Wednesday, 21 May 2014

Vaccines not associated with autism: a meta-analysis

I'm gonna warn you that this is probably the longest of my ramblings so far covering one of the most controversial topics linked to autism in recent years... so it might be best if I provide you with some music to start with (Pink Floyd and Breathe) and suggest that you get yourself comfortable.
The singer @ Wikipedia 

So then...

"Findings of this meta-analysis suggest that vaccinations are not associated with the development of autism or autism spectrum disorder".

That was the conclusion reached in a study published by Luke Taylor and colleagues [1] based on an analysis of the collected research literature involving well over a million children looking at the possibility of a relationship between vaccination and the subsequent development of autism. In that description of vaccinations, the authors included the use of the measles-mumps-rubella (MMR) vaccine and mercury / thimerosal (thiomersal) exposure from other vaccines. The authors reported no evidence of an increased risk for autism following such routine vaccinations.

In case you are really interested here is a list of the studies included in the meta-analysis:
Cohort studies: Andrews et al, 2004;  Hviid et al, 2003; Madsen et al, 2002; Uchiyama et al, 2007; Verstraeten et al, 2003.
Case-control studies: DeStefano et al, 2004; Mrozek-Budzyn et al, 2010; Price et al, 2010; Smeeth et al, 2004; Uno et al, 2012.

I might also refer you to other discussion about the Taylor study too (see here and see here and see here).

To describe this area of the autism landscape as a hot potato does little justice to the column inches and sound-bites generated down the years and indeed, how it has so passionately divided elements of the autism community. Dr Tom Insel, current head of the US National Institute of Mental Health (NIMH) perhaps described it best in his 'Four Kingdoms of Autism' post equating the reports of post-vaccination effects linked to the onset of autism as falling into the 'Injury' kingdom and how they contrasted with the views of the other kingdoms of thought. More on that post coming shortly...

Acknowledging the public health message about the very important value of vaccination even possibly linked to the "prevention" of a number of cases of autism according to some research [2] (open-access here) alongside the often very personal views held on this particular topic, I'm going to remind readers that this is a blog about autism research. The currency is peer-reviewed studies and science is meant to be cold, objective and impartial albeit based on probability not absolutes. It is with this in mind, that I want to go through some of the collected literature in this area. I might add that I don't profess that this blog entry is the most comprehensive overview of the available research literature, merely a snapshot covering what I think are some of the important points. As always, no medical advice is given or intended...

So:

