Breastfeeding and autism continued

"We found that the percentage of mothers who started breastfeeding was similar between the two groups, but mothers of children with ASD [autism spectrum disorder] breastfed for a shorter amount of time compared to mothers of children without ASD."

So said the findings reported by Gnakub Soke and colleagues [1] continuing a research theme that I've had some professional interest in down the years (see here) on whether breastfeeding (use, duration, etc) *might* have some important *links* to risk of offspring autism and/or related conditions (see here). The same caveats mention in some of my other musings on this topic come into effect when talking (briefly) about the Soke findings (i.e. no-one is saying that a lack of breastfeeding 'causes' autism). That being said, there might still however be some important science to do on how breastfeeding and/or the constituents of breast milk might have some important biological effects for the developing child (minus any psychobabble explanations).

The Study to Explore Early Development or SEED was the starting point for the Soke study (continuing an autism research theme), and specifically investigation into the: "associations between ASD and breastfeeding initiation (yes/no) and duration (months categorized in tertiles)." The findings suggested that (a) breastfeeding rates (initiation rates) were high in mums of children with ASD compared to not-autism controls (85% vs. 90%), and (b) "mothers of children with ASD were less likely to report duration of breastfeeding in the high (≥12 months) versus low tertile (<6 months)... or the middle (6-<12 months) versus low tertile."

I don't want to dwell too much on the whys-and-wherefores of the Soke findings but there are some important questions that need answering. Not least the question of why breastfeeding seems to end quicker for those mums of children who were subsequently diagnosed as having an ASD. Were these infants more difficult to feed (something which Kanner might have picked up on in his seminal paper describing autism)? What role does the presentation of the 'broader autism phenotype' (BAP) in mothers mentioned by Soke et al play in such findings? That last point in particular, draws on the need for lots more research into the experience of pregnancy and motherhood with the BAP (see here) and/or autism in mind (see here).

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[1] Soke GN. et al. Association Between Breastfeeding Initiation and Duration and Autism Spectrum Disorder in Preschool Children Enrolled in the Study to Explore Early Development. Autism Res. 2019 Mar 9.

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Breastfeeding and ADHD meta-analysed

Readers are asked to consider this post discussing the findings from Ping-Tao Tseng and colleagues [1] concerning breastfeeding and offspring attention-deficit hyperactivity disorder (ADHD) risk, an extension of other blogging chatter on the topic of breastfeeding and other offspring developmental outcomes (see here). The connections? Well, yes, both posts emphasise a possible *association* between breastfeeding and offspring development, but perhaps just as important, both posts will also emphasise how correlation is not necessarily the same as causation and how one has to be careful about making sweeping assumptions when it comes to breastfeeding *choice*...

Same as on the previous paper by Tseng and colleagues [2] I'll mention having a minor part to play in authoring the latest Tseng paper, and how such participation will in no way interfere with my hopefully critical musings on this latest publication.

The name of the research game this time around was to 'meta-analyse' the currently available collected peer-reviewed research literature into some sort of coherent 'where we're at' statement on the topic of breastfeeding practices and offspring ADHD risk. This wasn't about 'making' any new data; just synthesising what is already there on some specific topics: "(1) the difference in the duration of maternal breastfeeding between children with and without ADHD, and (2) the association between maternal breastfeeding and ADHD in children." A total of 11 articles pertinent to those research questions were identified and information was 'boiled down'.

Results: "an association was found between non-breastfeeding and ADHD children (adjusted OR = 3.71, 95% CI = 1.94 to 7.11, p < 0.001)." At first glance this looks like a pretty impressive *relationship* between 'non-breastfeeding' and the presence of a diagnosis of ADHD in offspring. It is, but it might not necessarily mean what you first think. Authors do mention how the early presentation of certain ADHD or possibly related traits might not have been conducive to successful breastfeeding behaviour to the point where a lack of 'cooperation' could have led to less breastfeeding. I'm not saying this is THE reason for the results we reported; merely that it is one possibility to entertain. There may also be other factors to take into consideration too (see here for example) minus any sweeping generalisations.

Whilst I am cautious about making too much of the Tseng findings - subsequent individual studies have reported no link [3] - other, more recent meta-analyses have arrived at similar conclusions to Tseng [4]. Yes, the Zeng paper [4] looked specifically at breastfeeding duration, and yes it was a meta-analysis that overlapped with material used in the Tseng study. But the conclusion - "maternal breastfeeding may reduce the risk of ADHD in children" - is similar, and again suggests closer inspection of any possible relationship specifically focused on the hows-and-whys.

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[1] Tseng PT. et al. Maternal breastfeeding and attention-deficit/hyperactivity disorder in children: a meta-analysis. Eur Child Adolesc Psychiatry. 2018 Jun 15.

[2] Tseng PT. et al. Maternal breastfeeding and autism spectrum disorder in children: A systematic review and meta-analysis. Nutr Neurosci. 2017 Oct 18:1-9.

[3] Schwenke E. et al. Predicting attention deficit hyperactivity disorder using pregnancy and birth characteristics. Arch Gynecol Obstet. 2018 Nov;298(5):889-895.

[4] Zeng Y. et al. Association between the different duration of breastfeeding and attention deficit/hyperactivity disorder in children: a systematic review and meta-analysis. Nutr Neurosci. 2018 Dec 21:1-13.

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Breastfeeding and autism meta-analysed

"This meta-analysis provides evidence that breastfeeding (exclusively or including additional supplements) may protect against ASD [autism spectrum disorder]. Prospective longitudinal research is required to disentangle the complex relationships and to explore potential pathophysiological mechanisms."

