“We have 16 studies already that clearly state that vaccines do not cause autism.”
-- Amy Pisani, Executive Director, Every Child By Two
“16 studies have shown no causal association between vaccines and autism, and these studies carry weight in the scientific industry.”
-- Dr. Nancy Snyderman, NBC Today Show Medical Editor
“The science is largely complete. Ten epidemiological studies have shown MMR vaccine doesn’t cause autism; six have shown thimerosal doesn’t cause autism.”
-- Dr. Paul Offit, “Autism’s False Prophets”
A NOTE FROM SAFEMINDS:
There are 16 epidemiological studies here on MMR vaccines, thimerosal and autism. These studies represent the most often cited papers by scientists, public health officials and members of the media when trying to refute any evidence of an association between vaccinations and autism.
There are serious methodological limitations, design flaws, conflicts of interest or other problems related to each of these 16 studies. These flaws have been pointed out by government officials, other researchers, medical review panels and even the authors of the studies themselves. Taken together, the limitations of these studies make it impossible to conclude that thimerosal and MMR vaccines are not associated with autism.
SafeMinds would like to acknowledge the previous work in this regard gathered by the “Fourteen Studies” project at Generation Rescue: http://www.14studies.org/about.html
One additional study on autism and thimerosal was published in September 2010 while this paper was in completed draft form. This study’s methods produced a result that demonstrated that thimerosal exposure was protective against autism. Further analysis of this study is forthcoming but not included here.
FLAWS AND LIMITATIONS OF MMR STUDIES
Major Reviews – There have been at least two major reviews of the main studies claiming to examine a potential association between MMR vaccine and autism spectrum disorders. They are the 2005 Cochrane Review and the 2004 Institute of Medicine Immunization Safety Committee Report.
1) The Cochrane Review: “Vaccines for measles, mumps and rubella in children.” October 2005.
According to their sponsors, the Cochrane Reviews report on published (and sometimes unpublished) studies which investigate the effects of interventions for prevention, treatment and rehabilitation in a healthcare setting. Most Cochrane Reviews focus on randomized controlled trials, but other types of evidence may also be taken into account. The reviews are considered by most experts to provide the gold standard of evidence-based medical science.
In 2005, Cochrane published a review of published studies on the safety and efficacy of MMR vaccine. Their search revealed more than 5,000 papers on the subject, though only 139 of them “possibly satisfied” the reviewers’ inclusion criteria. In the end, they reported on and summarized about 31 studies, only a few of which pertained to autism spectrum disorders (ASD).
Main results - MMR was “likely to be associated” with febrile convulsions within two weeks of vaccination, but “unlikely to be associated” with Crohn's disease, ulcerative colitis, mumps or autism.
General Limitations: the authors concluded that:
■ There was a moderate-to-high probability of bias in all but one of the cohort studies.
■ The internal validity of some studies was problematic, and the presence of selection, performance, attrition, detection and reporting biases influenced the reviewers’ confidence in these findings. The most common type of bias was selection bias.
■ There was only limited evidence of MMR’s safety compared to single component vaccines from studies with a low risk of bias. The few studies least likely to be affected by systematic error pointed to a likely association with increased febrile convulsions in the first two weeks post-vaccination.
■ The cohort studies’ conclusions “that MMR is ‘safe,’ ‘equally safe,’ ‘well-tolerated,’ or has ‘low-reactogenicity,’ need to be interpreted with caution given the potential for confounding.
■ In the cohort studies, the validity of the conclusions was affected by selective reporting in the comparative analysis, with just over half the responses from participants in some cases.
■ There was a lack of clarity in reporting and systematic bias which made it “impossible” to compare the various studies through quantitative synthesis of data.
■ There were general difficulties in ascertaining adequate numbers of unexposed children due to the high uptake of vaccines and the extent of vaccination programs. This is a methodological problem likely to be encountered in all comparative studies of established childhood vaccines.
■ There was a “lack of adequate description of exposures (vaccine content and schedules)” in all cohort studies.
■ The failure of any study to provide descriptions of all outcomes was a recurring problem.
■ Some reports offered inadequate explanations for missing data, accepting as ‘adequate’ explanations such as ‘nonresponse to questionnaire’ and ‘medical records unavailable’.
■ The external validity of the studies was low. Descriptions of the study populations, response rates, vaccine content and exposure - all important indicators of generalizability - “were poorly and inconsistently reported.”
■ There were inadequate and inconsistent descriptions of reported outcomes, limited observation periods (maximum 42 days) and selective reporting of results. All of these problems contributed to the reviewers’ decision not to attempt pooling data by study design
SUMMARY – Although the reviewers determined that MMR vaccine was “unlikely to be associated” with autism, they concluded that “meaningful inferences from individual studies lacking a non-exposed control group are difficult to make.” They added that there were disappointed by their inability to identify effectiveness studies with population or clinical outcomes.
Many critics question how the authors of Cochrane’s MMR Review could find an “unlikely” association with autism when - in the very same paper - they also concluded that:
(a) the design and reporting of safety outcomes in MMR vaccine studies, are largely inadequate and
(b) that critical design and reporting flaws need to be improved and standardized definitions of adverse events adopted.
Sallie Bernard, of SafeMinds, wrote that the Cochrane Review “gives MMR a free pass.” She said the review “Assumes that this version of vaccine is as safe as can be, and so beneficial there is no need to worry about the fact that the safety studies are inadequate. Would this happen for any other drug? Isn’t it possible, even probable, that the vaccine is effective but still has safety lapses and could be improved?”
In a review presented at the International Meeting for Autism Research (IMFAR) Carol Stott, a UK epidemiologist and Chartered Psychologist, wrote that, given the Cochrane Review’s conclusions, it is important to examine the extent to which the various clinical and population studies have been designed appropriately and with specific reference to the original hypothesis and, thus, to examine the extent to which claims of the hypothesis being refuted or supported are valid.
2) Institute of Medicine, “Immunization Safety Review: Vaccines and Autism.” May, 2004
In February 2004, the IOM’s Immunization Safety Committee held a hearing on the possible association between MMR, thimerosal and autism. The committee reviewed all published and unpublished epidemiological studies on causality as well as potential biologic mechanisms to explain a possible vaccine-autism causal association. Its findings were released in a May, 2004 report. The committee’s conclusions hold wide sway over many scientists, physicians and much of the media to this day.