  • Going back to the Kingdoms blog post from Dr Insel, I was taken by one sentence included in that entry: "While epidemiological studies do not support a link between vaccination and autism, those convinced that autism is an injury argue that population studies may obscure a link in rare individual cases". In light of this sentiment and the growing interest in the plural 'autisms' over autism, I'm gonna link to some research chatter about individual cases where vaccinations have been mentioned. The report by Eggers [5] talking about a case of autism coincidental to the administration of a smallpox vaccination seems to be one of the earliest suggestions of a possible link between the two issues. Causality was however "considered extremely unlikely" in that particular description. The case of Hannah Poling [6] including a response from her father, Dr Jon Poling [7] in light of another paper of his [8] represents a modern-day example. For those that might not know, this was the case of a young girl "diagnosed with encephalopathy caused by a mitochondrial enzyme deficit" who successfully won compensation "under the [US] Vaccine Injury Compensation Program (VICP)" correlating her vaccination history with her encephalopathy. You might notice a lack of the word 'autism' in that particular case description but rather the term "regressive encephalopathy with autistic features". Accepting the point that this was a legal decision, the mitochondrial bit to Miss Poling's presentation might draw one to the whole area of mitochondrial dysfunction and autism (see here) and, as some writers have talked about, whether there may be more research to do in this area [9]. I will also refer readers to some subsequent discussion on this issue based on the PIND study (see here and author response here).
  • I've previously discussed the very important paper by Mady Hornig and colleagues [10] (open-access here) in the context of regressive autism and gastrointestinal (GI) issues (see here). Outside of their suggestion that: "Autism with GI disturbances is associated with elevated rates of regression in language or other skills and may represent an endophenotype distinct from other ASD" were their findings of "strong evidence against association of autism with persistent MV [measles virus] RNA in the GI tract or MMR exposure". Alongside other work in this area [11] and here [12] the original suggestion on "the presence of measles virus and gut pathology in children with developmental disorder" by Uhlmann and colleagues [13] (open-access here) has not stood up well to independent scientific replication. 
  • The topic of developmental regression in autism is also something which has cropped up in quite a few of the reports where vaccination and autism are mentioned in the same sentence. The paper by Goin-Kochel & Myers [14] highlighted how parents tended to report “external mechanisms” (e.g., vaccinations, environmental toxins) where such regressive onset was present in their child compared with more genetic based views around a more "congenital type" of onset. The results from Richler and colleagues [15] reflect the consensus of quite a lot of the literature in this area, whereby they failed to find "evidence that onset of autistic symptoms or of regression was related to measles-mumps-rubella vaccination" in their cohort.
  • On a previous blog entry with a title with perhaps as spurious a connection to a piece of research that I have yet seen in autism research (see here) I mentioned the study by Gentile and colleagues [16] reporting: "Children with ASD have a similar level and seropositivity rate of antibodies against the MMR vaccine to same-age controls". I did talk about how the Gentile results were slightly at odds with other research in this area such as that from Singh and colleagues [17] who reported: "a significant increase in the level of MMR antibodies in autistic children" and how: "an inappropriate antibody response to MMR, specifically the measles component thereof, might be related to pathogenesis of autism". Singh further suggested [18] that such an elevated antibody response to MMR vaccine may be part and parcel of "autoimmune autistic disorder (AAD) as a major subset of autism". At the time of writing, I've seen no further research to prove or disprove this subset in the peer-reviewed literature, despite the fact that autoimmunity and autism does feature quite regularly in the research literature.
  • One final area worth mentioning is the question of whether other events around the time of vaccination might have an effect on any subsequent developmental outcome. I'm thinking specifically about the paper by Schultz and colleagues [19] talking about: "acetaminophen (paracetamol) use after the measles-mumps-rubella vaccination" and the raised odds ratios they report based on parental survey. Paracetamol has come in for some scientific stick in recent times (see here) and the question still remains unanswered about any link or not for such post-vaccination antipyretic use and autism risk. As an aside, the Taylor paper does include an epilogue following the main study report where the corresponding author Guy Eslick talks about his own family experiences of vaccination and one of his children having a "serious event" following vaccination. He talks about taking "proactive measures to reduce the risk of similar adverse effects" with his other children involving "a dose of paracetamol 30 min before the vacccination .. to reduce any fever that might develop after the injection". Indeed, staying on the topic of fever is the study by Shoffner and colleagues [20] (talked about here) suggesting again "a subgroup of patients with mitochondrial disease may be at risk of autistic regression with fever" and further "fever management appears important for decreasing regression risk". It's confusing.

Despite being over 15 years down the line from the original [retracted] 1998 paper which thrust vaccination and autism into the media spotlight and with quite a few investigations in the intervening period talking about no population-wide correlation between the two factors, this issue still courts research and publicity. As indicated in a previous post on immunisation uptake and siblings of children with autism (see here) there is still a degree of disconnect between the overall message from the research base and the views and opinions of some suggesting a link with specific cases. I'm not in any position to question anyone about their own individual child and observations. As the recent paper from Muskat and colleagues [21] suggested when autism comes to the hospital: "Supportive health-care providers were those who acknowledged parents as experts..." (even Dr Eslick confirms in the epilogue to the Taylor paper: "As a parent I know my children better than anyone..."). That being said, I have to reiterate the Taylor findings and their quite emphatic proclamation regarding a lack of evidence for any connection.

Without trying to dilute the important health message on the value of vaccination, I want to discuss a few potentially important final points which might also be pertinent. I am nearly finished I promise you.