So said the systematic review and meta-analysis published by Ping-Tao Tseng and colleagues [1] covering a [complicated] topic that has been discussed on this blog before (see here). I should mention that I was part of the 'and colleagues' bit to this latest paper; something that will in no way interfere with my hopefully critical musings on this latest publication.

Bearing in mind "a controversial relationship between ASD and breastfeeding" that exists in the peer-reviewed literature and the strong requirement not to make new mums feel bad just because they don't want to or can't breastfeed, the aim of the meta-analysing game was to synthesise the collected research literature into something like a coherent 'where we're at' statement. Seven studies out of a possible 20 were included for review, together including nearly 1500 children diagnosed with ASD and nearly 1200 not-diagnosed-with-autism controls.

Results: "Cumulatively, children with ASD, either in the form of clinical diagnosis or self-report, were significantly less likely to have been breastfed than children without ASD." I should add that 'self-report' refers to parents reporting on their child receiving a diagnosis of autism but not necessarily being independently confirmed by researchers or medical records. The strength of the association/effect was not to be sniffed at; with results even holding up when taking into account those "who were breastfed with additional supplementation."

Another important quote: "one should note the observational nature of these preliminary findings, whereby causation can clearly not be determined." What this means is that whilst variable A (breastfeeding) and variable B (autism or ASD) might be *associated* it is nigh on impossible to definitively say whether variable A *causes* or *protects against* variable B on the basis of the studies analysed. I might also suggest that the call for 'prospective longitudinal research' is also not likely to provide a definitive answer any time soon either, when taking into account how many other variables might be associated with risk of offspring autism and indeed, the plurality of the label and some related discussions on that topic (see here and see here). It's also noteworthy that autism rarely exists in some sort of diagnostic vacuum (see here) and how breastfeeding trends might be important there too [2] thus complicating any 'causative' picture.

Still, the Tseng results do provide some further information about this issue and a reiteration of the value of breastfeeding for many different reasons. Other studies have arrived at a similar conclusion insofar as the impact that breastfeeding *might* have on 'autistic traits' [3]; again, with more research to do.

Mechanisms of effect? Well, once again we're faced with a 'we don't know yet' scenario. Tseng et al speculated on various possible factors linked to breastfeeding and breast milk 'ingredients' that may be important (neurotrophic factors, oxytocin, fatty acid constitution, casomorphins) and could conceivably impact on risk of offspring autism. I'm also minded to add in the idea that the early presentation of autism in the first months of life [for some] could also potentially affect breastfeeding patterns; perhaps making breastfeeding practices more difficult and/or contributing to the early cessation of breastfeeding in some cases. Relevant mechanisms are likely to be complicated.

I appreciate that not everyone is going to be enthralled with this study or topic - no, it doesn't say that a lack of breastfeeding causes all autism - particularly when words like "protect against ASD" are also included in the text. All I can say is that we faithfully looked at the existing peer-reviewed research available to us in this area and went where the data instructed us to do so without fear or favour...

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[1] Tseng P-T. et al. Maternal breastfeeding and autism spectrum disorder in children: A systematic review and meta-analysis. Nutritional Neuroscience. 2017. Oct 18.

[2] Bar S. et al. Long-term neurodevelopmental benefits of breastfeeding. Curr Opin Pediatr. 2016 Aug;28(4):559-66.

[3] Boucher O. et al. Association between breastfeeding duration and cognitive development, autistic traits and ADHD symptoms: a multicenter study in Spain. Pediatr Res. 2017 Mar;81(3):434-442.

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Breastfeeding and autism (or autistic traits) continued?

"After adjustment for several confounders, longer duration of breastfeeding was independently associated with better cognitive development and with fewer autistic traits."

So said the paper by Olivier Boucher and colleagues [1] communicating findings based on the examination of data from "the INMA Project, a Spanish multicenter birth-cohort study" (an initiative that has cropped up on this blog before).

Including over 1300 children who were subject to a battery of psychometric and behavioural assessments, researchers set about examining how various scores might be 'associated' with breastfeeding patterns: "Duration of any, predominant, and exclusive breastfeeding." The results as I've mentioned, seemed to show something of a connection between breastfeeding and particularly when it came to 'autistic traits' as assessed by the Childhood Autism Spectrum Test (CAST). I'll leave readers to draw their own conclusions about the relevance of this finding. Insofar as the more general conclusion on breastfeeding potentially aiding offspring cognitive development, well, let's just say that this has previously been mentioned before in the research literature (see here).

Having talked about breastfeeding in the context of autism before on this blog (see here) I don't really want to head too far into the collected literature in this area alongside the other aspects/discussions that it draws in. All I will say is that the relationship between breastfeeding patterns and offspring autism/autistic traits is not likely to be straight-forward [2] (few things with regards to autism research ever are) and there could even be occasions when breast milk might not be the preferred option* (see here) (*I should reiterate that I am not providing medical or clinical advice on this blog). There are, for example, a multitude of potentially confounding variables that could impact on any association between the two; not least that early manifestations of offspring autism might already be present and impacting on the ease of breastfeeding practices during the very earliest days and weeks of infancy. I'm not gonna say too much more on this topic at this time but will perhaps return to the subject in future posts.

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[1] Boucher O. et al. Association between breastfeeding duration and cognitive development, autistic traits and ADHD symptoms: a multicenter study in Spain. Pediatr Res. 2016 Nov 15.

[2] Penn AH. et al. Breast Milk Protects Against Gastrointestinal Symptoms in Infants at High Risk for Autism During Early Development. J Pediatr Gastroenterol Nutr. 2016 Feb;62(2):317-27.

