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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Placental inflammation and autism?

The placenta. Quite an important part of the nine months that makes us; an organ exquisitely evolved to provide oxygen and nutrition to the developing embryo/foetus as well as removing various un-necessaries. Without it we wouldn't even be...

A recent paper by Jennifer Straughen and colleagues [1] suggests that when it comes to the placenta and it's important functions during gestation, there may be some interesting data pertinent to at least some cases of autism spectrum disorder (ASD). Indeed the authors note: "Histologic evidence of placental inflammation and maternal vascular malperfusion pathology are associated with ASD."

Based on identifying some 55 persons diagnosed with ASD and nearly 200 matched controls, researchers analysed findings based on placentas "reviewed as part of routine care." Although not particularly au-fait with the inner workings of the placenta, I understand that various 'issues' were screened for and some interesting observations made. Words like 'acute placental inflammation' and 'maternal vascular malperfusion pathology' are banded around; many of which seemed to be more frequently associated with a subsequent diagnosis of ASD. In short, there seemed to be quite a bit more going on with those placentas from mums of children with autism compared with the not-autism controls.

This is important work. I've talked about the placenta and offspring autism previously a few times on this blog (see here and see here for examples). Allied to the rather sweeping idea that autism 'begins in-utero' and there is a case to be made for further inspection of organs like the placenta [2] when it comes to at least some cases of offspring autism - some, but not all. Indeed, it is perhaps timely that other independent papers [3] remind us of the work of the late Paul Patterson et al and the concept of maternal immune activation (MIA) and how the required reprogramming of the maternal immune system during pregnancy might very much rely on optimal placental function to keep the developing child safe and sound...

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[1] Straughen JK. et al. The association between placental histopathology and autism spectrum disorder. Placenta. 2017. July 8.

[2] Schroeder DI. et al. Placental methylome analysis from a prospective autism study. Mol Autism. 2016 Dec 15;7:51.

[3] Bilbo SD. et al. Beyond infection - Maternal immune activation by environmental factors, microglial development, and relevance for autism spectrum disorders. Experimental Neurology. 2017. July 8.

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On genotype and environmental exposure patterns

I was rather interested to read the paper by Michela Traglia and colleagues [1] (open-access available here) concluding that: "maternal and fetal genetic make-up are important determinants of mid-gestational maternal circulating levels of some environmental organohalogens." Interested because, in these days of gene-environment interactions being applied to just about everything, the detail that is missing - which genes might potentially be linked to which environmental factors - has not yet been suitably addressed in the peer-reviewed science literature.

So, based on data - "serum levels of a set of 21 organohalogens in a subset of 790 genotyped women and 764 children" - derived from participants included in the Early Markers for Autism (EMA) Project, researchers set about assessing how genetics might impact on environmental pollutant exposure profiles. Maternal blood samples were collected at around 15-20 weeks pregnancy. Children provided blood samples via the fabulous resource that is the newborn screening program, where: "Newborn blood spots were collected on filter paper 1-2 days after birth." Maternal samples were analysed for various environmental pollutants and both sets of samples were analysed for the genetic material they contained pertinent to whether "circulating mid-gestational levels of organohalogens would be driven by common maternal genetic determinants, and that these results could shed light on the observed associations between the organohalogens and ASD [autism spectrum disorder]."

Results: yes, the authors "found evidence that a large proportion of maternal circulating levels of BB-153, BDE-47, -100, -153 [polybrominated congeners] and their sum was significantly controlled by common genetic factors." Those 'common genetic factors' typically referred to the presence of point mutations (SNPs) that litter everyone's genome and on occasion, can affect the function/production of specific biological processes. So: "Genome-wide association analyses identified significant maternal loci for p,p'-DDE... in the CYP2B6 gene and for BDE-28... near the SH3GL2 gene, both involved in xenobiotic and lipid metabolism." In other words, although the environmental pollutants measured are not great products in the first place (in terms of safety), a person's genetic make-up can influence how such products are eventually dealt with by the body and potentially onwards, what subsequent effects they might have.

