8 in 1000 babies born with foetal alcohol spectrum disorder

The results of the systematic review and meta-analysis published by Shannon Lange and colleagues [1] make for important reading with their conclusion that the global prevalence of foetal alcohol spectrum disorder (FASD) is estimated to be around 8 in 1000 live births. The accompanying editorial by Albert Chudley [2] rightly talks about 'high time for action' on the basis of such figures, particularly because FASD is a largely preventable condition and specific groups of people and specific geographical regions seem to carry elevated risk(s) when it comes to offspring FASD and so can be targeted for additional support.

Looking at the collected data from 24 studies examining the prevalence of FASD - a condition whereby babies exposed to alcohol in the womb present with specific morphological features and accompanying behavioural / cognitive issues - researchers concluded that around 7.7 per 1000 live births presented with FASD. They reported that 76 counties (of 187 countries providing data) showed an estimated prevalence rate for offspring FASD above 1% of total births. South Africa came top with over 1 in 10 births being estimated to present with FASD. Croatia, Ireland, Italy and Belarus filled the other top 5 hotspots for FASD with estimated prevalence rates between 3-5% of births derived from various methods.

'Special populations' are also mentioned in the Lange paper. Specifically: "the prevalence of FASD among special populations was 15.6 to 24.6 times higher among aboriginal populations... 5.2 to 67.7 times higher among children in care... 30.3 times higher in a correctional population... 23.7 times higher in a population with low socioeconomic status... and 18.5 times higher among a population in psychiatric care compared with the global prevalence among children and youth in the general population." One might argue that at least for some of these at-risk populations, issues such as binge drinking habits combined with an elevated risk of unplanned pregnancy [3] could lie at the root of the estimates detailed by Lange et al. I say that minus any sweeping generalisation but in light of the scientific 'facts' detailed in the latest review paper.

I note that some of the media around the Lange findings (see here) have already mentioned about some of the behavioural manifestations of FASD 'crossing over' with diagnoses such as attention-deficit hyperactivity disorder (ADHD) and autism. I would perhaps draw your attention to a previous blogging occasion when I discussed some of the research specifically looking at any overlap between autism and FASD (see here) and how one needs to be quite careful not to overplay any would-be links despite some data on possible overlap [4] (this paper was also from Lange).

Then to the specifics of the hows-and-whys of alcohol exposure in-utero causing FASD and whether effects might somehow be mitigated. Alcohol (ethanol) is a known teratogen [5] so effects are likely to be numerous in terms of how it affects the developing foetus. I note that the word 'epigenetics' has entered the vocabulary when it comes to possible mechanisms of effect(s) and that would suggest that at some point there may be ways and means of mitigating the effects of alcohol consumption at critical periods during pregnancy. At some point.

For now the message from Lange and colleagues is clear: FASD is not an uncommon finding in many different countries and different populations, and remains largely preventable. Abstinence from alcohol is advised before and during that special time (see here). And just in case anyone thinks I'm only zooming in on mums-to-be, dads might also heed similar advice at critical periods too.

Straight Edge from Minor Threat seems an appropriate song to conclude this post given what the song title means (veganism and the non-use of prescription medicines are optional extras I might add)...

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[1] Lange S. et al. Global Prevalence of Fetal Alcohol Spectrum Disorder Among Children and Youth. JAMA Pediatrics. 2017. Aug 21.

[2] Chudley AE. Fetal Alcohol Spectrum Disorder—High Rates, High Needs, High Time for Action. JAMA Pediatrics. 2017. Aug 21.

[3] Font-Ribera L. et al. Socioeconomic Inequalities in Unintended Pregnancy and Abortion Decision. Journal of Urban Health. 2008;85(1):125-135.

[4] Lange S. et al. Prevalence of Externalizing Disorders and Autism Spectrum Disorder among Children with Fetal Alcohol Spectrum Disorder: Systematic Review and Meta-analysis. Biochem Cell Biol. 2017 May 18.

[5] Randall CL. Alcohol as a teratogen: a decade of research in review. Alcohol Alcohol Suppl. 1987;1:125-32.

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Paediatric congenital heart disease and autism risk?

"Children aged 2-17 with CHD [congenital heart disease] were more likely than those without CHD to have had a diagnosis of autism spectrum disorder (crude OR, 4.6; 95% CI, 1.9-11.0) or intellectual disability (Crude OR, 9.1; 95% CI, 5.4-15.4)".

The traveller @ Wikipedia 

That was a key conclusion reported in the study by Hilda Razzaghi and colleagues [1] based on their analysis of data from "the 1997-2011 National Health Interview Survey", a US initiative which aims to provide "information on the health of the U.S. civilian noninstitutionalized population through confidential interviews conducted in households" (see here).