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Boucher O, Julvez J, Guxens M, Arranz E, Ibarluzea J, Sánchez de Miguel M, Fernández-Somoano A, Tardon A, Rebagliato M, Garcia-Esteban R, O'Connor G, Ballester F, & Sunyer J (2016). Association between breastfeeding duration and cognitive development, autistic traits and ADHD symptoms: a multicenter study in Spain. Pediatric research PMID: 27846197

Breast milk protects against GI symptoms in high risk autism?

Happy house @ Paul Whiteley

"Late weaning and EBM [exclusive breast milk] were associated with protection against GI [gastrointestinal] symptoms in High-risk infants."

That was one of the conclusions presented in the paper by Alexander Penn and colleagues [1] who asked some pretty important questions when it comes to the increasingly strong relationship between bowel issues and autism spectrum disorder (ASD) (see here).

"Using questionnaires, diet history and gastrointestinal problems were tracked prospectively and retrospectively in 57 High-risk infants, and for comparison, in 114 Low-risk infants (infants from families without ASD history)." The main aims of this study were to examine whether those at an enhanced risk for autism by virtue of having a sibling already diagnosed were at any greater risk of presenting with functional bowel symptoms, and whether such bowel issues were "associated with diet and age at weaning from breast milk."

Early weaning - the introduction of solid foods to an infant - seemed to be more frequently present in high-risk infants with bowel issues as did "a no breast milk (NBM) diet" compared with an exclusive breast milk diet. This was particularly true for the bowel symptom constipation and especially for those who were weaned earlier than 6 months of age.

The authors suggest that their data indicate that weaning and breast milk diet practices might have some bearing for the presentation of bowel symptoms in those at high-risk for autism. Further: "The greater prevalence of GI symptoms in High-risk infants suggests that GI dysfunction during early infant development may be a part of the ASD endophenotype." That all sounds rather important.

I'm drawing back from making too many sweeping statements about this research bearing in mind the participant number, the use of the term 'high-risk' and elements of the questionnaire design of the study. There is quite a bit more research required in this area.

That all being said, I do think there are more than a few future studies that might come from such findings. So, thinking back to the paper by Afzal and colleagues [2] and the idea that "consumption of milk to be the strongest predictor of constipation" among their cohort diagnosed with autism, is the suggestion that more attention might be needed for specific elements of the diet such as cows milk. Added to the findings from Kushak and colleagues [3] (see here for a past post on this work) regarding lactose intolerance as being pretty rife in their cohort with autism (importantly, "not identified by clinical history"), and clues start to emerge alongside possible alternative strategies (see here and see here)...

Music: Stevie Wonder - Superstition.

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[1] Penn AH. et al. Breast Milk Protects Against Gastrointestinal Symptoms in Infants at High Risk for Autism During Early Development. J Pediatr Gastroenterol Nutr. 2015 Jul 29.

[2] Afzal N. et al. Constipation with acquired megarectum in children with autism. Pediatrics. 2003 Oct;112(4):939-42.

[3] Kushak RI. et al. Intestinal disaccharidase activity in patients with autism: effect of age, gender, and intestinal inflammation. Autism. 2011 May;15(3):285-94.

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Penn AH, Carver LJ, Herbert CA, Lai TS, McIntire MJ, Howard JT, Taylor SF, Schmid-Schönbein GW, & Dobkins KR (2015). Breast Milk Protects Against Gastrointestinal Symptoms in Infants at High Risk for Autism During Early Development. Journal of pediatric gastroenterology and nutrition PMID: 26230900

Coeliac disease risk not affected by early feeding practices

I'd like to bring three papers to your attention, all united by their discussion of coeliac (celiac) disease, that most classic of autoimmune conditions in the most part managed by the use of a lifelong gluten-free diet.

First up are the papers by Elena Lionetti and colleagues [1] and Sabine Vriezinga and colleagues [2] which unfortunately pour cold water on the notion that the risk of developing coeliac disease (CD) can be somehow mitigated via the use of either the early or delayed introduction of gluten nor seemingly affected by breastfeeding habits. Indeed, as science has known about for sometime, genes and specifically the HLA genotype linked to CD, seem to be the important predictors of disease outside of gluten consumption itself.

Both the Lionetti and Vriezinga papers were published in the New England Journal of Medicine and were accompanied by an editorial by Jonas Ludviggson among others (he of the 'not CD but something else potentially linking gluten and some autism'). Both studies were based on randomised controlled trials.

The Lionetti study involved either the introduction of gluten at 6 or 12 months to at-risk infants (those with a first-degree relative with CD) and then examining: "the prevalence of celiac disease autoimmunity and of overt celiac disease among the children at 5 years of age". The numbers of participants involved featured in the hundreds so this was by no means an under-powered trial. The authors concluded that: "Neither the delayed introduction of gluten nor breast-feeding modified the risk of celiac disease among at-risk infants, although the later introduction of gluten was associated with a delayed onset of disease".

The Vriezinga study looked at whether introducing gluten early (between 4-6 months) might also offset the risk of CD. Again based on a pretty impressive participant number (N=944) comprising children with a first-degree relative with CD as well as being "positive for HLA-DQ2 or HLA-DQ8", participants were randomly assigned to either "100 mg of immunologically active gluten daily" or a placebo. Again, biopsy confirmed CD and some of the various serology associated with CD were the outcomes. The authors concluded: "As compared with placebo, the introduction of small quantities of gluten at 16 to 24 weeks of age did not reduce the risk of celiac disease by 3 years of age in this group of high-risk children".