Main Results: The committee concluded that the body of epidemiological evidence “favor” rejection of a causal relationship between the MMR vaccine and autism,” further stating that studies examining the association between MMR and autism consistently showed evidence of no association between the MMR vaccine and autism.
■ Because the “vast majority” of ASD cases cannot be accurately sub-classified, if there is a subset of individuals with autism syndrome triggered by exposure to vaccines, our ability to find it is very limited in the absence of a biological marker.
■ Although there is no convincing evidence to date that a clearly defined subgroup with susceptibility to MMR-induced autism has been identified, genomics and proteomics could reveal in the future whether or not any genetic susceptibility to vaccine-induced autism exists.
■ A lack of unexposed children is another limitation. The committee noted that they had previously called for studies to enroll children whose families opted against the MMR vaccine, but so far, this type of study has been difficult to do with sufficiently large numbers.
■ The committee also noted that its 2001 report did not exclude the possibility that MMR “could contribute to autism in a small number of children because the epidemiological studies lacked sufficient precision to assess rare occurrences.”
■ They also noted that it was possible that epidemiological studies would not detect a relationship between autism and MMR vaccination in a subset of the population with a genetic predisposition to autism.
The latter two points are covered in the introduction to this document. While the points are well received, it is important to note that ‘epidemiological’ studies lack neither precision nor accuracy simply by virtue of them being ‘epidemiological’. It is entirely possible to design population based studies to maximize the likelihood of identifying small effect sizes; the fact that this hasn’t yet been achieved in the vaccine-autism debate is the fault of the workmen, not the tools.
SUMMARY: The IOM Committee gave far more emphasis to epidemiological (population based) studies than biological studies, such as clinical studies in children, laboratory studies, and animal model studies. Since the IOM report was released in May, 2004, a large amount of biological data have been generated from several published studies to support an association between vaccines – including MMR - and ASD. A new IOM review that includes these studies is needed.
INDIVIDUAL MMR STUDIES
The Cochrane Review and the 2004 IOM Report both referenced a number of MMR-autism studies when concluding that the evidence favors rejection of a causal association. These papers make up the bulk of the MMR investigations included in the “16 studies” referred to by Doctors Snyderman and Offit. They include nine studies on MMR:
1) A Population-Based Study of Measles, Mumps, and Rubella Vaccination and Autism.
Authors: Kreesten Meldgaard Madsen, M.D., Anders Hviid, et. al.
Publication & Date: New England Journal of Medicine, November 7, 2002.
Details: This paper is often referred to as the “Danish MMR Study”. The authors conducted a retrospective cohort study of all children born in Denmark from January 1991 through December 1998. Information on MMR-vaccination status and on autism status was obtained via Danish health records. Out of 537,303 children in the cohort, 440,655 (82.0 percent) had received the MMR vaccine. A total of 316 children with a diagnosis of autistic disorder and 422 with a diagnosis of other autism-spectrum disorders were identified (a proportion of 13.7-per-10,000, or about 1-in-730).
Results: After adjusting for potential confounders, the relative risk of autistic disorder among MMR-vaccinated children vs. the unvaccinated group was 0.92 and the relative risk of another autistic-spectrum disorder was 0.83. In other words, MMR-exposed children were 17-percent LESS likely to have an ASD than unexposed children: The vaccine reportedly had a statistically significant “protective effect.”
Authors’ Conclusions: “This study provides strong evidence against the hypothesis that MMR vaccination causes autism.”
WHAT CRITICS SAID:
Walter Spitzer, Professor Emeritus of Epidemiology, McGill University et al., in a letter published in the March, 2003 issue of the NEJM, noted that there were still some methodological problems outstanding with regard to the Danish study.
Spitzer charged that researchers did a clinical record review of just 40 cases (13%), which he claimed was inadequate, especially if the purpose was only to validate an existing diagnosis. Spitzer claimed that ‘…without a multidisciplinary review of original lifetime records as well as double verification in a large descriptive single cohort, important errors would have been unavoidable, both in classification and numbers for the numerators.” Spitzer et al. also raised the question of whether pediatric clinical psychologists, pediatric neurologists and speech therapists were involved in the review and whether the reviewers were blind as to exposure status.
Though the power of the published study was high, it was “misleading,” Spitzer et al. claimed. In elaborating this point Spitzer et al. explained that if, for example, one assumed a vulnerability to MMR-induced disease in 10% of the regressive ASD cases, with 95% of this group being vaccinated, and if 80% of the non-regressive ASD cases were also assumed to be vaccinated, then “the odds ratio for MMR as a risk factor for regressive autism would be 4.17.”
However, if children with autism, regardless of sub-types, were combined and compared against non-affected controls, the odds ratio would plummet to just 0.97. “Thus a small non-statistically significant reduction in uptake of MMR in the 90% of non-regressive autistic children would mask a strong causal association in a small subgroup,” Spitzer et al. Whilst the sub-group might be small, they claim, ‘…conservatively the 10% would represent 50,000 children in the U.S. alone with a financial burden of disease to parents and government of at least $1.25 billion per year.”
Goldman and Yazbak, in a letter published in the Journal of American Physicians and Surgeons, pointed out the “substantial under-representation of autism diagnoses and vaccination status for children born in the later study years.” Children with ASD in Denmark are diagnosed at about 5 years old; many were simply too young to receive an ASD diagnosis by the end of the study period. This would apply to all children under the age of 36 months and, in a practical sense, to many of the 3-5 year olds. Among children born in 1997 and 1998, who made up a substantial proportion (39%) of the total years of observation time, many had yet to even receive an MMR vaccine all.
In fact, ASD prevalence among children aged 5-9 years increased from a mean of 8.38/100,000 in the pre-licensure era (1980-1986) to 71.43/100,000 in 2000, making the adjusted prevalence rate-ratio 4.7 for the post-licensure period compared with the pre-licensure period. This suggested a temporal association between the introduction of MMR vaccination in Denmark and an almost five-fold increase in autism cases.
Mark Blaxill, SafeMinds director, in an unpublished critique written for SafeMinds , criticized the use of person years rather than prevalence by birth group as the choice of outcome measure. He pointed out that although person-years is common incidence measure in epidemiological studies, it is an odd choice in the study of a chronic disease like autism. He argued that “there is no really good reason (and the authors offer none) to consider duration of the disorder as opposed to its presence. Autism is generally considered a lifelong disorder, so the effect is the same among two year olds as it is among eight year olds.”
