Reproductive stoppage related to autism

The paper by Thomas Hoffmann and colleagues [1] on reproductive stoppage - the decision to not have more children - in couples with a child already diagnosed with an autism spectrum disorder (ASD) is the source for today's post. This is both an important and delicate area to talk about so I tread very carefully in my discussions.

The Holy Infants @ Wikipedia 

A few details first:

• Based on records held at the California Department of Developmental Services, children born between 1990 and 2003 with a subsequent diagnosis of ASD were identified, and details on full and half-siblings extracted.
• Data from control participants without any record of autism or ASD were compared to ascertain "the reproductive behaviors of parents after the birth of a child with ASD vs an unaffected child".
• Results: 19 710 "case families" were initially identified from Services records and compared against data from 36 215 "pure control families". Whilst for the first few years after the birth of a child who was subsequently diagnosed with an ASD case families showed reproductive behaviour "similar to that of control parents", as time went on reproductive stoppage became more pronounced. Families with a child with autism were about a third less likely to have subsequent children than control families. This effect was also noted when later-born children were diagnosed with an ASD and "among women who changed partners".

Although the precise reasons why reproductive stoppage occurred with greater frequency among families affected by ASD are not given in the Hoffmann paper, some of the associated media discussion of this study (see here) talk about possible influences. It "could be due to concerns about having another child with the disorder or that parents feel they are unable to care for additional children after having one on the spectrum already" are some of the ideas being suggested. Parental stress is another concept banded around by some too.

Having talked about recurrence risk and autism previously on this blog (see here), there is another important message to be taken from the Hoffmann study outside of reproductive behaviours in families with a child with ASD. The issue of stoppage can have an important effect on discussions about recurrence risk as per other reports on this topic [2] and as has been suggested in the latest paper, how recurrence risk estimates can be under-estimated as a result. Indeed, the authors reported that when taking stoppage into account, recurrence risk estimates move up a few percentage points for both full and half siblings (8% full siblings becomes 10% and 3% for half-siblings becomes ~5%) based on their data. I might add that birth order studies in connection to ASD may also be similarly influenced by stoppage too [3].

I was also taken by some discussion on a paradox as a function of the Hoffmann results. The idea being that if autism was wholly genetic, then such reproductive stoppage should be "diminishing" any classical genetic fragility to autism over time. Clearly however, this is not the case as rates of autism, estimated rates of autism, are still climbing and much greater focus is being directed to other factors in autism causation outside of the 'genes are king/queen' mantra. Interestingly, published in the same journal as the Hoffmann paper, another paper by Kristen Lyall and colleagues [4] perhaps provides some further discussion on this topic and their conclusions supporting a: "role of additive genetic influences in concentrating inherited ASD susceptibility in successive generations and the potential role of preferential mating, and suggest that typical variation in parental social functioning can produce clinically significant differences in offspring social traits". I might add that I'm not necessarily coming down on the side of assortative mating being the ultimate factor affecting offspring autism risk, but it might offer at least some explanation for the autism genetics paradox also tied into concepts like the broader autism phenotype (BAP) too.

As mentioned at the beginning of this post, the issue of reproductive stoppage when it comes to families touched by autism is both an important and sensitive issue. The decision or not to have additional children when a family is already affected by autism is a personal one and most likely influenced by many different and often very individual factors. I don't doubt that some of those factors are the same that every family faces irrespective of autism or not: time, space, money, etc. but perhaps with the added discussions about 'risk' and the various 'what if' scenarios...

Music to close, and another song doin' the rounds in our house: Let it go (from Disney's Frozen movie). A treat also for some of my brood for bringing home their first Martial Arts trophies... Kiai!

----------

[1] Hoffmann TJ. et al. Evidence of Reproductive Stoppage in Families With Autism Spectrum Disorder. JAMA Psychiatry. 2014. June 18.

[2] Jones MB. & Szatmari P. Stoppage rules and genetic studies of autism. J Autism Dev Disord. 1988 Mar;18(1):31-40.

[3] Schmidt K. et al. Brief report: Asperger's syndrome and sibling birth order. J Autism Dev Disord. 2013 Apr;43(4):973-7.

[4] Lyall K. et al. Parental Social Responsiveness and Risk of Autism Spectrum Disorder in Offspring. JAMA Psychiatry. 2014. June 18.