The final paper to discuss today is that published by Elfström and colleagues [3] (open-access here) and the findings of their systematic review and meta-analysis looking at "associations between coeliac disease and type 1 diabetes". Type 1 diabetes, distinct from type 2 diabetes, is an autoimmune condition whereby the insulin producing cells of the body have been destroyed. The Elfström paper coincidentally carrying Dr Ludviggson as a co-author, concluded that: "More than one in twenty patients with type 1 diabetes have biopsy-verified coeliac disease" and onwards that there may be some substance to the idea that birds of an autoimmune feather flock together (see here). Indeed, I've previously covered the possibility of a connection between Type 1 diabetes and CD (see here) and how, for example, some of the research on [General] zonulin might be potentially very informative to this area (see here).

There's little more for me to say in this post aside from reiterating that when it comes to CD, genotype combined with gluten exposure seems to be the most important factors in disease onset and progression. That's not to say that a gluten-free diet might be the only tool in the management arsenal (see here) nor that other variables might not potentially impact on CD risk (see here) but for now, screening and where indicated, gluten avoidance, seem to be the primary measures to be undertaken.

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[1] Lionetti E. et al. Introduction of Gluten, HLA Status, and the Risk of Celiac Disease in Children. N Engl J Med. 2014 Oct 2;371(14):1295-1303.

[2] Vriezinga SL. et al. Randomized Feeding Intervention in Infants at High Risk for Celiac Disease. N Engl J Med. 2014 Oct 2;371(14):1304-1315.

[3] Elfström P. et al. Systematic review with meta-analysis: associations between coeliac disease and type 1 diabetes. Aliment Pharmacol Ther. 2014 Oct 1. doi: 10.1111/apt.12973.

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Lionetti E, Castellaneta S, Francavilla R, Pulvirenti A, Tonutti E, Amarri S, Barbato M, Barbera C, Barera G, Bellantoni A, Castellano E, Guariso G, Limongelli MG, Pellegrino S, Polloni C, Ughi C, Zuin G, Fasano A, Catassi C, & the SIGENP (Italian Society of Pediatric Gastroenterology, Hepatology, and Nutrition) Working Group on Weaning and CD Risk (2014). Introduction of Gluten, HLA Status, and the Risk of Celiac Disease in Children. The New England journal of medicine, 371 (14), 1295-1303 PMID: 25271602



Vriezinga SL, Auricchio R, Bravi E, Castillejo G, Chmielewska A, Crespo Escobar P, Kolaček S, Koletzko S, Korponay-Szabo IR, Mummert E, Polanco I, Putter H, Ribes-Koninckx C, Shamir R, Szajewska H, Werkstetter K, Greco L, Gyimesi J, Hartman C, Hogen Esch C, Hopman E, Ivarsson A, Koltai T, Koning F, Martinez-Ojinaga E, Te Marvelde C, Pavic A, Romanos J, Stoopman E, Villanacci V, Wijmenga C, Troncone R, & Mearin ML (2014). Randomized Feeding Intervention in Infants at High Risk for Celiac Disease. The New England journal of medicine, 371 (14), 1304-1315 PMID: 25271603



Elfström P, Sundström J, & Ludvigsson JF (2014). Systematic review with meta-analysis: associations between coeliac disease and type 1 diabetes. Alimentary pharmacology & therapeutics PMID: 25270960

Neonatal jaundice and risk of autism?

The research of Mu-Hong Chen and colleagues from Taiwan appears on this blog quite a bit. Regular readers may already have read about the work of this group looking at various aspects on and around autism including the association with allergic and autoimmune conditions (see here) and the possibility of a link between asthma and ADHD (see here). Much of the strength of the data and results produced by this group lies in their examination of the National Health Insurance Research Database (NHIRD) which covers a large proportion of the Taiwanese population. Big data in action you might say, bearing in mind correlation and causation are not the same thing.

Chen Chengpo @ Wikipedia 

A further publication by Chen and colleagues [1] adds to the research collection from this group and their suggestion that: "Newborn exposure to hyperbilirubinemia was related to the increased risk of developing ASD [autism spectrum disorder], any developmental delay, and developmental speech or language disorder in later life". This conclusion was reached on the basis of an examination of some 2000 newborns presenting with neonatal jaundice compared with over 8000 matched controls without, following up on the subsequent rates of autism and other developmental diagnoses such as ADHD et al. Aside from the autism correlation, the authors also reported that phototherapy - treatment with light for newborn jaundice - was probably not going to be a significant factor in the suggested relationship. Just in case you need some more background about jaundice, I might refer you to quite a good, quite recent, overview (see here).

Hyperbilirubinemia leading to jaundice has been talked about a while back on this blog (see here). Since that post in early 2011, several other papers have been published which, on the whole, have suggested that jaundice might indeed be something to look at with autism risk in mind. The systematic review from Amin and colleagues [2] is quoted as suggesting: "jaundice, assessed by total serum bilirubin (TSB), was associated with ASD" based on data from several other research reports. Further, Mamidala and colleagues [3] reported that based on their analysis of pregnancy and birth-related variables in relation to autism offspring risk, the presence of neonatal jaundice was one of the more marginally significant associations found in their cohort. Even further, Froehlich-Santino and colleagues [4] talked about neonatal jaundice and autism risk in the context of sex differences: "jaundice was associated with an increased risk for ASDs in females".