Analyzing the Denmark data using case prevalence measures reveals importance problems with Madsen et al. according to Blaxill. Most notably, he points out that the most straightforward analysis of the data provided by the study authors directly contradicts their conclusion (see table below). The actual prevalence of autism in the 440,655 children who received MMR vaccinations in Denmark was 6.1 per 10,000 as compared to the rate of 4.9 per 10,000 in the 96,648 unvaccinated children. At the population level, the risk of autism was therefore 26% higher in the group vaccinated with MMR, a calculation the authors never reported. Blaxill highlighted two biases:
Unadjusted Relative Risk of Autism in MMR-Vaccinated Danish Children
Rates per 10K
1. Biased exposure adjustment. Madsen et al. introduce an adjustment for the timing of diagnosis relative to the timing of MMR vaccination. The authors determined that six of the children diagnosed with autism and seven of those diagnosed with other autistic spectrum disorders had such an early onset of the symptoms that the disorder was diagnosed before the MMR vaccine was administered. They decided that this reversed sequence of events argued against a causal role for MMR in autism, so they placed these vaccinated children in the group they called "unvaccinated" even though they had clearly received MMR vaccine. In moving autistic children into the unvaccinated group, the authors increased the pool of unvaccinated children by 13% and reduced the pool of vaccinated children by 2%. This adjustment substantially reduced the relative risk of autism among the vaccinated group, from 1.26 in the table above to 1.09 at the population level.
The MMR hypothesis argues more specifically, however, that vaccination of an otherwise normal child will contribute to an autistic regression. To test this hypothesis, the most relevant population would exclude all cases with early onset autism, both from the vaccinated group (as the study authors chose to do) and from the unvaccinated group (which they chose not to do). The method chosen by the authors artificially raised the incidence rate in the control group. If, instead of moving early onset (but clearly vaccinated) cases into the "unvaccinated" group, the authors had removed all early onset cases from both groups, they would have increased the relative risk of autism in the vaccinated group to 1.28, instead of reducing it to 1.09.
2. Age adjustment bias effect. The use of person-years also had a more direct effect on the published risk of MMR on autism, by introducing a skew in the sample by age group. In reporting a relative risk 0.92 (a level that suggests a protective effect of MMR in autism) rather than the case-based relative risk of 1.09, the authors weighted certain portions of their sample (the older children with more person-years) more heavily than others. Given the wide variation of risk by age, extra weight was actually given to portions of the sample with relative risks well below 0.92. Blaxill made a rough calculation of the relative risks of autism comparing children born in 1997-98 (children were one and two years of age when the data was collected) to those born between1991-96. This calculation shows an even higher protective effect (relative risks of 0.87 and 0.77 for children with autism and autism spectrum disorders, respectively).
The distribution of relative risks is highly variable across birth years, more than would be expected under the null hypothesis of no vaccination effect. This raises questions about the quality of the vaccination data records among the older children. The apparent high rate of autism among unvaccinated older children could reflect lost vaccination records or other data integrity problems.
Carol Stott, Mark Blaxill, and Dr. Andrew Wakefield, claimed in the Journal of American Physicians and Surgeons, that Madsen et al. appeared to have adjusted inappropriately for age. That being the case, Stott et al. argued, the findings need to be reinterpreted,” Stott et al. went on to state that in the absence of such adjustment, there is a statistically significant 45% excess risk of autism in recipients of the MMR vaccine and therefore, an apparent association between MMR and autism in this Danish population.
In addition, Stott et al. argued that a proper trend analysis would compare autism rates not by age at diagnosis but rather by date of birth. They obtained data from the same registry used by the authors that showed a clear upward trend in autism rates in birth cohorts born after the introduction of MMR in Denmark (see below). ASD Prevalence in Denmark by year of birth, 1982-1992. Annual growth rate before MMR was -0.5%, but rose to 14.8% after MMR introduction in 1986.
Moreover, Stott et al. claimed that the authors of the Danish study had selected a particular adjustment to their population groupings that removed a total of 13 ASD cases from the vaccinated group and placed them in the unvaccinated group. This single adjustment reduced the relative risk of autism associated with MMR vaccination at the population level by 17%, from 1.26 to 1.09, Stott et al. claimed that if the authors had removed all cases diagnosed before two years of age from their risk analysis, the relative risk at the population level would have risen from 1.26 to 1.28.
And Blaxill added another commentary of his own: “I conclude that the authors’ conclusion is not warranted. In my opinion, the Madsen article is useful in many ways but it definitely does not rule out MMR as a cause of autism, particularly not in a subgroup of the affected children.”
WHAT THE COCHRANE REVIEW SAID:
■ Follow up on medical records terminated just one year after the last day of admission to the cohort. “Because of the length of time from birth to diagnosis, the Cochrane reviewers felt it became ’… increasingly unlikely that those born later in the cohort could have a diagnosis.”
■ The study was judged to have a “moderate” probability of bias.
■ Interpretation of the study was “made difficult by the unequal length of follow up for younger cohort members” and the “use of date of diagnosis rather than onset of symptoms for autism.”
■ The study failed to report complete vaccine identification information, “including lot numbers, adjuvants, preservatives, strains, product and manufacturer.”
■ There was inadequate description of exposures, such as vaccine content and schedules.
■ The study suffered from “clearly missing unintended-event data” and many participants were missing for adverse event monitoring. Adverse event data were missing in up to 1-in-5 participants (20%).
■ The study failed to provide descriptions of all outcomes monitored.
Madsen et al. argue no effect of MMR vaccination on autism in Danish children and even suggest there might be a protective effect to MMR exposure. Unfortunately, their study is plagued with questionable methodological choices, unexplained data anomalies and biased adjustments. In any study that asks a fundamental question about relative proportions of exposure in affected vs. unaffected groups, accurate definitions and classifications of (a) exposure and (b) affected status are crucial to the validity of any conclusions drawn from the data. Numerous criticisms of Madsen et al. highlight a source of error in one or another of these classifications. Methodology questions aside, more straightforward approaches to the population data they report suggest an increased risk of autism in Danish children based on MMR exposure, especially when adopting a case-based approach rather than relying on person-years. A simple comparison of autism rates by birth year shows a clear increase in autism rates after the introduction of MMR in Denmark. These analyses demonstrate that frequent references made based on Madsen et al. regarding the safety of MMR are incorrect.