Additionally: "results suggest that the maternal circulating levels of some compounds were more highly influenced by fetal genetic factors than maternal genetics." This leads into another aspect of the current study whereby foetal genetic factors might also play a part in "controlling the toxicant disposition between mother and fetus." Specifically, authors noted that aspects of the individual genetics of a foetus (distinct from its mother) "contributed to the levels of BDE-100... and PCB187... near the potential metabolic genes LOXHD1 and PTPRD, previously implicated in neurodevelopment."

And finally: "We confirmed that the serum levels of BDE-100, -153 and the total sum of PBDEs were significantly lower in mothers of ASD-affected children compared to mothers of control children." This is interesting in light of other discussions about PBDEs and autism in particular (see here). The authors do discuss various scenarios to account for their results not least that "transplacental transfer of organohalogens during pregnancy may be driven by the fetal genome expressed in placenta." Further analyses of the 'placentome' might therefore be indicated.

To reiterate, this is interesting research. It tells us that many [adverse] environmental exposures, whilst typically to be avoided, don't act on the body in a uniform way as a function of differing genomes and differences in the ways that the body 'handles' such exposures. With autism in mind, this is not necessarily new news (remember paraoxonase gene variants and organophosphate metabolism [2] and air pollution and offspring autism?) but is a useful reminder. Such work also provides a template for looking at the myriad of other environmental factors put forward to influence autism risk and whether individual product safety is necessarily the only or most important factor when it comes to assessing relative risk profiles.

I might finally also draw your attention to a recent interesting meta-analysis of the various environmental risk factors potentially linked to autism [3] (open-access) and another article talking about similar things [4] (open-access) (thanks Annabelle). Genes and environment, genes and environment...

Music: Petula Clark sings the Beatles? Personally, I think it's better than the original...

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[1] Traglia M. et al. Independent Maternal and Fetal Genetic Effects on Mid-gestational Circulating Levels of Environmental Pollutants. G3 (Bethesda). 2017 Feb 24. pii: g3.117.039784.

[2] 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. Mol Psychiatry. 2005 Nov;10(11):1006-16.

[3] Modabbernia A. et al. Environmental risk factors for autism: an evidence-based review of systematic reviews and meta-analyses. Molecular Autism. 2017; 8: 13.

[4] Parker W. et al. The role of oxidative stress, inflammation and acetaminophen exposure from birth to early childhood in the induction of autism. Journal of International Medical Research. 2017. Jan 20.

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Traglia M, Croen LA, Lyall K, Windham GC, Kharrazi M, DeLorenze GN, Torres AR, & Weiss LA (2017). Independent Maternal and Fetal Genetic Effects on Mid-gestational Circulating Levels of Environmental Pollutants. G3 (Bethesda, Md.) PMID: 28235828

Gestional exposure to Group B Streptococcus and an autism model

"Overall, these data show for the first time that gestational exposure to GBS [Group B Streptococcus] plays an important role in the generation of neurodevelopmental abnormalities reminiscent of human autism spectrum disorders (ASD)."

I chose to discuss the findings reported by Marie-Julie Allard and colleagues [1] on this blog for various reasons. That this research team already have some research 'form' when it comes to looking at GBS [2] is one; another is the idea that they report "new evidence in favor of the role of a common and modifiable infectious/inflammatory environmental factor in human ASD pathophysiology." With all the focus these days on how there may be some kind of foetal programming going on during the nine months that made us pertinent to the risk of developing autism for some, this line of research also potentially offers up the idea that said programming needn't always be related to the genome we are born with.

GBS infection during pregnancy and birth is not something to be taken lightly. As a primary cause of bacterial infections in newborns, this type of infection can in extreme cases lead to septicaemia (blood poisoning) and also meningitis. This all stems from the fact that around 25-30% of healthy human adults carry this bacteria around in their gut and/or genitourinary tract with no apparent issues for the majority. In rare cases however, infants traversing the birth canal of a mother carrying GBS can come into contact with the bacteria and processes are then set in motion...

