese fathers and 0.14% (59 of 41 603) in children of fathers with normal weight (BMI <25), generating an adjusted OR of 1.73 (95% CI: 1.07–2.82)". And with regards to Asperger syndrome: "The risk was 0.38% (18 of 4761) in children of obese fathers and 0.18% (42 of 22 736) in children of normal-weight fathers, and the adjusted OR was 2.01 (95% CI: 1.13–3.57)". Ergo, potentially double the risk of offspring autism when fathers were categorised as overweight or obese based on body mass index (BMI).

It goes without saying that the suggestion of a link between paternal weight and offspring risk of autism is by no means proved by this latest research. Think correlation not being the same as causation as one reason why we should not just accept the results of this work at face value irrespective of how enthusiastic researchers might be about their data and what they were able to control for as potential interfering variables. That also BMI has it's 'issues' when it comes to defining healthy weight is another reason for caution where muscle mass for example, is not accounted for in such a simplistic formula.

But all that doesn't mean the results are not interesting...

In recent times I've noticed quite a bit more research looking at the potential role of father's health and wellbeing on offspring development treading in the footsteps of how ageing might play a role. Take for example the recent opinion piece in Nature titled 'Sins of the father' which introduces another side to the Surén results: the science of epigenetics. The paper by Lambrot and colleagues [2] is as good an example as any on how a father's nutritional status with folate in mind, might impact on offspring health. I'm not asking you to take this as fact; merely that the focus on maternal nutrition and offspring outcome might not be the only important variable in any relationship.

Harking back to another paper by the Surén research group (including Drs Hornig and Lipkin) [3] reveals nutrition to be something that the authors had probably thought about with the current results in mind. On that occasion, the focus was on the elevated risk of autism in cases of a short inter-pregnancy interval (see here) and mention of a "depletion of micronutrients" as a possible factor. Shadows indeed of the work of the late David Barker and his foetal programming hypothesis.

I do believe there are more investigation to be done building on the Surén results. I've already made mention of folate in the father-offspring relationship given the link between the folate cycle and the availability of methyl groups for the process of DNA methylation, an important epigenetic process. One might also wonder about the body of work looking at more traditional genetic issues in the genes involved in that cycle such as everyone's favourite Scrabble gene and enzyme:  Methylenetetrahydrofolate reductase (MTHFR) and its growing links with some autism (see here). Could issues with MTHFR present in fathers confer susceptibility to offspring autism, or weight issues pertinent to an elevated risk via epigenetic mechanisms? That being said, I'm sure that any relationship is going to be complicated and not necessarily relevant to every child diagnosed with an autism spectrum condition.

Music to close. In memory of author Sue Townsend and her Adrian Mole series of books... Profoundly in Love with Pandora.

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[1] Surén P. et al. Parental Obesity and Risk of Autism Spectrum Disorder. Pediatrics. 2014. April 7.

[2] Lambrot R. et al. Low paternal dietary folate alters the mouse sperm epigenome and is associated with negative pregnancy outcomes. Nature Comms. 2013; 4: 2889.

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

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Suren, P., Gunnes, N., Roth, C., Bresnahan, M., Hornig, M., Hirtz, D., Lie, K., Lipkin, W., Magnus, P., Reichborn-Kjennerud, T., Schjolberg, S., Susser, E., Oyen, A., Smith, G., & Stoltenberg, C. (2014). Parental Obesity and Risk of Autism Spectrum Disorder PEDIATRICS DOI: 10.1542/peds.2013-3664

A macroepigenetic approach to autism?

Summary and review papers are always excellent fodder for a blog post because of the ideas and hypotheses they can generate based on a synthesis of lots of different research across different areas. Everyone strives to be 'lateral thinkers' during such papers in an attempt to fit together evidence pertinent to their viewpoint. As to how many actually succeed in making that magical connection is a slightly different story.

One recent review paper which caught my eye was this one by Dufault and colleagues* (full-text) which looked at some of the evidence for the role of diet and toxic substances in the environment as being involved in the increasing numbers of cases of autism in the United States (see the 2012 CDC figures here). I tread carefully with this line of thinking bearing in mind the headline which was covered as part of my post on obese mums and risk of autism - "Obesity in pregnancy causing rise in autism cases" - er, not exactly that simple.