2) Neurologic Disorders After Measles-Mumps-Rubella Vaccination.
Authors: Annamari Mäkelä, MD, J. Pekka Nuorti, MD, and Heikki Peltola, MD,
Publication & Date: Pediatrics, November 2002
Details: This paper is often referred to as the “Finnish MMR Study”. The authors conducted a retrospective cohort study linking individual MMR vaccination data with a hospital discharge register among 535,544 children in Finland, aged 1-to-7 years old, who were vaccinated between November 1982 and June 1986 in Finland. The authors looked for changes in the overall number of hospitalizations for autism after vaccination throughout the study period and for hospitalizations due to inflammatory bowel disease for children with autism. For encephalitis and aseptic meningitis, they compared the number of events observed within 3 months after vaccination to the number of events in the subsequent 3-month intervals for 24 months.
Results: Of the 535,544 vaccinated children, 199 were hospitalized for encephalitis, 161 for aseptic meningitis, and 352 for autistic disorders (a rate of 6.7-per-10,000). In 9 children with encephalitis and 10 with meningitis, the disease developed within 3 months of vaccination, revealing no increased occurrence within this designated risk period. Because there is no specific “risk period” for autism following vaccination, the authors looked for changes in the number of hospitalizations for autism after MMR vaccination for the study as a whole. They found no clustering of autism hospitalizations, which ranged from 3 days to twelve and a half years. None of children with ASD had hospital visits for inflammatory bowel diseases.
Authors’ Conclusions: “We did not identify any association between MMR vaccination and encephalitis, aseptic meningitis, or autism.”
WHAT CRITICS SAID:
F. Edward Yazbak, MD: Makela et al. were so intent on shooting down Wakefield’s work that even in a paper titled “Neurologic disorders after MMR,” they found a way to mention that no hospitalized children with autism had IBD. But regardless of what Makela says, the fact is that the number of individuals who received assistance for IBD from the Social Security Institution in Finland doubled in nine years (from 9,737 in 1992 to 20,807 in 2001).
The whole study is based on ONE comparison. If the children in the first group developed symptoms of encephalitis and meningitis within two weeks of vaccination, then causation is implied (medically and medico-legally). In this case, a comparison with the control group is meaningless and the author’s conclusion is unwarranted.
WHAT THE COCHRANE REVIEW SAID:
■ This study suffered from a “moderate” risk of bias.
■ It was “weakened” by the loss of 14% of the original birth cohort and the effects of the rather long time frame of follow up. What the impact of either of these factors was in terms of confounders is open to debate.
■ The long follow up for autism was due to the lack of a properly constructed causal hypothesis.
■ The study failed to report complete vaccine identification information, including lot numbers, adjuvants, preservatives, strains, product and manufacturer.
■ There was a lack of adequate description of exposure (vaccine content and schedules).
■ The authors provided “inadequate” explanations for missing information, even though there were clearly missing unintended-event data on as many as 20% of the participants.
■ The study had discrepancies in reporting of denominators and was classified to be at moderate risk of bias.
What the IOM said: The study suffered from one primary limitation: its exclusive reliance on hospitalization records. This made it impossible to identify children with ASD who were not hospitalized, but rather seen in an outpatient setting. The IOM went on to say that “While the authors stated that it is common in Finland for children with autism to be admitted to the hospital for observation and testing, a diagnosis of autism does not always involve hospitalization.”
What Science-Based Medicine.com said: “Using ‘hospitalizations’ as criteria for finding children with autism (is) not a good way to find autism cases, I agree.”
The “Finnish MMR study” fails to make explicit the exact definition of ‘caseness’, particularly with respect to autism. The criticisms leveled at the study are crucially important in this respect. First, there is a failure to differentiate between autism per se, and the sub-group who are proposed to be at increased risk (i.e. those with regressive onset). There is also a degree of circularity in the statement that those whose encephalitis was ‘unrelated to vaccination’ were excluded. To deselect particular cases before analysis, on the basis of a proposed non-relationship between exposure and outcome is poor epidemiological practice. Further, it implies that decisions about causality were made after the event, on the basis of criteria which were not made explicit to the reader. At face value, the exclusion of these cases would appear to work in favor of those proposing a possible association between exposure and hospitalization; but this would only be the case if the lack of association was real. No evidence is presented which allows formulation of an opinion on this. The most problematic factor, however, is in the assumption that children hospitalized ‘for autism’ somehow represent the very well defined group of children that are proposed to be at risk of an adverse event following vaccination. This assumption simply has no validity, and neither, therefore, do any conclusions based on data related to this group.
3) No evidence for a new variant of measles-mumps-rubella-induced autism.
Publication & Date: Pediatrics October 2001
Abstract Online at: http://www.ncbi.nlm.nih.gov/pubmed/11581466
Details: A link had been hypothesized between MMR vaccine and a type of ASD where developmental regression and gastrointestinal symptoms appear shortly after vaccination. The hypothesis involves 3 claims: 1) this is a new type of ASD, 2) this new type is responsible for the reported ASD rate increase, and 3) this new type is associated with symptoms suggestive of persistence of measles infection. If such a new "autistic enterocolitis" syndrome had some validity, then 1 or more of the following 6 predictions should be supported by empirical data:
1) Childhood disintegrative disorder has become more frequent
2) The age of first parental concern for ASD children exposed to MMR is closer to the average age of vaccination than in non-exposed children
3) ASD regression autism has become more common in MMR-vaccinated children
4) The age of onset for regressive ASD clusters around the MMR and is different from that of autistic children without regression.
5) Children with regressive autism have distinct symptom and severity profiles
6) Regressive autism is associated with gastrointestinal symptoms and/or inflammatory bowel disorder.
The authors used three samples. Data on 96 children (95 immunized with MMR at a median age of 13.5 months) in the UK who were born between 1992 and 1995 and had a PDD diagnosis were compared with data from two other clinical samples (1 pre-MMR [n = 98] and 1 post-MMR [n = 68]) of patients with autism. Reliability was excellent on Autism Diagnostic Interview-Revised (ADI-R) scores, age of parental concern, and developmental regression. Data on bowel symptoms were also available from pediatric and parental sources, while vaccination dates were obtained from computer records.