Bearing in mind that not every study has reported a connection between neonatal jaundice and autism, or at least neonatal hyperbilirubinemia [5] and the quite high frequency of jaundice in newborns present in the population as a whole, one needs to treat any association with a degree of caution. That being said, data is data and results are results so some further inspection is perhaps indicated in this area.

When I posted the details of the Chen study to Facebook, it led to an interesting stream of comments and discussions about the meaning of the jaundice correlation and how it may play into some other areas in relation to autism. The genetic condition Gilbert's syndrome was mentioned as a function of jaundice being a primary manifestation there. This fairly common condition, affecting between 5-10% of the population, is not life-threatening (indeed might even be protective against the risk of other conditions). I was particularly interested in some of the biochemistry behind Gilbert's syndrome and the suggestion that the process of glucuronidation is affected in cases [6]. It jogged my memory of a recent post where I discussed the work of Stein and colleagues [7] and how reduced glucuronidation was observed in their cohort of children with autism, suggesting that sulphation might not be the only pathway with an autism connection.

Another commentator also posted an interesting question about how neonatal jaundice might also tie into the practice of breastfeeding and subsequently impact on autism risk. Just so you know, breastmilk jaundice is a recognised entity and is thought to be due to either inadequate milk intake leading to dehydration or components of breastmilk affecting the metabolism of bilirubin [8]. The discussion led to the paper by Mary Clark [9] and her opening line: "Breastfed infants are more likely to be jaundiced than infants who are formula fed" which subsequently led to the question: "does that mean that breastfeeding causes autism?". Now, I don't want to venture too far into the issue of 'bitty' and autism (see here) or make any sweeping generalisations about what may or may not be associated with the onset of autism but do feel that this question warrants more research attention. I note the paper from Al-Farsi and colleagues [10] who reported an "increased ASD risk is generally associated with suboptimal breast-feeding practices" and that's all I'm going to say on the matter at present.

If there is some take-home message from this post, it is that alongside the body of literature talking about the potential adverse effects of neonatal jaundice, hyperbilirubinemia [11] even in the very long term [12] it would perhaps be wise not to overlook some effect yet falling into the description of the autism spectrum, with the requirement for quite a bit more investigation.

Music then... since we are almost there, Summertime by Ella and Louis, best enjoyed looking out onto a sunny meadow sipping something cold and chatting about Eurovision.

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[1] Chen M-H. et al. Is neonatal jaundice associated with autism spectrum disorder, attention deficit hyperactivity disorder, and other psychological development? A nationwide prospective study. Res Autism Spec Disord. 2014; 8: 625-632.

[2] Amin SB. et al. Is neonatal jaundice associated with Autism Spectrum Disorders: a systematic review. J Autism Dev Disord. 2011 Nov;41(11):1455-63.

[3] Mamidala MP. et al. Prenatal, perinatal and neonatal risk factors of Autism Spectrum Disorder: a comprehensive epidemiological assessment from India. Res Dev Disabil. 2013 Sep;34(9):3004-13.

[4] Froehlich-Santino W. et al. Prenatal and Perinatal Risk Factors in a Twin Study of Autism Spectrum Disorders. J Psychiatr Res. 2014. March 29.

[5] Croen LA. et al. Neonatal hyperbilirubinemia and risk of autism spectrum disorders. Pediatrics. 2005 Feb;115(2):e135-8.

[6] de Morais SM. et al. Decreased glucuronidation and increased bioactivation of acetaminophen in Gilbert's syndrome. Gastroenterology. 1992 Feb;102(2):577-86.

[7] Stein TP. et al. Autism and phthalate metabolite glucuronidation. J Autism Dev Disord. 2013 Nov;43(11):2677-85.

[8] Hargreaves T. & Piper RF. Breast Milk Jaundice. Arch Dis Child. Apr 1971; 46(246): 195–198.

[9] Clark M. Clinical update: understanding jaundice in the breastfed infant. Community Practitioner. 2013; 86: 42-45.

[10] Al-Farsi YM. et al. Effect of suboptimal breast-feeding on occurrence of autism: a case-control study. Nutrition. 2012 Jul;28(7-8):e27-32.

[11] Seidman DS. et al. Neonatal hyperbilirubinemia and physical and cognitive performance at 17 years of age. Pediatrics. 1991 Oct;88(4):828-33.

[12] Hokkanen L. et al. Adult neurobehavioral outcome of hyperbilirubinemia in full term neonates-a 30 year prospective follow-up study. PeerJ. 2014 Mar 4;2:e294.

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Chen, M., Su, T., Chen, Y., Hsu, J., Huang, K., Chang, W., Chen, T., & Bai, Y. (2014). Is neonatal jaundice associated with autism spectrum disorder, attention deficit hyperactivity disorder, and other psychological development? A nationwide prospective study Research in Autism Spectrum Disorders, 8 (6), 625-632 DOI: 10.1016/j.rasd.2014.03.006

Dioxin exposure and autistic traits?

As promised in a previous post, today I'm turning my attention to the paper by Muneko Nishijo and colleagues [1] and their conclusion of "a specific impact of perinatal TCDD [2,3,7,8-tetrachlorodibenzo-p-dioxin] on autistic traits in childhood, which is different from the neurotoxicity of total dioxins (PCDDs/Fs) [polychlorinated dibenzo-p-dioxins/furans]".

TCDD @ Wikipedia 

With all the recent chatter about [surrogate] environmental markers and the numbers of cases of autism spectrum disorders and environmental toxicants and autism risk it is indeed timely that the Nishijo paper comes to publication now. Environmental factors, however you wish to define this, are certainly no stranger to autism research, and are fast finding a place in the autism research psyche, perhaps in part due to the rise and rise of the science of epigenetics (see here) as a bridge between genetics and environment. Genes, or rather the blueprint that is your genome, might not necessarily be your destiny and all that jazz...