I was drawn to the Dufault paper on several levels. Mention of the word 'epigenetics' (I'm sure you've grown tired of me describing this as changes to gene function over changes to the genome) was a pretty big attraction. As a sidelines, epigenetics is something which the ALSPAC are also working up to now some of their cohort has hit the magical age of 21 years old (see here) alongside some interest from people like David Barker, he of the Barker hypothesis.

I digress.

Reference also to the possible effects of diet and environment on cases of autism was also a big pull from the Dufault paper. Richard Deth (pronounced Deeth) on the authorship list was also a draw given some of his past research on methylation and autism (including reference to the D4 dopamine receptor) and the hyperhomocysteinemia findings which have frequented this blog from time to time.

The latest paper is full-text but a few pointers:

• 'Macroepigenetics' is a term introduced by this paper which refers to "... the process of examining food supplies and their impact on body metabolism and gene function along with what is known about environmental exposures across populations".
• Mercury features quite heavily in this paper and in particular, the mercury toxicity model, detailing the link between dietary elements, deficiencies in certain essential metals like zinc and environmental exposures to heavy metals. I know there is still some heated debate about things like mercury and whether or not exposures to different types of mercury might be implicated in at least some cases of autism. I'm not going to say anything else about this particular discussion for now.
• Consumption of high fructose corn syrup (HFCS) also gets a mention in the paper. To my mind, this is one of the first times HFCS has been linked to autism outside of a past paper from some of the same authors** (full-text). The theory goes that among other things, HFCS has the propensity to affect levels of calcium and zinc; low levels of zinc imply that certain metal binding proteins such as metallothionein might not function optimally to remove heavy metals such as mercury. At this point I would link to an interesting post by Dr Emily Deans on fructose malabsorption in relation to depression highlighting how, alongside other issues with carbohydrate metabolism, problems with fructose can potentially link to problems with zinc. I hasten to add that Dr Deans' discussions are strictly limited to the suggestion of a link between fructose malabsorption and depression and nothing else.
• Paraoxonase-1 (PON-1), everyone's favourite organo-phosphate (OP) pesticide detoxifier, also gets a mention. Accepting that most people are exposed to some degree of OP residues, the authors present data on the amount of residue present in food and how crops such as wheat and corn seem to be top of the pops in terms of residue amount. Corn obviously being a required raw material in the process of making HFCS and indeed mercury has also been found in samples of HFCS. The implication being that fructose and/or mercury can affect the expression of PON1 and this might be dose-dependent, which when coupled to data from this study by D'Amelio and colleagues*** (full-text) on the expression of PON1 in US and Italian cohorts, suggests a reduced ability in the US group to metabolise some OPs.
• Methionine, homocysteine and various compounds in-between are also discussed in the paper with particular reference to oxidative stress and DNA / histone methylation. Some interesting facts: PON1 turns out to be pretty essential for reducing homocysteine levels and high homocysteine levels are associated with the under-methylation - hypomethylation - of DNA. This might, just might, tie into these findings suggestive of an inverse relationship between homocysteine levels and PON1 arylesterase activity in a group of children with autism.

I hope you are still here after reading all that. It's taken me a few reads of the paper to start to come to grips with all the various strands of evidence incorporated and the overview presented here is not intended to be a definitive one. I suppose the main conclusion is that various factors might be implicated in producing an epigenetic response in autism including pesticide exposures, heavy metals and dietary components like HFCS. The sum of these factors being greater than the individual factors acting alone. 

I admit that I'm not totally convinced by all the issues discussed in this paper as being universally applicable to all cases of autism. Here in the UK, as in Italy and other parts of Europe, HFCS is still only tentatively findings its way into the shopping baskets of this nation of shopkeepers. Having said that, I have seen nothing that suggests autism has the same aetiological roots across all nations as indeed this paper asserts differences. Added to the fact there is some pretty convincing evidence that for example, zinc deficiency can be comorbid to cases of autism as per a post from a few months back, I have an open mind to the concepts detailed in the paper.