Results: The authors state that prevalence of childhood disintegrative disorder was 0.6-per-10 000 – a very low rate, consistent with other estimates, and not suggestive of an increased frequency of this form of pervasive developmental disorder in samples of children who are immunized with MMR. Meanwhile there was no difference in the timing of first parental concern between the two MMR-exposed samples (19.3 and 19.2 months) and the pre-MMR sample (19.5 months). “Thus” the authors claim “MMR immunization was not associated with a shift toward an earlier age for first parental concerns.
Meanwhile, the proportion of children with developmental regression reported in the post-MMR sample (15.6%) was no different from the pre-MMR sample (18.4%); and there was no suggestion that ASD regression had increased in frequency since MMR was introduced. The authors note that children with regressive ASD had no other developmental or clinical characteristics, a finding which, they claim, would have argued for a specific, etiologically distinct phenotype. Parents of regressive ASD children detected the first symptoms at a very similar age (19.8 months) to those of autistic children without regression (19.3 months), and the difference in time between MMR vaccination and parental recognition was not significant (248 vs. 272 days). GI symptoms were reported in 18.8% of cases, with constipation the most common (9.4%).
No inflammatory bowel disorder was reported, nor was there any association between regression and GI symptoms. Only 2.1% of the sample had both GI symptoms and regression, “a rate (sic) that did not exceed chance expectations.”
Author’s Conclusions: “No evidence was found to support a distinct syndrome of MMR-induced autism or of ‘autistic enterocolitis’,” and the study adds to “large-scale epidemiologic studies that all failed to support an association between MMR and autism at the population level.”
WHAT CRITICS SAID:
Critics question the basic assumptions behind the hypothesis, namely that if ‘autistic enterocolitis’ is real, then one or more of the authors’ six predictions would be borne out by the data.
■ Prediction (1) - "childhood disintegrative disorder has become more frequent". According to the study, the prevalence of childhood disintegrative disorder was very low, 0.6/10,000, and therefore had not become more frequent. But that figure is many times lower than estimated prevalence of regressive autism found in other studies, suggesting that the two cannot be equated.
■ Prediction (2) - "the mean age of first parental concern for autistic children who are exposed to MMR is closer to the mean immunization age than in children who are not exposed to MMR."
The mean age at first parental concern was 19.3 months in the two MMR samples and 19.5 months in the pre-MMR sample. But just because one might expect to find a difference, the similar results do not really prove anything. For example, children in the pre-MMR sample were still exposed to live virus from monovalent measles.
■ Prediction (3) - "regression in the development of children with autism has become more common in MMR-vaccinated children." The study found that regression in MMR-vaccinated children was no more common than regression in the pre-MMR sample, and had not increased in frequency. Furthermore, the children who did regress were no more likely to have other developmental or clinical characteristics, which would have supported the argument for a distinct regressive ASD phenotype.
The problem here is that the samples were quite small: two MMR-exposed samples of 96 and 68 children and one pre-MMR sample of 98. With numbers this small, only a few cases either way would have impacted the results.
■ Prediction (4) - "the age of onset for autistic children with regression clusters around the MMR immunization date and is different from that of autistic children". The study found that parents of autistic children with developmental regression detected the first symptoms at a very similar age (19.8 months) to those of autistic children without regression (19.3 months). The study also found that the mean intervals from MMR to parental recognition of autistic symptoms were comparable in autistic children with or without regression (248 days vs. 272 days, not significant).
Vaccine-induced regression would not necessarily be expect to cluster around the time of MMR vaccination, but could be delayed by weeks, months, or even years in some individuals. There is no reasonable scientific justification to believe the children who regressed following MMR should be recognized at a different time than those who did not regress after the vaccine. And though the difference was deemed to be “not significant” (248 vs. 272 days) it is still an unexplained margin of 10%.
■ Prediction (5) - "children with regressive autism have distinct symptoms and severity profiles."
Not enough is known about ‘autistic enterocolitis’ to make such an assumption about external characteristics into a key test.
■ Prediction (6) - "regressive autism is associated with gastrointestinal symptoms and/or inflammatory bowel disorder".
It is impossible to say that none of these children had signs of inflammatory bowel disorder because none of them underwent colonoscopy.
WHAT THE COCHRANE REVIEW SAID:
■ This study was assessed as having a “high likelihood” of bias.
■ In fact, the number of biases and their likelihood to negatively impact the study “was so high that interpretation of the results was impossible.”
■ The population description in this study raised doubts about the generalizability of the
conclusions to other settings.
■ This study failed to report complete vaccine identification information, including lot numbers, adjuvants, preservatives, strains, product and manufacturer.
■ There was a lack of adequate description of exposure (vaccine content and schedules) in the study.
■ This study failed to report any vaccine strains at all and failed to provide descriptions of all outcomes monitored.
The Fombonne and Chakrabarti study is flawed in a variety of ways. The biggest weakness is in its misinterpretation of the actual hypothesis of an association between a specifically defined sub-group of children and the exposure (MMR) of interest. It is on this erroneous understanding that the authors’ assumptions are based. The assumptions are not valid and any findings based on them are consequently of little interest. The inadequate study design (in terms of poor definitions of cases, controls and exposures) also means that any other uses to which the data might be put are extremely limited.
4) MMR vaccination and pervasive developmental disorders: a case-control study.
Authors: Smeeth L, et al.
Publication & Date: Lancet, September 11, 2004;364:963-9
Abstract online at: http://www.ncbi.nlm.nih.gov/sites/entrez.
Details: The authors conducted a matched case-control study using the UK General Practice Research Database. They included children born in 1973 or later who were diagnosed with a pervasive developmental disorder at a GP physician setting between1987 and 2001. Controls were matched on age, sex, and general practice.
Results: 1,294 cases and 4,469 controls were included. Of the PDD cases, 1,010 (78.1%) received the MMR vaccine before their recorded diagnosis, compared with 3671 controls (82.1%) before the age at which their matched case was diagnosed. After adjustment for age at joining the database, the odds ratio for association between MMR and pervasive developmental disorder was 0.78 for the non-practice matched control group and 0.86 for the practice matched control group. Once again, the vaccine apparently had a protective effect: MMR vaccinated children were 22% less likely to have PDD compared with the non-practice matched control group and 14% less likely to have PDD than the practice matched control group. “Findings were similar when restricted to children with a diagnosis of autism, to those vaccinated with MMR before the third birthday, or to the period before media coverage of the hypothesis linking MMR with autism.