Allard et al started with the hypothesis that "GBS-induced gestational infection/inflammation has a deleterious neurodevelopmental impact on uninfected offspring" and set about looking at this potential issue in a rodent model - "a new preclinical rat model" no less. They reported that placentas exposed to GBS "exhibited chorioamnionitis characterized by the presence of Gram-positive cocci and polymorphonuclear cells, with the latter being significantly more prominent in the labyrinth of male offspring." Whilst interesting, this is not necessarily new news. But... when it came to looking at the brain and behaviour of male rat offspring exposed to GBS, there appeared to be a few features potentially "reminiscent of human autism spectrum disorders (ASD)." So: "autistic-like behaviors, such as abnormal social interaction and communication, impaired processing of sensory information and hyperactivity" were noted in this group. The conclusion being that science may have yet another animal model of autism (is this a good or bad thing?) and that GBS-exposed placentas might have implications for offspring developmental outcome.

The previous research paper by this group [2] had already provided some important details pertinent to this line of investigation. "Surprisingly, only male offspring were affected by these combined autistic-like traits" went one of their conclusions on that previous research occasion, insofar as GBS-exposed placentas and their onward effects. They also suggested that there may be some important effects to be had from the "materno-fetal inflammatory response to GBS" coinciding with quite a lot of peer-reviewed data suggesting immune system and inflammatory signalling involvement when it comes to pregnancy and offspring risk of autism (see here and see here).

Stressing that animal models of autism are not necessarily the same as the complexity of autism in it's lived form, the Allard findings are potentially important. Added to something of an important body of research looking at artificial modelling of bacterial infection and its potential importance to offspring outcomes (see here) one can see that the so-called protective cocoon of our mother during the months of our earliest development is not an impenetrable force-field by any stretch of the imagination. Indeed, such an association may go much further than just autism (see here).

Insofar as the 'where next?' in terms of research in this area, well, I might suggest that looking at the rates of offspring autism in women positive or negative to GBS could represent a good research start and perhaps taking things from there. Although there may be some way to go in determining the precise mechanism of GBS exposure in-utero in relation to any possible heightened risk of autism, science might also consider other findings from this research group [3] on how 'intervening' in issues related to inflammation at certain critical periods, might eventually provide some 'protection' for the developing brain...

Oh, and I'll be coming to the paper by Jiang and colleagues [4] in a future post.

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[1] Allard MJ. et al. A sexually dichotomous, autistic-like phenotype is induced by Group B Streptococcus maternofetal immune activation. Autism Res. 2016 May 25.

[2] Bergeron JD. et al. White matter injury and autistic-like behavior predominantly affecting male rat offspring exposed to group B streptococcal maternal inflammation. Dev Neurosci. 2013;35(6):504-15.

[3] Girard S. et al. IL-1 receptor antagonist protects against placental and neurodevelopmental defects induced by maternal inflammation. J Immunol. 2010 Apr 1;184(7):3997-4005.

[4] Jiang HY. et al. Maternal Infection during Pregnancy and Risk of Autism Spectrum Disorders: A Systematic Review and Meta-analysis. Brain Behav Immun. 2016 Jun 7. pii: S0889-1591(16)30154-4.

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Allard MJ, Bergeron JD, Baharnoori M, Srivastava LK, Fortier LC, Poyart C, & Sébire G (2016). A sexually dichotomous, autistic-like phenotype is induced by Group B Streptococcus maternofetal immune activation. Autism research : official journal of the International Society for Autism Research PMID: 27220806

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 the folding placenta

Men don't generally talk about placentas it has to be said. But today, in the name of blogging, I'm going to.

I'm going to start by telling you how the placenta really is a marvel of biological engineering. An absolutely vital part of our existence in-utero that nourishes us and protects us during our earliest days living in the amniotic sac. Little wonder that whole nations have come to revere the placenta as mother, sibling even doubles of ourselves (see here). Although I have to say I do draw the line at placenta pate.