I have to say that I was pretty interested in these findings (even though this is not the first time that neurodevelopmental outcomes have been tied to CHD); a view it seems, that was shared by the authors of the paper, bearing in mind the very wide confidence intervals (CIs) detailed for both conditions and the reliance on second-hand reporting over actual independent screening results. I can't readily offer any one 'smoking gun' explanation for the findings specifically in relation to the autism spectrum but will draw your attention to some discussion about the potential causes of congenital heart disease provided by the NHS Choices websites and how they might tie in.

So: various genetic conditions including Down's syndrome are linked to CHD [2] and the net seems to be closing in on some of the underlying genetics around the association [3]. Although still in need of quite a bit more study, there is a growing appreciation that a diagnosis of autism / autistic traits can coexist alongside a diagnosis of Down's syndrome (see here). As per a recent conversation (thanks Marilyn), one also wonders how this autism - Down's syndrome link might also play out with regards to other areas of the autism research landscape such as dietary effects for example...

Next up is maternal diabetes. As per the NHS Choices entry: "It is estimated that 3 to 6% of women with diabetes who become pregnant will give birth to a baby with a heart defect". Autism and maternal diabetes is an interesting topic which has again cropped up in the autism research literature [4]. If you want my take on the Xu meta-analysis paper and related literature, look no further...

After that is a role for alcohol consumption during pregnancy and mention of the condition called foetal alcohol syndrome (FAS). I have talked about FAS and foetal alcohol spectrum disorder (FASD) before on this blog in the context of autism (see here) but can't readily conclude that the links are overly strong between FAS/FASD and autism presentation.

"A rubella infection can cause multiple birth defects, including congenital heart disease". An interesting association given the history of rubella and autism based to quite a large extent on the work from Stella Chess [5]. I don't know enough about the rate of rubella infection in pregnant women to make any informed statement about how this risk factor might tie into both CHD and autism but the numbers of non-immune women do seem to be quite alarming here in the UK [6].

Influenza during pregnancy? "Women who get flu during the first trimester (three months) of pregnancy are twice as likely to give birth to a baby with congenital heart disease than the general population" according to the NHS Choices website. Regular readers of this blog might already know that I tend to talk quite a bit about how infection - immune system response to infection - during pregnancy seems to have some link to subsequent offspring psychology and development (see here). The link is not altogether straight forward with autism in mind and potentially better related to concepts like fever or fever control [7] but still, there might be more to do here.

The final links - certain medications taken during pregnancy, phenylketonuria (PKU) and exposure to organic solvents during pregnancy - have also, to various extents, been linked to autism (see here and see here for example).

I may very well just be plucking at straws trying to link the causes of CHD with some of the suspected 'causes' of autism (some autism at least) but it strikes me that if one was to further pursue the findings reported by Razzaghi et al those would be the places to start (assuming some shared effect). As per the reports of other physiological findings potentially manifesting alongside a diagnosis of autism (see here), some additional screening of children on the autism spectrum where one or more of the correlates of CHD are suspected might be indicated.

Peter Gabriel and Kate Bush with a beautiful song to close: Don't Give Up.

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[1] Razzaghi H. et al. Long Term Outcomes in Children with Congenital Heart Disease: National Health Interview Survey. J Pediatr. 2014 Oct 8. pii: S0022-3476(14)00820-8.

[2] Laursen HB. Congenital heart disease in Down's syndrome. Br Heart J. Jan 1976; 38(1): 32–38.

[3] Ramachandran D. et al. Contribution of copy-number variation to Down syndrome-associated atrioventricular septal defects. Genet Med. 2014 Oct 23. doi: 10.1038/gim.2014.144.

[4] Xu G. et al. Maternal diabetes and the risk of autism spectrum disorders in the offspring: a systematic review and meta-analysis. J Autism Dev Disord. 2014 Apr;44(4):766-75.

[5] Chess S. Follow-up report on autism in congenital rubella. J Autism Child Schizophr. 1977 Mar;7(1):69-81.

[6] Skidmore S. et al. Is the MMR vaccination programme failing to protect women against rubella infection? Epidemiol Infect. 2014 May;142(5):1114-7.

[7] Zerbo O. et al. Is maternal influenza or fever during pregnancy associated with autism or developmental delays? Results from the CHARGE (CHildhood Autism Risks from Genetics and Environment) study. J Autism Dev Disord. 2013 Jan;43(1):25-33.

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Razzaghi H, Oster M, & Reefhuis J (2014). Long Term Outcomes in Children with Congenital Heart Disease: National Health Interview Survey. The Journal of pediatrics PMID: 25304924

Autism, fetal alcohol syndrome and thyroid hormone?

