"Progesterone hormone treatment significantly increased the risk of ASD"

The quote titling this post - "Progesterone hormone treatment significantly increased the risk of ASD [autism spectrum disorder]" - comes from the findings reported by Michael Davidovitch and colleagues [1].

Researchers set out to examine whether there was any *association* between the receipt of infertility treatments and offspring risk of a diagnosis of autism spectrum disorder (ASD). They concluded that use of IVF treatment - in vitro fertilisation, where a woman's egg(s) are removed and fertilised outside of the body then 'put back in' - probably doesn't show any significantly enhanced risk for offspring autism. When however it came to the use of progesterone hormone treatment complementing such assisted reproductive methods, there may be something to see...

Before going further into these findings, I want to hark back to some discussions (see here) on the previous research in this area. The paper by Liang Liu and colleagues [2] meta-analysing the peer-reviewed literature on the use of assisted reproductive technology (ART) and offspring risk of autism did suggest there might be something more to see; albeit concluding that: "The complexity of ART treatment renders the identification of individual risk factors extremely challenging." I say this on the basis that various different 'pregnancy and birth' factors have been *correlated* with offspring autism risk down the years (see here for example) and teasing apart which ones are the more 'important' is difficult to say the least.

The Davidovitch study relied on data for over 100,000 children (males) born between 1999 and 2008. Authors identified approaching one thousand children diagnosed with an ASD representing about 1% of the total cohort. As well as looking at IVF, they also examined "five hormone treatments" pertinent to ART, singling out progesterone hormone treatment as part of their observations.

There is lots more work to be done in this area before too many sweeping generalisations are made. Aside from the issue of teasing out exactly what conception/pregnancy variables *might* be related to offspring risk of autism (including reproduction itself!) there is a question of mechanism(s) to also consider. The authors refer to the term "epigenetic modification by progesterone" but only few details are provided. I might also at this point introduce a recent piece from Jill Escher [3] who provided some really interesting commentary on how synthetic hormone drugs *might* have played a role in her own family circumstances as a template for some further studies. I say this bearing in mind that progesterone should not be too readily confused with progestins [4].

To close, I also read some other work from Michael Davidovitch recently [5] talking about cell (mobile) phone use and "the development of joint attention in infants" pertinent to "the development of autistic features among a vulnerable subgroup of infants." I'm slightly less enthralled about such suggestions and the strength of any 'technology use cause autism' sentiments but am willing to keep an open mind on how our fascination with mobile phones *might* impact on parent-child interactions (but not necessarily in the context of autism)...

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[1] Davidovitch M. et al. Infertility treatments during pregnancy and the risk of autism spectrum disorder in the offspring. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2018. June 1.

[2] Liu L. et al. Association between assisted reproductive technology and the risk of autism spectrum disorders in the offspring: a meta-analysis. Scientific Reports. 2017; 7: 46207.

[3] Escher J. Bugs in the program: can pregnancy drugs and smoking disturb molecular reprogramming of the fetal germline, increasing heritable risk for autism and neurodevelopmental disorders? Environ Epigenet. 2018 Apr 26;4(2):dvy001.

[4] Spark MJ. Progesterone or progestogen or progestin; which is it? BMJ. 2009; 339: b4380.

[5] Davidovitch M. et al. The Role of Cellular Phone Usage by Parents in the Increase in ASD Occurrence A Hypothetical Framework. Medical Hypotheses. 2018. June 7.

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Assisted Reproductive Technology conception and autism

I noticed recently that the paper by Christine Fountain and colleagues [1] reporting that "incidence of diagnosed autism was twice as high for ART [assisted reproductive technology] as non-ART births" has been making some media headlines.

Based on an analysis of an impressive participant number "using linked records from the California Birth Master Files for 1997 through 2007, the California Department of Developmental Services autism caseload for 1997 through 2011, and the Centers for Disease Control and Prevention's National ART Surveillance System for live births in 1997 through 2007" authors looked at nearly 6 million births in California, USA. Including nearly 49,000 "ART-originated infants" and 33,000 "cases of autism diagnosed by the Department of Developmental Services", they set about looking at whether there was any difference between "births originated using ART with births originated without ART for incidence of autism."

They concluded that there was perhaps more to see when it came to ART births and autism albeit not necessarily a clear-cut relationship. Multiple births and "adverse prenatal and perinatal outcomes" seemed to play quite an important role in the 'association' reported, leading to quotes like this from others: "The results indicate that reducing multiple births during ART may be beneficial for decreasing the risk of autism."

This is not the first time that ART and some of the specific techniques linked to ART such as IVF (in vitro fertilisation) have been talked about with autism in mind. I have discussed the topic previously on this blog (see here) based on the findings reported by Venla Lehti and colleagues [2] for example. In that case, as in other instances [3], the results were less than impressive on any general association. These independent analyses did not rule out specific factors perhaps requiring further investigation, but overall the effect of ART on general autism risk was not particularly great.

The take-home message is that whilst ART might impact on autism risk, the techniques themselves included under the ART banner are probably not the primary source of any risk. Rather, as we've seen on quite a few other occasions, issues around gestation and birth (see here) might be the important variables which itself asks some interesting questions about autism research areas such as the use of twins (see here) among other things...

Music: Rihanna et al - Umbrella.

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[1] Fountain C. et al. Association Between Assisted Reproductive Technology Conception and Autism in California, 1997-2007. Am J Public Health. 2015 Mar 19:e1-e9.

[2] Lehti V. et al. Autism spectrum disorders in IVF children: a national case-control study in Finland. Hum Reprod. 2013 Mar;28(3):812-8.

[3] Sandin S. et al. Autism and mental retardation among offspring born after in vitro fertilization. JAMA. 2013 Jul 3;310(1):75-84.

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Fountain C, Zhang Y, Kissin DM, Schieve LA, Jamieson DJ, Rice C, & Bearman P (2015). Association Between Assisted Reproductive Technology Conception and Autism in California, 1997-2007. American journal of public health PMID: 25790396

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