  • From the paper by Roberta Kwok [22] "vaccines are biological products with biological effects". The lessons from the Pandemrix flu vaccine - narcolepsy story for example, highlight how, in some very rare cases, there may be adverse effects following vaccination. Research linking the urabe-containing MMR vaccine and aseptic meningitis [23] is another example, although I hasten to add I've not found any peer-reviewed evidence to suggest that aseptic meningitis is related to autism onset. Vigilance is the watchword, and as the paper by Woo and colleagues [24] describes, there are mechanisms in place to monitor reported adverse events even where autism is mentioned. It should be noted that Taylor and colleagues did not include certain papers in their meta-analysis "that recruited their cohort of participants solely from the Vaccine Event Reporting System (VAERS) in the United States" because of "its many limitations and high risk of bias including unverified reports, underreporting, inconsistent data quality, absence of an unvaccinated control group and many reports being filed in connection with litigation". 
  • The paper by Nyhan and colleagues [25] (open-access here) talking about the outcomes of various vaccine promotion messages offers some important advice when trying to increase public confidence in the vaccination program. One of the most important points raised from the study is to test the message: "the importance of measuring beliefs and behavioral intent when assessing health interventions". I might also drop in the study by Dixon & Clarke [26] at this point too.
  • In a previous post discussing the paper by Akins and colleagues [27] I hinted at the links formed by some people interested in the complementary and alternative medicine (CAM) arena and certain views on the topic of vaccination. It's not by any means a universal relationship but certainly some purveyors of CAM do hold some alternative views on the value of vaccination. As per the paper by Ernst [28] "a campaign to clarify the risk-benefit profile of immunisations for both users and providers of CAM" may be a good idea but bearing in mind what Nyhan et al recently reported.

To once again reiterate, the conclusions of the Taylor paper based on meta-analysis of a significant number of study participants add to the message that vaccines are probably not associated with autism onset. This should have important implications for health promotion and onwards the goals of eradicating diseases which only a few decades ago were killing hundreds/thousands of people (see here). I'd like to link to a passage from the very famous author Roald Dahl and for example, how measles changed his world alongside a very informative infographic from the US CDC estimating that some 13.8 million deaths have been averted worldwide between 2000-2012 thanks to vaccination against measles and rubella.

In light of the Poling decision and the various gaps in the research base on issues such as post-vaccination paracetamol use or fever or underlying mitochondrial or autoimmune issues being potentially associated with autism, science still though has an important role to play in this area. I've also talked about outliers before on this blog (see here) and might also point you in the direction of how even something like those horde of bacteria which call our GI tract home might also be something to look at [29] (discussed on a sister blog entry). If anything else research should continue to ensure the already established safety profile of vaccination(s) continues [30] alongside other important issues such as how vaccines are administered [31] and the importance of timely vaccination [32] in order to aid any additional PR that might be needed. It may even perhaps illuminate new directions on the underlying genetics and biology of at least some of the autism spectrum disorders as per the implications from those Berger findings [2] and that older work on congenital rubella and autism risk...

And rest.

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[1] Taylor LE. et al. Vaccines are not associated with autism: An evidence-based meta-analysis of case-control and cohort studies. Vaccine. 2014. 9 May.

[2] Berger BE. et al. Congenital rubella syndrome and autism spectrum disorder prevented by rubella vaccination--United States, 2001-2010. BMC Public Health. 2011 May 19;11:340.

[3] Uno Y. et al. The combined measles, mumps, and rubella vaccines and the total number of vaccines are not associated with development of autism spectrum disorder: the first case-control study in Asia. Vaccine. 2012 Jun 13;30(28):4292-8.

[4] DeStefano F. et al. Increasing exposure to antibody-stimulating proteins and polysaccharides in vaccines is not associated with risk of autism. J Pediatr. 2013 Aug;163(2):561-7.

[5] Eggers C. Autistic syndrome (Kanner) and vaccination against smallpox. Klin Padiatr. 1976 Mar;188(2):172-80.

[6] Offit PA. Vaccines and Autism Revisited — The Hannah Poling Case. NEJM. 2008; 358:2089-2091

[7] Poling JS. Vaccines and Autism Revisited. NEJM. 2008; 359:655-656

[8] Poling JS. et al. Developmental regression and mitochondrial dysfunction in a child with autism. J Child Neurol. 2006 Feb;21(2):170-2.

[9] Weissman JR. et al. Mitochondrial disease in autism spectrum disorder patients: a cohort analysis. PLoS One. 2008;3(11):e3815.

[10] Hornig M. et al. Lack of association between measles virus vaccine and autism with enteropathy: a case-control study. PLoS One. 2008 Sep 4;3(9):e3140.