Alcohol is the drug of choice for many people these days. For most, it's a case of the odd glass of wine here or there or a beer whilst sat outside in the garden during the summer we're supposed to be basking in at the moment.

The grape @ Wikipedia 

But there is no getting away from the fact that alcohol is a drug, and by all accounts, a drug which very readily impacts on the lives of many, many people. Outside of all the social ills associated with excessive alcohol consumption, there is also in some cases, a price to pay for infants born to those who drink alcohol to excess during pregnancy. The condition is called fetal alcohol syndrome or fetal alcohol spectrum disorder.

I've talked about FAS / FASD previously on this blog (see here). The crux of that post was the often confusing message sent out about how much alcohol is 'safe' to consume when a woman is pregnant and how one has to be very careful when presenting a potential link between FAS / FASD and a condition like autism.

Enter then a new study by Elif Tunc-Ozcan and colleagues* on the topic of a rodent model of FASD and some potentially interesting findings. There has already been some press discussion about this paper as per entries like this one.

Given the overlap between the presentation of FASD and autism (being very careful here), Tunc-Ozcan et al set out to see if they could identify some of the "molecular characteristics related to ASD in an animal model of FASD" to further inform both conditions. Rats were the participants of choice and as a starting point feeding pregnant rats one of a number of diets, one of which included supplementation with ethanol - the fancy chemical name for alcohol.

They then looked at the offspring of the various groups of rats based on examination of memory and social behaviours alongside the expression of certain genes tentatively related to autism in the hippocampus. They also looked at some of the facets of thyroid functioning as a function of supplementing one of the rat groups consuming ethanol with thyroxine. This last part stems from a body of work suggesting that in-utero exposure to alcohol might affect thyroid function which then subsequently impacts on facets of brain development**.

The results: well, keep in mind that this was a study of rats not humans, but alcohol did indeed impact on thyroid chemistry in exposed offspring. Males seemed to be particularly sensitive on measures of the behavioural effects of alcohol exposure. Talk about your fragile male. Quite a few of those candidate genes potentially involved in autism were also "significantly increased in the hippocampus of male offspring" exposed to alcohol.

Importantly, it seemed that co-administration of thyroxine with the inclusion of alcohol in the maternal diet seemed to have something of a protective effect on the areas studied in offspring. The word 'normalized' (North American spelling) is used to denote the various changes described.

As you might imagine, there is some interest in these results. I'll stress again that this was a study of rats and how rats are rats and not humans with all their complexities. The study authors have also made the important point that: "The study does not mean alcohol consumed by the mother is the cause of autism". With all the potential for stigma based on such results, I'll reiterate again that the authors are not saying that autism is caused by mothers drinking alcohol.

Again, I've talked about thyroid function with autism in mind quite a while back (see here). Within that entry was the suggestion (evidence-based suggestion***) that levels of thyroxine (T4) in the newborn might be to some degree linked to the risk of a later diagnosis of autism. One could also put this in the perspective of the results by Tunc-Ozcan and colleagues too.

I had a few additional thoughts about this study. I'm speculating so please humour me. I wondered for example, whether maternal consumption of alcohol talked about in this rat study might have had some more generalised effects on things like gut bacteria. It's quite widely known that alcohol is not great news for gut bacteria as per reports on consumption of alcohol and SIBO (see here). I'm speculating that this might also translate into potential effects for offspring too? Another even more outlandish thought for your consideration: auto-brewery syndrome. I know that this is not exactly an idea with a great deal of legal merit (see here) but the scientific literature is dotted with case studies suggesting that it can, and does happen**** as a consequence of some unusual fermentation in the deepest, darkest recesses. With all the focus on gut bacteria and autism, is it beyond the realms of possibility that something like this might show some subtle effect?

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* Tunc-Ozcan E. et al. Low-Dose Thyroxine Attenuates Autism-Associated Adverse Effects of Fetal Alcohol in Male Offspring's Social Behavior and Hippocampal Gene Expression. Alcohol Clin Exp Res. 2013 Jun 13. doi: 10.1111/acer.12183.

** Kornguth SE. et al. Impeded cerebellar development and reduced serum thyroxine levels associated with fetal alcohol intoxication. Brain Res. 1979; 177: 347-360.

*** Hoshiko S. et al. Are thyroid hormone concentrations at birth associated with subsequent autism diagnosis? Autism Res. 2011 Dec;4(6):456-63. doi: 10.1002/aur.219.

**** Dahsan A. & Donovan K. Auto-Brewery Syndrome in a Child With Short Gut Syndrome: Case Report and Review of the Literature. J Ped Gastroenterol Nutr. 2001; 33: 214-215.