Authors’ Conclusions: “Our findings suggest that MMR vaccination is not associated with an increased risk of pervasive developmental disorders.”
WHAT CRITICS SAID:
■ Problems in the study design operate against the probability of detecting an increase in risk.
■ There are significant changes from the methodology first proposed and subsequently cited in the present paper. Critics say it was crucial that case groups comprised only regressive, or late-onset, PDD, but Smeeth et al. confess (on p 967) that they were unable to do this.
■ The small sample size is an issue – In order to complete such a matched-pair study with an estimated control exposure rate of 80%, the appropriate sample size would be 7,145 cases - almost six times the number of cases used in Smeeth et al.
■ Two failings (below) in particular are “of such significance as to invalidate the conclusion that MMR vaccine is not associated with onset of autism in children.” (Wakefield)
■ The authors state that they were “not able to separately identify the subgroup of cases with regressive symptoms to investigate the hypothesis that only some children are vulnerable to MMR-induced disease and that this is always regressive. In this single statement they make it clear that they have not conducted an investigation of “what has been referred to as ‘the Wakefield hypothesis.’"
■ The paper “cannot be said to have concluded anything of relevance to the (Wakefield) hypothesis and has been grossly over-interpreted.
■ Despite the authors’ assurance that all diagnoses would be validated by a detailed review of hospital letters and information from parental questionnaires, only 25% of cases had their records examined and no questionnaire was used.
■ Other “substantial changes in the methodology” were also not explained in the paper, which therefore “meets neither the criteria for testing the original question nor those laid-down by the authors themselves.”
WHAT THE COCHRANE REPORT SAID:
■ Although the study “appeared to be carefully conducted and reported,” the database used “had no unexposed (to MMR) representative controls.” And though the 4% to 13% figure of unexposed controls was regarded by the authors as “representative,” such small numbers “may indicate some bias in the selection of controls.”
■ This underrepresented control “problem appeared to provide the rationale for the design of DeStefano 2004” (another study reviewed by Cochrane).
■ In this study, it was “impossible” to determine the “precise nature of controlled unexposed to MMR and its generalizability.”
■ This study suffered from a “moderate” risk of bias.
■ This study failed to report complete vaccine identification information, “including lot numbers, adjuvants, preservatives, strains, product and manufacturer.
■ This study failed to report any vaccine strains at all.
■ The authors provided “inadequate” explanations for missing information, even though there were “clearly missing unintended-event data” on as many as 20% of the participants.
The Smeeth et al. study goes a step further in highlighting the inadequacy of study designs that fail to isolate the correct case-group by specifically stating their intention to do so, (in a pre-study protocol discussion) and then clearly informing the reader that they failed to deliver on this intention. This represents a fundamental and fatal failure to address the right hypothesis. This means, in turn, that the study fails to add any data of scientific value regarding the vaccine-autism hypothesis whatever its other features might be.
5) “Age at first measles-mumps-rubella vaccination in children with autism and school-matched control subjects: a population-based study in metropolitan Atlanta.”
Authors: Frank DeStefano, et al.
Publication & Date: Pediatrics, February 2004
Details: The authors conducted a case-control study in metropolitan Atlanta, where 624 ASD case children were identified from multiple sources and matched to control 1,824 children on age, gender, and school. This study assessed the association between MMR vaccine and the onset of autism among three age strata: up to 18, 24 and 36 months Vaccination data were abstracted from immunization forms required for school entry. Records of children who were born in Georgia were linked to Georgia birth certificates for information on maternal and birth factors.
Results: The overall distribution of ages at MMR vaccination among children with autism was similar to that of matched control children. 70.5% of ASD cases and 67.5% of control children were given the MMR vaccine between 12 and 17 months of age. Similar proportions of case and control children were vaccinated before 18 or before 24 months. “No significant associations for either of these age cutoffs were found for specific case subgroups, including those with evidence of developmental regression.” More case (93.4%) than control children (90.6%) were vaccinated before 36 months, and this association was strongest in the 3- to 5-year age group.
Authors’ Conclusions: “Similar proportions of case and control children were vaccinated by the recommended age or shortly after and before the age by which atypical development is usually recognized in children with autism (i.e. 24 months). Vaccination before 36 months was more common among case children than control children, especially among children 3 to 5 years of age, likely reflecting immunization requirements for enrollment in early intervention programs.”
WHAT CRITICS SAID:
The authors did not discuss the causes of the present epidemic now affecting the United States, but “simply stated that the MMR was unlikely to be the cause of regressive autism because children diagnosed with autistic disorders in Atlanta, Georgia received their first MMR vaccine at about the same age as unaffected children.”
DeStefano and colleagues performed a case-control study comparing age at first MMR vaccination in children from the Atlanta metro area (2). By 36 months of age, significantly more cases with autism (93%) had received MMR than controls (91%)(Odds Ratio 1.49; 95% confidence interval [CI] 1.04-2.14). This association was strongest in the 3 to 5-year age group with an Odds Ratio of 2.34. Due to diagnostic delay, a significant proportion of this group had yet to be diagnosed with autism, potentially underestimating this risk. Moreover, in a subgroup analysis looking at children with different disease characteristics, they found a significant association between MMR vaccination by 36 months and autistic children with no evidence of mental retardation (IQ>70; OR 2.54 [1.20-5.00]). The odds ratios were increased to 3.55 in a subgroup analysis adjusted for birth weight, multiple gestation, maternal age and maternal education, thus strengthening the association between age-of-exposure to MMR and autism.
WHAT THE COCHRANE REPORT SAID:
■ Even though the authors concluded there was “no significant difference” between cases and controls in the age at first vaccination up to 18 months and 24 months, more cases received MMR before 36 months, making the two group different in an important sense.
■ This conclusion “showed bias in the enrollment of cases which may not be representative of the rest of the autistic population of the city of Atlanta, USA where the study was set.”
■ This study offered “inadequate explanations” for missing data.
■ This study had the highest rate of excluded cases – more than one-third of the total – among all studies reviewed by Cochrane.
■ Reporting on vaccine coverage and the “structure of comparisons” in this study were unclear, “raising the possibility of bias.”
■ This study suffered from a “moderate” risk of bias.