[11] Baird G. et al. Measles vaccination and antibody response in autism spectrum disorders. Arch Dis Child. 2008 Oct;93(10):832-7.

[12] D'Souza Y. et al. No evidence of persisting measles virus in peripheral blood mononuclear cells from children with autism spectrum disorder. Pediatrics. 2006 Oct;118(4):1664-75.

[13] Uhlmann V. et al. Potential viral pathogenic mechanism for new variant inflammatory bowel disease. Mol Pathol. 2002 Apr;55(2):84-90.

[14] Goin-Kochel RP. & Myers BJ. Congenital Versus Regressive Onset of Autism Spectrum Disorders.
Parents' Beliefs About Causes. Focus Autism Dev Disord. 2005; 20: 169-179.

[15] Richler J. et al. Is there a 'regressive phenotype' of Autism Spectrum Disorder associated with the measles-mumps-rubella vaccine? A CPEA Study. J Autism Dev Disord. 2006 Apr;36(3):299-316.

[16] Gentile I. et al. Response to measles-mumps-rubella vaccine in children with autism spectrum disorders. In Vivo. 2013 May-Jun;27(3):377-82.

[17] Singh VK. et al. Abnormal measles-mumps-rubella antibodies and CNS autoimmunity in children with autism. J Biomed Sci. 2002 Jul-Aug;9(4):359-64.

[18] Singh VK. et al. Phenotypic expression of autoimmune autistic disorder (AAD): a major subset of autism. Ann Clin Psychiatry. 2009 Jul-Sep;21(3):148-61.

[19] Schultz ST. et al. Acetaminophen (paracetamol) use, measles-mumps-rubella vaccination, and autistic disorder: the results of a parent survey. Autism. 2008 May;12(3):293-307.

[20] Shoffner J. et al. Fever plus mitochondrial disease could be risk factors for autistic regression. J Child Neurol. 2010 Apr;25(4):429-34.

[21] Muskat B. et al. Autism comes to the hospital: The experiences of patients with autism spectrum disorder, their parents and health-care providers at two Canadian paediatric hospitals. Autism. 2014. May 8.

[22] Kwok R. The real issues in vaccine safety. Nature. 2011; 473: 436-438.

[23] Dourado I. et al. Outbreak of aseptic meningitis associated with mass vaccination with a urabe-containing measles-mumps-rubella vaccine: implications for immunization programs. Am J Epidemiol. 2000 Mar 1;151(5):524-30.

[24] Woo EJ. et al. Developmental regression and autism reported to the Vaccine Adverse Event Reporting System. Autism. 2007 Jul;11(4):301-10.

[25] Nyhan B. et al. Effective messages in vaccine promotion: a randomized trial. Pediatrics. 2014 Apr;133(4):e835-42.

[26] Dixon G. & Clarke C. The effect of falsely balanced reporting of the autism-vaccine controversy on vaccine safety perceptions and behavioral intentions. Health Educ Res. 2013 Apr;28(2):352-9.

[27] Akins RO. et al. Utilization Patterns of Conventional and Complementary/Alternative Treatments in Children with Autism Spectrum Disorders and Developmental Disabilities in a Population-Based Study. J Dev Behav Pediatr. 2014; 35: 1-10.

[28] Ernst E. Rise in popularity of complementary and alternative medicine: reasons and consequences for vaccination. Vaccine. 2001 Oct 15;20 Suppl 1:S90-3.

[29] Lamousé-Smith ES. et al. The intestinal flora is required to support antibody responses to systemic immunization in infant and germ free mice. PLoS One. 2011;6(11):e27662.

[30] Lievano F. et al. Measles, mumps, and rubella virus vaccine (M-M-R™II): a review of 32 years of clinical and postmarketing experience. Vaccine. 2012 Nov 6;30(48):6918-26.

[31] Saroja Ch. et al. Recent trends in vaccine delivery systems: A review. Int J Pharm Investig. 2011 Apr;1(2):64-74.

[32] Hambridge SJ. et al. Timely Versus Delayed Early Childhood Vaccination and Seizures. Pediatrics. 2014. May 19.

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ResearchBlogging.org Taylor LE, Swerdfeger AL, & Eslick GD (2014). Vaccines are not associated with autism: An evidence-based meta-analysis of case-control and cohort studies. Vaccine PMID: 24814559