----------

Hoffmann, T., Windham, G., Anderson, M., Croen, L., Grether, J., & Risch, N. (2014). Evidence of Reproductive Stoppage in Families With Autism Spectrum Disorder JAMA Psychiatry DOI: 10.1001/jamapsychiatry.2014.420

Autism risk and interpregnancy interval

Pregnancy issues and adverse birth factors 'associated' with the development of autism in offspring is a topic which has cropped up more than once on this blog, as autism research strives to identify as many possible 'risk' factors potentially linked to symptom onset. Lots of different birth-related variables have been analysed and put forward as potential candidates related to risk (see this post) ranging from birth weight (see here) to birth order (see here) and even season of conception/birth (see here).

Let me out... @ Wikipedia  

That's not to say however that anything concrete in terms of generalised offspring risk of autism has emerged from these various lines of research inquiry. Indeed, as per the study by Schieve and colleagues* (which I've already blogged about) hinted, many of these factors may be contributory but not necessarily 'causative' of autism when looked at on a population scale. This bearing in mind that I've not introduced the various 'exposure' events during pregnancy which have also been linked to offspring autism risk (e.g. the emerging valproate story) and the idea that population risk does not necessarily always translate into personal circumstances and risk.

Another factor which has seen some research action is the idea that having children in close temporal succession to one and another - a short interpregnancy interval - might also elevate the risk of the second child presenting with autism. The paper by Cheslack-Postava and colleagues** (full-text) hinted at this effect as per their conclusion: "children born after shorter intervals between pregnancies are at increased risk of developing autism". I note that Dr Emily Deans over at Evolutionary Psychiatry carried some discussion on this paper too (see here).

The more recent paper by Nina Gunnes and colleagues*** adds to the literature on this topic; indeed coming to pretty much the same conclusion: "interpregnancy intervals shorter than 1 year were associated with increased risk of autistic disorder in the second-born child". Based on yet more analysis out of Norway (although I am unsure whether this was a MoBa study or not), researchers looked at the records of several thousand sibling pairs in order to identify the length of the interpregnancy interval (IPI) and whether autism was mentioned in the records of second-born children. Their conclusion about short IPI and an elevated risk of autism in second-born children seemed to be particularly pertinent to those children born 9 months after their sibling compared with those born 3 years or later after their sibling.

A few points are worthy of mention. The very discerning readers out there might have already spotted a couple of familiar names attached to the Gunnes paper authorship in the form of Mady Hornig and Ian Lipkin (see this quite recent post).

I note also the authors suggest that a "depletion of micronutrients" might have something to do with the explanation for the short IPI-autism association, which carries hints of the late David Barker's hypothesis (see here) and is pretty much in line with what Dr Deans previously mentioned. Indeed, to reiterate her discussion about baby 'sucking out' whatever nutrients it needs from its host (i.e. mum) I can remember similar words being told when my/our brood were due for an appearance. With all the current fascination on things like folic acid and autism (see here and here), one might very easily say that there is a possible link to be had there, bearing in mind Gunnes and colleagues did not assay for or report on maternal or offspring folic acid levels at any point during their study.

If also I had to play devil's advocate on such 'association' research I might point out that looking at the IPI alone and knowing relatively little about the family or offspring in terms of their lives is still methodologically problematic. We don't for example know about any medical or psychiatric familial history which might also be an important modifier of offspring risk. I assume the authors already controlled for whether sibling number one had a formal diagnosis of autism (as per the autism recurrence data previously discussed), but did they for example, ask about the potential presence of sub-clinical signs and symptoms associated with something like the broader autism phenotype for example? Were they also able to comment on any additional siblings after child number two and the elevated risk or not for them presenting on the autism spectrum either alone or as a function of IPI?

Then there's the volume of research suggesting that a short IPI might also increase the risk of reduced birth weight**** or the risk of preterm birth***** which I assume have been controlled for, but still one wonders about their impact on the presentation of offspring autism and any wider links (see here). I might also draw readers' attention to an interesting correspondence from Downs & Jonas****** (full-text) with regards to research suggesting a link between short IPI and risk of offspring schizophrenia. In short(!), one has to be careful of making too much of such association data at the current time.

That being said, I don't want to take anything away from the Gunnes study and results. It was a well-powered study and they got what they got. Their data also add to the various other information suggesting that when it comes to having children, mums (and dads) are advised to give themselves a bit of breather between kids.

Some music to finish. How about Robbie & Kylie?