 Folding time @ Wikipedia  

The reason for all this appreciation of the placenta follows the publication of a paper by Cheryl Walker and colleagues* who, as part of the MARBLES initiative (don't you just love these acronyms), reported that looking for trophoblast inclusions (TIs) in the placenta "could serve as a predictor for children at elevated risk for autism spectrum disorder (ASD)".

Trophoblasts by the way, are a specialised group of cells which play an important role in processes like embryo implantation. Trophoblast inclusions are abnormal cell cluster which form, "a distinctive microscopic placental morphological abnormality" linked to tissue folding described by some of the same authors in earlier work in this area**.

In the most recent paper, the authors detail the blinded examination of 117 placentas (used of course) from "at-risk" siblings of children already diagnosed with an autism spectrum disorder (ASD) compared with 100 control specimens for the frequency of TIs. Whereas control placentas had no more than 4 TIs, the at-risk sibling placentas "had an eight-fold increased odds of having two or more TIs" according to accompanying press.

Prediction values, as in blinded prediction of those at-risk siblings compared to controls were reported according to the number of TIs identified. In other accompanying press literature on this study, a figure of 90%+ accuracy is reported "to identify without prior knowledge which of the placentas came from the younger sibling of a child with autism, and which from another study participant who did not have autism in the family".  This however was offset by corresponding issues with sensitivity. The implication for this work being that examining placentas might yield either important information about the subsequent risk of a child developing autism or an ASD and/or lead to new clues about the prenatal environment linked to cases of autism.

I highlighted the previous paper by some of the authors in this area and note how in that study they were actually looking at archived placental tissue from those who were subsequently diagnosed with ASD (n=13). Indeed in that study, TIs were reported as present in 5 of the 13 samples from participants with ASD (38%) compared with 8 of 61 controls (13%). You can perhaps see from these figures that we are probably not talking about an all-or-nothing relationship when it comes to TIs 'predicting' autism or not.

There's no doubt that the Walker results are interesting and potentially informative if reproducible bearing in mind I'm still a little unclear on the hows and whys of TIs and autism risk. Sure, the authors speculate that this might be part and parcel of some of the genetic landscape of autism, given the link between TIs and chromosomal disorders***, but that might not be the whole story**** (thanks Natasa) and with some interesting knock-on effects***** (open-access). Please note I am not making links between any specific infection, autism and TIs at this point.

I'm very interested in this whole area of pregnancy and gestation as perhaps being critical times for autism, sorry the autisms; recognising that this area of investigation might not cover every case of autism - think regression for example. I'm minded also to take you back to the Barker hypothesis (see this post) and think whether or not one might extrapolate some of the work on placental functioning****** to overlap with autism risk? Just thinking out loud as others eminently more qualified than I already have.

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* Walker CK. et al. Trophoblast inclusions are significantly increased in the placentas of children in families at risk for autism. Biol Psychiatry. April 2013.

** Anderson GM. et al. Placental trophoblast inclusions in autism spectrum disorder. Biol Psychiatry. 2007; 61: 487-491.

*** Kliman HJ. Structural abnormalities in the placenta. BMC Pregnancy and Childbirth. 2012; 12(Suppl 1): A3.

**** Banks J. et al. Chlamydia trachomatis infection of mouse trophoblasts. Infection & Immunity. 1982; 38: 368-370.

***** de la Torre E. et al. Chlamydia trachomatis infection modulates trophoblast cytokine/chemokine production. J Immunol. 2009; 182: 3735–3745.

****** Henrikson T. & Clausen T. The fetal origins hypothesis: placental insufficiency and inheritance versus maternal malnutrition in well-nourished populations. Acta Obstetricia et Gynecologica Scandinavica. 2008; 81: 112–114.

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Walker, C., Anderson, K., Milano, K., Ye, S., Tancredi, D., Pessah, I., Hertz-Picciotto, I., & Kliman, H. (2013). Trophoblast Inclusions Are Significantly Increased in the Placentas of Children in Families at Risk for Autism Biological Psychiatry DOI: 10.1016/j.biopsych.2013.03.006