The Nishijo paper in a little more detail:

• Set in Vietnam, which it has to be said, has seen more than its fair share of chemical exposures in recent history, the authors looked at the possibility of perinatal dioxin exposure being linked to the presence of autistic traits based on a sample of 153 infants. This follows other work by this group looking at dioxin exposure and more generalised infant neurodevelopment [2] as part of a wider research agenda. Dioxins for those who might not know, are categorised as environmental pollutants, and because of their biological persistence, are deemed pretty hazardous to human and other animal health (see the WHO fact sheet here). It's accurate that I mentioned Agent Orange in reference to the chemical load witnessed in Vietnam because Agent Orange was contaminated with TCDD - the chemical name for dioxin -  and there are some very scary quotes about TCDD being for example "perhaps the most toxic molecule ever synthesized by man". The US IOM report 'Veterans and Agent Orange' provides some sober reading on the topic.
• Scare tactics aside, the authors assessed the levels of TCDD in breast milk as part of a larger analysis of various other dioxins (PCDDs, PCDFs) based on analysis of samples via GC-MS. Actually quite a good overview of their methods can be found in another paper by this group [3] (open-access). Data from these analyses were transformed to form something called the TEQ (Toxic Equivalent) which basically gives you some idea of the toxicity of these classes of compounds relative to TCDD. TCDD has a value of 1 so setting the gold standard of toxicity. 
• Offspring were followed-up based on the use of the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) and specifically with autism in mind, the Autism Spectrum Rating Scales (ASRS).  
• Results: exposure groups (mild and high) were determined according to a cut-off level of 3.5 pg/g fat of TCDD being detected and results were reported according to gender. So: "The high-2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposed groups... showed significantly higher Autism Spectrum Rating Scale (ASRS) scores for both boys and girls than the mild-TCDD exposed groups, without differences in neurodevelopmental scores". This indicates some kind of dose-dependent relationship between TCDD exposure and autistic traits in study participants. When it came to looking at any connection between other PCDDs/Fs and autistic traits, nothing significant was picked up. Ergo, TCDD exposure seemed to have specifically impacted on infant autistic traits.

These are interesting results, of that there is no doubt. I could start to go on about correlation not being the same as causation, or how the ASRS might not necessarily have been the best instrument to use in this particular instance given it being standardised on American children and not officially translated into Vietnamese. That also it is not a professionally-administered instrument is another potential gap. But I'm not going to let all that get too far in the way of the Nishijo findings.

I see from some of the additional data from this paper that there were some other differences noted across the high and mild TCDD exposure groups which may be relevant to the results. When comparing boys and girls in the high and mild exposure groups, I note that mean birth weight was lower in the high exposed group compared to the mild exposed group (average 2920g vs. 3298g respectively) for boys. Realising that low birth weight is not an exclusively autism-correlated phenomena (see here) one might however consider this to be something which could potentially have affected the results obtained.

As per the discussions about the geographical location of this study [4], one of the question which then needs to be asked is whether the possibility of a TCDD exposure link is something applicable to other areas and other cases of autism/autistic traits. I'm no expert on TCDD so cannot readily answer this question aside from directing you to some data from the US Environmental Protection Agency on sources of TCDD. It does appear that there are quite a few potential sources of TCDD; although food seems to be the most widely cited source of exposure in modern times. By saying that I'm not trying to panic anyone, given that many countries do monitor foods for dioxin levels (see here) and act accordingly when high levels are detected.

Still, if we assume that there may be many roads towards a diagnosis of autism or the presentation of autistic traits, and that those roads may not be the same in every part of the world, the Nishijo results make for an interesting addition to the research landscape. As to mechanisms of effect, well take your pick; TCDD is categorised an endocrine disruptor so potentially falling into the same type of effect as that discussed by Rzhetsky and colleagues [5]. I also note some research chatter about TCDD and GABA [6] with specific mention of GAD (see here for some description of what this is). Jumping on the epigenetics bandwagon however, one might also suggest some further inquiry in that area if results like those by Manikkam and colleagues [7] are anything to go by, bearing in mind the continued focus on sperm and eggs and autism risk. That all being said, I don't doubt that it's going to be a complicated effect from TCDD with various factors involved.

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[1] Nishijo M. et al. 2,3,7,8-Tetrachlorodibenzo-p-dioxin in breast milk increases autistic traits of 3-year-old children in Vietnam. Mol Psychiatry. 2014 Mar 18.

[2] Tai PT. et al. Dioxin exposure in breast milk and infant neurodevelopment in Vietnam. Occup Environ Med. 2013 Sep;70(9):656-62.

[3] Nishijo M. et al. Impact of perinatal dioxin exposure on infant growth: a cross-sectional and longitudinal studies in dioxin-contaminated areas in Vietnam. PLoS One. 2012;7(7):e40273.

[4] Banout J. et al. Agent orange footprint still visible in rural areas of central Vietnam. J Environ Public Health. 2014;2014:528965.

[5] Rzhetsky A. et al. Environmental and state-level regulatory factors affect the incidence of autism and intellectual disability. PLoS Comput Biol. 2014 Mar 13;10(3):e1003518.

[6] Hays LE. et al. Evidence that GABAergic neurons in the preoptic area of the rat brain are targets of 2,3,7,8-tetrachlorodibenzo-p-dioxin during development. Environ Health Perspect. 2002 Jun;110 Suppl 3:369-76.