The authors suggest that their review of gene-environment interactions with a particular slant on autism in the United States might offer a kind of template for other individuals or groups to conduct and report similar papers for other potential factors and in other parts of the world. I would champion this notion that we do need to start looking at more complicated patterns of potential risk factors for autism, whether based on endophenotypes, geography or other factors, with a focus on how environment and genes might be working variably, but synergistically.

To finish, I have been getting a little too carried away with the Beautiful South lately and so to conclude, a Song for Whoever (the video is not the real song video but the sound was the best quality).

* Dufault R. et al. A macroepigenetic approach to identify factors responsible for the autism epidemic in the United States. Clinical Epigenetics. April 2012.
DOI: 10.1186/1868-7083-4-6

** Dufault R. et al. Mercury exposure, nutritional deficiencies and metabolic disruptions may affect learning in children. Behavioral & Brain Functions. 2009; 5: 44.
DOI: 10.1186/1744-9081-5-44

** D'Amelio M. et al. Paraoxonase gene variants are associated with autism in North America, but not in Italy: possible regional specificity in gene-environment interactions. Molecular Psychiatry. 2005; 10: 1006-1016
DOI: 10.1038/sj.mp.4001714

Epigenetics 101 and autism

Just relaxing @ Paul Whiteley

Ladies and Gentlemen. In the red corner, several million/billion years in the making, the current champion, genetics. In the blue corner, weighing in at several billion/trillion pounds, the challenger, environment.

[OK fellas, a good clean fight].

Ladies and Gentlemen... lets get ready to rumble!

Dramatic opening to post finished as I offer one of my more descriptive entries on the emerging field of epigenetics and some of the research already carried out with specific regards to autism spectrum conditions. I admit that I am sailing on the waves of current interest in this field with this post, being brought to it by the news that we may be seeing a lot more of the word 'epigenetics' in autism research circles soon as per this announcement on funding for Prof. Margaret Daniele Fallin based at Johns Hopkins Bloomberg School of Public Health and an accompanying 'what is epigenetics' post by Autism Speaks. The news that poverty might also have an epigenetic angle also took my interest (take note Politicians the world over).

Epigenetics has been mentioned before on this blog; normally posting a link to this piece in Time magazine about why your DNA is not necessarily your destiny. In short, epigenetics is the study of changes to gene activity without alterations to the genetic code passed down at least one generation. Epigenetics is quite an intellectually satisfying approach for lots of reasons; primarily perhaps because instead of pitting genes against environment in some kind of grudge match boxing contest, it actually suggests that our environment - our diet, our various stresses and exposures right from our earliest days - can affect gene activity by switching genes on or off. Synergy in action.

Another interesting article on epigenetics recently appeared on the Scientific American blog. I don't want to plagiarise what is a very good article, but there are some interesting data and concepts discussed which I do want to mention.

• I can't pretend to be an expert in this area so I won't try. Instead I refer you to quite a good introduction which presents the terms chromatin (the stuff of chromosomes), the DNA-protein mix nicely packaged up to fit into a cell nucleus, and histone, the scaffold around which DNA is wrapped to form nucleosomes.
• There are various ways that histone can be 'modified' including acetylation, methylation and phosphorylation. Such modifications have onward effects which have been described in a 'histone code' which seems to be growing all the time.
• The concept of Lamarckism is gaining in popularity as a consequence of the epigenetics tide. Lamarckism basically states that certain characteristics acquired by a parent can be passed to offspring. So coupled to epigenetics, parental (or grandparental) nutrition for example, might alter gene expression which then gets passed down to successive generations. I'm thinking Barker hypothesis and thin-fat bodies.

I've talked before about genetics on this blog and how whichever way you look at it, genes, mutations, etc. we are all very much a product of mutation and the emerging view is that genetics in relation to autism is a very, very, very complicated thing. I would hasten to add that concepts of Lamarckism are not to be viewed as another 'blame game' idea given that exposure events are likely to be multiple and complex and, as per the wartime famine studies related to the Barker hypothesis, events are not always likely to be under our control.

Very interesting, I (hope I) hear you say. But what about autism?

Well, epigenetics is obviously quite a new area for autism simply because a quick search of PubMed (26/01/12) only reveals 37 entries for the words 'autism and epigenetics'. That's not however to say that there isn't some interesting data already available to look at as I hope I will show.

