"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 and risk of offspring autism meta-analysed

"Our study indicated that the use of ART [assisted reproductive technology] may [be] associated with higher risk of ASD [autism spectrum disorder] in the offspring. However, further prospective, large, and high-quality studies are still required."

So said the results of the meta-analysis published by Liang Lui and colleagues [1] (open-access) surveying the peer-reviewed research literature - "11 records (3 cohort studies and 8 case-control studies)" - between 2006 and 2015. ART covers a variety of techniques "to achieve pregnancy and live birth" most notably including IVF (in vitro fertilisation) and artificial insemination. Some, but not all, of the studies included for review suggested an *association* between ART use and enhanced risk of offspring autism particularly in "European and Asian populations." The authors were however unable to tease apart which specific ART(s) might be associated with a higher risk than others.

This is not the first time that this topic has been covered on this blog (see here). On that previous occasion I intimated that the source of any risk from ART on offspring autism was not yet identified and, in some cases, other birth factors might exert some effect. In short, it's more complicated than paper titles can transmit.

Does my opinion change as a result of these meta-analysed findings? Well, not really. I appreciate the findings reported by Lui and colleagues but I still think other birth factors might come into play outside of just ART exerting a primary effect. Not least is the possibility that issues affecting fertility in the first place might be particularly relevant among other confounders. I echo the sentiments of the authors that more research might be required in this area but with the various stresses and strains being placed on autism research resources these days, I'm not inclined to suggest that this area should necessarily be top of this list of priorities. Sorry.

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

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Liu L, Gao J, He X, Cai Y, Wang L, & Fan X (2017). Association between assisted reproductive technology and the risk of autism spectrum disorders in the offspring: a meta-analysis. Scientific reports, 7 PMID: 28387368

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