The DeStefano et al. study contains a number of important methodological flaws. Notably, however, the study group showed significant differences between cases and controls in age at vaccination. To dismiss this as being unimportant simply on the basis of similar overall proportions of case and control children being vaccinated by the recommended age is careless at best; contrived at worst. This is one of the few studies where any attempt has been made to look at a group of children with regressive onset, and it is one of the few to have demonstrated differences in age of exposure between case and control groups. This provides direct support for a role of MMR in increasing autism risk. That this alone didn’t raise questions and stimulate genuine discussion in the paper itself is striking.
6) “Autism and measles, mumps, and rubella vaccine: no epidemiological evidence for a causal association.”
Authors: B Taylor, et al.
Publication & Date: Lancet. 1999 Jun 12;353(9169):2026-9
Details: The authors studied children with autism born since 1979 who were identified from special needs/disability registers and special schools in eight North Thames health districts, UK. Clinical records were linked to immunization data from the child health computing system. Investigators looked for trend changes in incidence or age of diagnosis when MMR was introduced to the UK in 1988. Clustering of onsets within defined post-vaccination periods was investigated by the case-series method. The researchers also recorded information on bowel problems (when they exceeded 3 months in duration), onset of parental concern about the child’s development, and regression (if there was documented decline in the child’s development or parents reported loss of skills).
Results: We identified 498 cases of autism (261 of core autism, 166 of atypical autism, and 71 of Asperger's syndrome. There was a steady increase in cases by year of birth with no sudden "step-up" or change in the trend line after the introduction of MMR vaccination. There was no difference in age at diagnosis between the cases vaccinated before or after 18 months of age and those never vaccinated. There was no temporal association between onset of autism within 1 or 2 years after vaccination with MMR Developmental regression was not clustered in the months after vaccination. No significant temporal clustering for age at onset of parental concern was seen for cases of core autism or atypical autism with the exception of a single interval within 6 months of MMR vaccination.
Authors’ Conclusions: “The authors reported a significant increase in onset of parental concern at six months post vaccination. They argued that this may have been due to multiple testing, caused by an unclear causal hypothesis, and concluded that the evidence did not support an association with autism. “If such an association occurs, it is so rare that it could not be identified in this large regional sample,” they wrote.
WHAT CRITICS SAID:
■ Older children, born in 1984-1986, also received the vaccine as part of the United Kingdom’sCatch-up campaign.
■ The authors erroneously concluded that the rise in autism started several years before MMR was introduced and therefore had nothing to do with this vaccine. In fact a substantial number (n=36) of their cohort had formed part of the Catch-up campaign, and the step-up in autism occurred at precisely the time the first children received MMR vaccine in North London.
■ In their defense, the authors claimed that review of the records in the older recipients of MMR had identified parental concerns before MMR vaccination. They used this argument as justification for interpretation of a graph which simply presented number of children with autism versus year of birth, and owed nothing to apparent expressions of parental concern.
■ The authors tested the hypothesis of temporal clustering of age at diagnosis of autism in defined time periods post MMR vaccination, an analysis which, because of the considerable delay in diagnosis, is likely to bias towards a negative finding.
■ Despite this, they still found significant clustering of diagnoses by 6 months post MMR.
■ The authors tested a hypothesis and found a positive association.
WHAT THE COCHRANE REPORT SAID:
■ The absence of unvaccinated controls limits the inductive statements that can be made from this study.
■ The authors were “uncertain as to the power and generalisability of the findings from the single case-only design study.”
■ “This study demonstrates the difficulties of drawing inferences in the absence of a non-exposed population or a clearly defined causal hypothesis.”
■ This study failed to report complete vaccine identification information, “including lot numbers, adjuvants, preservatives, strains, product and manufacturer.”
■ This study failed to report any vaccine strains at all.
WHAT THE IOM SAID
There was an association between bowel problems and developmental regression – with almost twice the rate of bowel symptoms found in the regressive population. Thirty-one of the 118 children [26 percent] with regression and 49 of the 351 children [14 percent] without regressive autism reported bowel symptoms. “Single and multivariable logistic regression models, however, showed no association with these factors and MMR vaccine.”
Taylor et al. is another study that set out to address the issue of vaccine exposure in the correct set of (regressive onset) children and found an association between exposure and age of onset (within 6 months of exposure) and between regressive onset autism and bowel disease – both factors of crucial importance to the Wakefield hypothesis. The fact that the authors report the findings, but fail to discuss their potential importance, devalues the paper substantially. In addition, the design was not one from which observations on causality could be made and should be considered a descriptive study. Nonetheless the study provides clear evidence to support further evaluation of the precise factors outlined by the Wakefield hypothesis as being key to the potential MMR-autism association.
7) “No effect of MMR withdrawal on the incidence of autism: a total population study”
Authors: Hideo Honda, Yasuo Shimizu, and Michael Rutter,
Publication & Date: Journal of Child Psychology and Psychiatry. June, 2005.
Abstract online at: http://www.ncbi.nlm.nih.gov/pubmed/15877763
Details: The authors studied cumulative incidence of ASD up to age seven for children born from 1988 to 1996 in Kohoku Ward, Yokohama, Japan. Japan is unique, because MMR was introduced in 1989 and discontinued in April 1993. ASD cases included all cases of pervasive developmental disorders according to ICD-10 guidelines.
Results: MMR coverage dropped considerably in Yokohama in the birth cohorts of 1988 through 1992, (because of safety concerns over the strain of live mumps virus being used), and not a single MMR vaccine was administered in 1993 or thereafter. “In contrast, cumulative incidence of ASD up to age seven increased significantly in the birth cohorts of years 1988 through 1996 and most notably rose dramatically beginning with the birth cohort of 1993.”
Authors’ Conclusions: “The significance of this finding is that MMR vaccination is most unlikely to be a main cause of ASD, that it cannot explain the rise over time in the incidence of ASD, and that withdrawal of MMR in countries where it is still being used cannot be expected to lead to a reduction in the incidence of ASD.”
CRITIQUES OF THE STUDY
■ The study tells us little about ASD incidence of ASD prior to 1988, when MMR was introduced. But we do know that the published prevalence of ASD did not exceed 25-per-10,000 at any time in Japan prior to 1988.
■ Annual incidence of ASDs for children born in 1987 was 20-per-10,000, but after MMR was introduced, in 1988, annual incidence more than quadrupled, to 85.9-per-10,000 for children born in 1990.