[7] Manikkam M. et al. Dioxin (TCDD) Induces Epigenetic Transgenerational Inheritance of Adult Onset Disease and Sperm Epimutations. PLoS ONE. 2012; 7(9): e46249.

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Nishijo M, Pham TT, Nguyen AT, Tran NN, Nakagawa H, Hoang LV, Tran AH, Morikawa Y, Ho MD, Kido T, Nguyen MN, Nguyen HM, & Nishijo H (2014). 2,3,7,8-Tetrachlorodibenzo-p-dioxin in breast milk increases autistic traits of 3-year-old children in Vietnam. Molecular psychiatry PMID: 24637425

Caesarean section and coeliac disease?

"Here I go again on my own". So went the lyrics to the song from Whitesnake, a band formed in the bracing breeze of the North East of England. Hair, yes they had lots of that. The Bruce Willis muscle vest, yes they had that too and the spandex trousers. Despite confessing a degree of infatuation with the 1980's rock scene, I am not devoting another post to it. Rather this is another post (hence, here he goes again) on risk and possible association with that old favourite, coeliac disease; this time with birth by caesarean section (c-section).

The papers in question are this one published in Pediatrics (full-text) and this more descriptive article published in the journal Gut Microbe (again full-text here) from the same author group which suggested that those born by c-section were at greater risk of developing coeliac disease. I hopefully am not going to gross out my (male) readers too much with my brief description of the c-section: an incision made in the front wall of the abdomen and womb to gain access (and give exit) to the infant, all under appropriate anaesthetic of course. Planned c-sections are not normally done under epidural or spinal block, and generally accompanied by the words "you might feel a bit of pulling and tugging" as operation 'delivering baby' commences. There are lots of different reasons for a c-section; not least multiple births (twins, triplets, etc), a breech presenting baby or in emergency cases, where for example, labour is not progressing or there is some immediate risk to the baby.

C-section born babies tend to be a little more 'baby-like' when they make an appearance because they don't have to travel through the rather cramped birth canal where they can sometimes get a bit of a 'conehead' and some bruising (which is not generally permenant I might add). One of the bonuses however of this often quite difficult journey, aside from clearing the airways, is that baby picks up quite a bit of mum on the way down in the form of various bacteria colonising the route some of which has been suggested to be protective against a few things in later life. It is with this in mind that the studies of interest have focussed on.

Getting back to those studies then. The main Pediatrics paper did the science-y bit analysing data from nearly 2000 live births. They compared the birth experience of several groups: those diagnosed with coeliac disease (CD), those with Crohn's disease, those with ulcerative colitis, those with GI disease (not otherwise specified) and asymptomatic controls free of gastrointestinal disease. There is a slightly different detail to this paper in that they use the acronym CD to denote Crohn's disease whereas I use it to denote coeliac disease.

The authors report a few important findings:

• The rate of caesarean section deliveries is on the rise (15% increase between 1991 and 2007).
• Rates of c-section delivery were elevated in CD compared with the control sample (OR: 1.83, CI: 1-18-2.85).  
• Whilst breastfeeding rates were fairly similar across the groups, children with CD showed the highest rates of breastfeeding (86.6%) and for the longest period too (mean 5.18 months) despite birth by c-section being associated with a decreased likelihood of being breastfed.
• The male:female ratio was quite a bit less even across the CD group compared with the other groups (65% female).

There are a few elements of these results which are perhaps slightly counter-intuitive and have been highlighted by the study authors. The main ones being the fact that picking up mum's bacteria via a natural delivery may offer some degree of protection against CD above and beyond other inflammatory bowel diseases given the links that have been made between bacteria and such conditions. Also is the issue of breastfeeding, which despite being highest and longest for the CD group did not seem to offer very much in the way of enhanced protection against developing CD. I should perhaps add at this point that timing of gluten introduction may also have played a role here.

I have already posted on breastfeeding in relation to autism and so am not going to make too much more of this side of the data. The possible protective effects of a non c-section birth against developing CD are interesting and coincide with similar data. Other studies have for example, looked specifically at the bacterial differences between c-section and non c-section babies and reported higher levels of total gut bacteria and, in particular, higher levels of Bifidobacteria. There is also some initial evidence that certain strains of Bifidobacteria might have the ability to alter the inflammatory effects caused by gliadin (at least in the petri dish) which would fit in with the results obtained in the Pediatrics study. Added to the fact that CD is associated with perturbed Bifidobacterial colonisation, the link perhaps gets stronger (at least with regards to Bifidobacteria).

This for me is a very interesting area of research, which provides a fascinating look into how mother nature and our environment shape our very complicated lives from beginning to end. I have touched upon the concept of 'risk' before and the obvious caveat that risk is by no means equivalent to certainty. In this case, non c-section delivery reduced the risk of developing CD but so might lots of other variables, known and unknown; not least the fact that we all seem to host our own unique(?) bacterial profile influenced by lots of different things including our environment and psychology.

Bitty and autism

'I want bitty' says Harvey, the archetypal Peter Pan 'mummy's boy'.

Most people in the UK who have watched the comedy show Little Britain will know about Harvey and his constant desire for 'bitty'. For those who are perhaps unfamiliar with our quite eccentric humour here in the UK (we did of course bring the world the Ministry of Silly Walks), bitty in this case, is slang for breastfeeding or breast milk. Harvey is a character who despite being a grown-up, well-to-do man with a fiancee, still quite enjoys being breastfed by his mum, having never quite moved out of his infancy on this issue. The character is a parody for all those people out there - mostly men - who despite being quite capable, refuse to grow up and break from 'mummy's apron strings'. For the mums also who want to keep their precious at that age when the bond was so close.