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Tunc-Ozcan E, Ullmann TM, Shukla PK, & Redei EE (2013). Low-Dose Thyroxine Attenuates Autism-Associated Adverse Effects of Fetal Alcohol in Male Offspring's Social Behavior and Hippocampal Gene Expression. Alcoholism, clinical and experimental research PMID: 23763370

Fetal alcohol syndrome

Pregnancy is a special time for both prospective mum and dad. OK, dad's role is a little more 'peripheral' at this stage; more about support and understanding, doing that little more around the house - 'its called a washing machine' - and generally just being there when, for example, the words 'could you nip out and get me some pickled onions darling' are said late at night.

Pregnancy is also an important time for both foetal (English-spelling) and maternal health; as information comes thick and fast about health, diet, nutrition and exercise. So, lots of things to do (exercise, folic acid(!), etc) and lots of things to avoid (smoking, drinking alcohol, eating raw shellfish, old paintwork, etc). Whilst there is some good evidence behind these dos and don'ts, in recent times some of the suggestions have been the source of some debate. 


Take for example the advice about drinking alcohol during pregnancy. Down the years, there's been an almost operatic battle about what is and isn't a safe level of alcohol consumption during pregnancy. It seems some days expectant mums are advised no alcohol at all during pregnancy, other days reports come out saying a little moderate consumption is probably going to be alright. I can perhaps see how it all could be quite confusing (as per other health advice - see here). 


More confusion has arrived at the time of writing, as several studies have recently emerged looking at alcohol consumption during pregnancy and future offspring development (see here) followed by quite a few headlines such as this one from the BBC "Moderate drinking in early pregnancy branded 'safe'". I might add that I am not endorsing this or any other stance but would also direct readers to this post by the NHS Choices website for some balance regarding the publications in question.


I have to say that I always get a little bit nervous when something is 'branded safe'; thinking back to a certain British Politician and a daughter's hamburger a few years back. Indeed, these latest studies got me thinking about alcohol and pregnancy and how, if it is so safe, do we arrive at something called fetal alcohol syndrome (FAS). I want to talk about FAS with autism in mind but tread very, very carefully here so as not to make connections where none exist.


A short description first. FAS is quite a nebulous term characterised by quite a lot of different symptoms covering everything from cognitive and learning issues to specific facial features to other overlapping features more readily covered under the more general term fetal alcohol spectrum disorder (FASD). Some quite recent research (here) has reiterated the cognitive side of things as being central to the effects of alcohol exposure.


With autism - autistic behaviours - in mind, the research path goes something like this:

• Various cases of the presence of FAS and autism are dotted around the research landscape. So, this paper by Nanson* seems to be one the earliest, describing six cases of children with FAS who also "fulfill the criteria for diagnosis of autism". Followed in succession by this paper by Harris and colleagues** and a few others.
• I was drawn to this short reply by Eric Fombonne*** (click 'show summary') on the question of an association between FAS and autism in light of the previous findings. Drawn to it because some good issues are raised here, not least that autism is not universal to all children with FAS (2% of cases is the suggestion) and also that the other features normally accompanying FAS are not normally associated with autism. Indeed, there is a strong argument in this piece that the coincidence of autism in FAS is nothing more than just a chance finding as per the recent autism prevalence figures.
• Further analysis of the presentation of behavioural features in cases of autism vs. FASD has also revealed some interesting issues. Bishop and colleagues**** described a comparative study based on ADOS and ADI measures in both groups. They suggested that whilst social issues like appropriate behaviour and peer relationships were common between the groups, the core 'social affect' behaviours (as it will become) seem to be firmly rooted in autism not FASD. The lack of other control groups (speech and language delay, learning disability, etc) is a bit of a short-coming to this study but the results still hold up demonstrating differences between autism and FASD.

There are other papers mentioning autism and FAS / FASD but I have to say the suggestion of a link between these conditions is rather unimpressive based on the current data. That's not to say that certain behaviours linked to autism might not also be present in FAS / FASD, but that autism as a diagnostic package is likely not to show strong associations with these conditions.

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* Nanson JL. Autism in fetal alcohol syndrome: a report of six cases. Alcoholism, Clinical & Experimental Research. 1992; 16: 558-565.

** Harris SR. et al. Autistic behaviors in offspring of mothers abusing alcohol and other drugs: a series of case reports.. Alcoholism, Clinical & Experimental Research. 1995; 19: 660-665.

*** Fombonne E. Ask the Editor: Is exposure to alcohol during pregnancy a risk factor for autism? JADD. 2002; 32: 243.


**** Bishop S. et al. Re-examining the core features of autism: a comparison of autism spectrum disorder and fetal alcohol spectrum disorder. Journal of Child Psychology & Psychiatry & Allied Disciplines. 2007; 48: 1111-1121.