----------

* Schieve LA. et al. Have secular changes in perinatal risk factors contributed to the recent autism prevalence increase? Development and application of a mathematical assessment model. Ann Epidemiol. 2011 Dec;21(12):930-45.

** Cheslack-Postava K. et al. Closely spaced pregnancies are associated with increased odds of autism in California sibling births. Pediatrics. 2011 Feb;127(2):246-53.

*** Gunnes N. et al. Interpregnancy Interval and Risk of Autistic Disorder. Epidemiology. 2013 Sep 16.

**** Smits LJ. et al. The association between interpregnancy interval and birth weight: what is the role of maternal polyunsaturated fatty acid status? BMC Pregnancy Childbirth. 2013 Jan 25;13:23.

***** De Franco EA. et al. A short interpregnancy interval is a risk factor for preterm birth and its recurrence. Am J Obstet Gynecol. 2007 Sep;197(3):264.e1-6.

****** Downs JM. & Jonas S. Short inter-pregnancy interval and schizophrenia: overestimating the risk. Br J Psychiatry. 2012; 200: 160.

----------

Gunnes N, Surén P, Bresnahan M, Hornig M, Lie KK, Lipkin WI, Magnus P, Nilsen RM, Reichborn-Kjennerud T, Schjølberg S, Susser ES, Oyen AS, & Stoltenberg C (2013). Interpregnancy Interval and Risk of Autistic Disorder. Epidemiology (Cambridge, Mass.) PMID: 24045716

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?  

----------

* 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.

----------

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

Autism and birth order

Being resident in the United Kingdom with its often quirky customs and practices, I know a thing about the power of birth order. Whilst offering no opinion on the rights and wrongs of our monarchy system, I do know that first born (sons) tend to get the lion's share when it comes to 'ruling over us' (with the same offer soon to be granted to first born daughters apparently).

The science of birth order has found some interest for lots of different things; potentially relating to our measured intellectual ability and our personality and disposition for example. I don't quite know if I believe such sweeping generalisations from this collected body of research, but I guess many of these more psychological differences might reflect the trials and tribulations of the family dynamic and that bullying big brother or sister.

Health has also come under the birth order spotlight. The idea that first born children are more likely to suffer with allergies, including food allergies than subsequent siblings, is an interesting concept potentially tied into things like the hygiene hypothesis. Parents of more than one child probably know already about the concept of 'bringing infections home to share' with siblings and what joys that can bring alongside the 'first baby being wrapped in cotton wool' effect.

A recent paper by Turner and colleagues* suggests that there may be more than a passing association between birth order and 'risk' of autism. The theory goes that depending on where you are in relation to your sibling/s, might determine some risk of autism or facet of autism. This is nothing new. For quite a few years now, various groups have suggested that in some cases, there may be a 'pattern' of risk based on your position in the sibling stakes. Some have linked this back to parental age; others have talked about genetics; others have talked about other factors.

Turner and colleagues approached this question in a slightly more 'mathematical' way than has been previously applied. The methods and results, bearing in mind that the paper is open-access:

• Three different cohorts were included for analysis, based on the AGRE, NIMH and Simons Simplex collections. AGRE and NIMH were primarily composed of multiplex families (families with more than one child presenting with autism) whilst the Simons Simplex was comprised of one child with autism, the other sibling not. The total number of families and children included was notable.
• Statistics were applied (rank-sum test, inverse rank-sum test, chi-squared) and suggested that for multiplex families (more than 1 child with autism) there was an inverse-V shape pointing towards the middle ranks being more likely to be diagnosed (particularly the second child) and in simplex families, risk is linear and increases with each additional birth, also potentially linked to gender. 

Before we get too carried away with these results (and the various biases included), it is important to understand that mathematical models and statistics are fine for looking at risk and trends in data in a theoretical sense, but when it comes to real life, the whole thing becomes a lot more complicated. I think back to the recent article on low birth weight covered in this post and the subsequent comments left by many parents of children with autism on many websites indicating their child's birth weight did not fall into that category. Lots of factors involved.

Still data like this, alongside other information, all adds to the body of literature. In these days of biological phenotypes of autism, this could represent an interesting variable. There is one little detail mentioned in the paper which I find very interesting: a possible role for epigenetics - changes in gene activity without changes in the genetic code - or to you and me, environmental factors. It works in flies and most probably works for humans too; although at this stage, I make no comparisons with the topic in question.

* Turner T. et al. Quantifying and modeling birth order effects in autism. PLoS ONE. October 2011.