This overview paper by N. Carolyn Schanen* (full-text) is as good a start as any. It is quite a long paper and not exactly easy to follow unless you are a molecular biologist, but nevertheless it offers some interesting discussions not least forecasting where we are today in terms of lacking any significant, universal genetic markers for autism.

This paper by Mehler and Purpura** (full-text) also has some interesting discussions about epigenetics. Appreciating that there is some degree of speculation in the text on their theory "of a functionally impaired locus coeruleus-noradrenergic (LC-NA) system", I find myself also drawn to their ideas on fever potentially affecting the presentation of symptoms in some cases of autism as per other research among the literature and the possible involvement of antipyretics in some cases.

Finally, this paper by Grafodatskaya and colleagues*** I think sets the tone for where genetics research might be heading in autism research with epigenetics at the helm. Noting that the authorship list includes Peter Szatmari who commented on the twins study published last year (the game changer!), it is difficult to argue against the notion that genes and genetic research is in the midst of a revolution. A revolution where the boxing match between nature and environment might just be replaced by an altogether more understanding relationship.

Cue the candle-lit dinner and (b)romantic music... (for my non-UK audience, read more about the background to this song here).

* Schanen NC. Epigenetics of autism spectrum disorders. Human Molecular Genetics. 2006; 15: R138-R150.

** Mehler MF. & Purpura DP. Autism, fever, epigenetics and the locus coeruleus. Brain Research Reviews. 2009; 59: 388-392.

*** Grafodatskaya D. et al. Autism spectrum disorders and epigenetics. Journal of the American Academy of Child and Adolescent Psychiatry. 2010; 49: 794-809.

Barker hypothesis and thin-fat bodies

Viewers here in the UK can, for a limited time, watch this weeks edition of Horizon on BBC2. It is a really interesting programme this week on our first nine months of being, including the theory postulated by Prof. David Barker - the Barker hypothesis of how our birth weight might predict our health later in life. The long and short of theory is simply that low birth weight might increase our risk of various conditions such as coronary heart disease and type 2 diabetes. The reasons why are perhaps slightly more complicated.

It is an interesting theory with a number of lines of evidence potentially supportive. The programme highlighted the studies conducted in Pune, India including this one by Yajnik and colleagues* which suggested that low birth weight children showed a greater level of impaired glucose tolerance, a potential early indicator of future diabetes complications. The paradox is that in India, most of the population are living pretty healthy lives by Western standards: thin bodies, a diet following and exceeding the Western 5-a-day slogan in terms of fruits and vegetable intake and good standards of physical activity, yet have quite high rates of more 'Western' diseases like heart disease and type 2 diabetes considered to be related to our more sedentary lifestyles.

Having said that when you look closer at those 'thin' people, looking at things like the percentage of body fat, these are in fact thin people with fat people bodies: normal body mass index (BMI) but higher percentages of body fat. The programme highlighted one potentially important factor related to birth weight; micronutrients and particularly ideas that low maternal vitamin B12 and low folic acid might make offspring more prone to the thin-fat body and the onward health effects suggested.

A second line of evidence was that derived from the studies on the wartime famine in Holland (sorry, the Netherlands) and the suggested effects on children born to mothers who experienced the famine. This study by Ravelli and colleagues** kinda sums it up: mums exposed to famine especially during the later stages of pregnancy resulted in offspring with decreased glucose tolerance as adults.

I don't claim to understand all the concepts highlighted in the programme and relevant to the Barker hypothesis and there is some evidence to the contrary. What is perhaps most interesting is that we live in a world where our access to food has never been better, certainly over the past 60 years or so, yet ironically the food we eat, or rather the food our mother's or grandmothers ate, might be so deficient in certain nutrients that our physical health and longevity may be at risk. The challenge is to know more about potential mechanisms (including things like the efficiency of the placenta) and make the necessary dietary changes for the sake of future generation health.

* Yajnik CS. et al. Fetal growth and glucose and insulin metabolism in four-year old Indian children. Diabetic Medicine. April 1995.
** Ravelli ACJ. et al. Glucose tolerance in adults after prenatal exposure to famine. Lancet. January 1998.