Anyway. A while back I posted an 'other musings' entry on early infant feeding practices in light of the disparity of views of when to start weaning children from milk to food. One of the debates included as part of that story was the issue of breastfeeding. On purpose I did not get into the nitty-gritty debate of 'breast vs. bottle' being as I am the wrong gender to comment and respectful of the fact that such a decision is a matter of personal, informed choice or in some cases no choice. I am however interested in the various research into breastfeeding with regards to autism and lots of other childhood and developmental issues and areas.

Like many people have said before me, there is no doubt that breast milk has quite a lot going for it. If you need convincing, have a look at this document from the WHO detailing the beneficial effects of breastfeeding on areas such as health and intelligence (schooling). There is, as always, an important caveat attached to this document and the research in general, in that correlation does not necessarily imply causation and hence whilst an association might be strong statistically, there could be (and are) lots of other factors which influence such effects. Still breast milk, in its various stages and forms, carries quite a lot of nourishment and important compounds which can potentially help get a developing child off to a good start as well as being good for mum also. Suffice to say that before we got so good at making the modern infant formula feed, breast milk was the only (safe) way of nourishing a young infant for many, many generations of women.

The research base regarding breastfeeding and autism covers quite a bit of ground. Kanner, in his early descriptions talked about early feeding problems in his cohort but did not specify whether due to breast or formula. I don't really want to get too stuck on looking at any general association between breastfeeding rates and autism simply because (a) I think this is perhaps too simplistic an association to make (see correlation/causation argument above), and (b) there is always that risk of stigmatising mums who did or didn't breastfeed when all too often there are some complex processes in any decision made. The brief mention I will give to the analysis of breastfeeding rates in mothers with a child/children with autism suggests that there is no cut-and-dried answer of association.  The study that my colleagues and I have published touching upon this area, suggested that breastfeeding rates were fairly high (60-69%) according to sub-diagnostic groups we looked at compared with the UK average of about 55% exclusive breastfeeding for the first 4 weeks of infancy. Other studies have shared such notions. Other parental surveys have reported slightly different results. Final answer: not cut-and-dried.

When it comes to any direct effects of breastfeeding in relation to autism, there are a couple of themes which emerge related to the composition of breast milk: a possible role of environmental pollutants and the structural composition of breast milk in relation to things like fatty acids and those pesky casomorphins which perhaps need addressing.

I am going to try and be quite careful when talking about contamination from environmental pollutants and breast milk. Careful because 'environmental pollutants' covers such a wide range of chemicals and compounds, some naturally occurring and some more man-made. Careful also because some of the studies indicating increasing environmental exposures found in breast milk have to be balanced against those indicating decreasing exposure in breast milk. Geography and other factors such as smoking seem to play their role, as does the influence of maternal diet. There is some small suggestion that higher levels of specific environmental contaminants passed through mothers milk are associated with specific outcomes for the child at later ages. Again with my balancing act in full.. er, balance, there is however quite a lot of evidence pointing in the other direction, suggesting that such contamination of milk are not associated with any specific negative outcomes, including results from some rather large studies here and here.

Where do the studies specifically with autism in mind stand on this issue? Well, they don't stand anywhere because aside from some discussion on what happens to rats who are given doses of selected pollutants equivalent to that derived from breast milk showing some neural disorganisation, there is very little direct evidence on pollutant composition of breast milk in relation to autism. Indeed, the recent CHARGE study on PBDEs in plasma of children with autism (not specifically looking at breast milk!) suggested that levels of this one class of pollutants showed no difference from controls, although all groups presented with high levels. Going back to that very complicated issue of parental age and autism, another study touched upon another possible contributing variable in that the longer we leave it to have children, the more scope there may be for parental (mother) accumulation of environmental pollutants to be potentially passed on through breast milk. Whether this could have an effect specifically on autism, I don't know.

The other issue about breast milk potentially linked to autism is its composition; with specific focus on fatty acids and casomorphins. There has been quite a bit of speculation about specific types of fatty acids in breast milk. This review provides quite a good overview of what types of fatty acids might be most important, their relative quantity in breast milk and associations with outcome. Readers of this blog might remember that fatty acids have cropped up quite a few times with regards to autism (and ADHD). There is some common sense in perhaps thinking that the fatty acids in breast milk might show some involvement with autism given the various studies indicating potential fatty acid deficiencies in some cases. I would perhaps temper this statement by saying that formula milk manufacturers have also caught on to this (and GOS and FOS), and generally include them in their formulations also.

The other side of this issue is in relation to breast milk and casomorphins. I know there has been a bit of a debate in relation to casomorphins (and gluteomorphins) with respect to autism and this is perhaps fodder for another post. What is widely accepted is that mammalian milk protein (casein) is eventually broken down to its constituent peptides and amino acids via hydrolysis. Mammalian milk covers human milk as well as milk from cows, goats, sheep, etc. Given the continued speculation on the involvement of casomorphins in some conditions including autism, there is perhaps some grounds for further research into any possible relationship. Is there any variability in the level of casomorphins according to the different stages of milk and is this consistent across all lactating mothers? This and other questions on things like lactose intolerance and breast milk might be interesting to examine in light of the recent Harvard findings on autism.

Given the length of this post and to save anymore people from switching off, I will stop there. I am not going to post any links to videos of Harvey and 'bitty' so as not to offend. Instead I offer a short excerpt from a movie that some of you may have seen which offers a new perspective on breastfeeding.