■ But then, MMR coverage began to decline dramatically, as concerns over the mumps viral component grew. ASD incidence likewise declined during this period, to 55.8 for children born in 1991 – representing a drop of 35%.
■ Following complete discontinuation of MMR in 1993, ASD incidence rose again, this time quite dramatically, to 161-per-10,000 for children born in 1994. However, during this time the recommended schedule was changed to include three single vaccines (M-M-R, given four weeks apart), which gained widespread acceptance, causing coverage to increase significantly.
■ For all practical purposes, children vaccinated according to the new schedule were still receiving 'M-M-R' at around age one. Giving the three separate vaccines in such close proximity amounts to overlapping exposure, in biological terms.
■ Early MMR trials showed clear evidence of 'interference' between the viruses in the combined vaccine, mediated through an altered immune response. The safety consequences of this 'interference' are completely unknown.
■ Children who have natural measles (or single measles vaccine) and natural mumps infections within the same year are at significantly greater risk of later inflammatory bowel disease, which is consistent with an 'interference' phenomenon that could increase the risk of long-term measles virus infection and delayed disease.
■ The authors are wrong to examine MMR as the single exposure of interest, when in biological terms, exposure to M-M-R through three consecutive monovalent vaccines actually increased after 1993 when MMR was discontinued.
■ The data, therefore, could be interpreted as indicating a major influence of the pattern of exposure to these vaccine viruses on ASD incidence in this Japanese population.
■ More importantly, the data suggest a possible re-challenge effect of close temporal exposure to these three vaccine viruses on ASD incidence at the population level, whereby the exposure (MMR) has been introduced, removed (voluntarily through lack of public confidence), and then re-introduced (as M, M, and R close together).
■ ASD numbers increased and decreased in direct proportion to the total number of children vaccinated with the three live viruses. There is evidence of an effect not only from de-challenges and re-challenges, but there is also a “dose-response” relationship on a population level.
■ Such a dose-response relationship on a population level is rare; and is evidence of a possible causal association.
■ The interpretation by Public Health officials that this is the “last word on the subject” and that these data prove that MMR is safe is misleading and suggests a very limited perspective of the issues and a misunderstanding of published concerns on viral interference in a trivalent live-virus vaccine.
Undisclosed Conflict of Interest: Co-author Michael Rutter has close associations with the drug industry, including GlaxoSmithKline. He was a paid expert witness on their behalf in the UK MMR vaccine damage litigation. That was not declared in the Honda/Rutter paper.
Despite the methodological problems in Honda et al., and quite apart from the fact that an ecological study of this kind cannot be used to make attributions about causality, the unrecognized challenge-rechallenge effect of vaccination on autism rates in Japan provide yet another piece of support for the MMR-autism link. Because this study failed to clearly interpret the true population risk in the exposure of interest--assuming the removal of an exposure that in reality had remained-- the conclusions drawn by the authors are based on erroneous reasoning. Although drawing overly strong conclusions about an association between MMR-type exposures and autism would be premature in light of the study’s ecological design constraints, the data clearly indicate that further scrutiny of the data is required.
8) “Pervasive Developmental Disorders in Montreal, Quebec, Canada: Prevalence and Links With Immunizations.”
Authors: Eric Fombonne, MD, et al.
Publication & Date: Pediatrics, July 2006
Details: This cohort study surveyed 27,749 children born from 1987 to 1998 who went to 55 schools in the largest English-speaking school district in Montreal, Quebec. Children with PDDs (the Canadian term for ASD) were identified by a special needs team. The investigators looked at exposure to thimerosal by age 2 years and MMR coverage - which was estimated using vaccination rate surveys. The Canadian schedule called for an MMR injection at 12 months of age, up to 1995, when a second dose at 18 months was added.
Results: The authors found 180 children (82.8% of them males) with a PDD diagnosis at the surveyed schools, for a prevalence rate of 64.9 per 10,000. For autistic disorder, the rate was 21.6-per-10,000; for PDD-NOS it was 32.8-per-10,000; and for Asperger’s syndrome, 10.1-per-10,000. “A statistically significant linear increase in pervasive developmental disorder prevalence was noted during the study period,” the authors wrote. The PDD prevalence in thimerosal-free birth cohorts was significantly higher than among children who received thimerosal (59.5-per-10,000 vs. 82.7-per-10,000 – in other words, thimerosal-exposed children were 16% less likely to have an ASD).
Meanwhile, MMR coverage averaged 93% during the study period, though rates declined from 96.1% in the older birth cohorts (1988–89) to 92.4% in younger birth cohorts (1996–1998). Thus, PDD rates “significantly increased” during the same period when MMR uptake rates “significantly decreased.” Moreover, PDD prevalence went up at the same rate before and after the second MMR dose was introduced in 1996, “suggesting no increased risk of pervasive developmental disorder associated with a 2–measles-mumps-rubella dosing schedule before age 2 years. Additional analyses to test for the potential effects of exposure or diagnosis misclassification yielded the same results.”
Authors’ Conclusions: PDD prevalence in Montreal was high, and increased in recent birth cohorts, as it had in most other countries. This rise was due to “a broadening of diagnostic concepts and criteria, increased awareness and, therefore, better identification, (and) improved access to services.” There was no evidence that PDD had become more frequent, regression with autism had not become more common, and children with regressive autism did not have different profiles to those in the control group. These results “ruled out” an association between PDD and 1- or 2-dose MMR vaccinations.
WHAT CRITICS SAID
■ Fombonne et al. evaluated children enrolled in only one of Montreal’s five school boards, Lester B. Pearson School Board (LBPSB), but they cautioned that PDD rates in LBPSB may not have been representative of rates elsewhere and suggested that data from other school boards should be assessed but claimed, “this information was not available in the survey data that we could obtain.”
■ Data from all five Montreal school boards was easily obtainable from the Ministry of Education of Quebec, and they showed that enrollment at LBPSB in 2003-04 represented only 14% of all total school board enrollments in Montreal, but the PDD rates were significantly higher than all four other school boards combined. In some cohorts, prevalence was three times higher in LBPSB than in other districts.
■ Fombonne et al. could not possibly have accurately estimated the citywide rates of PDD merely by assessing just this one school board; any conclusions about a relationship between vaccines and PDD rates in Montreal may be seriously flawed.
■ By choosing to study only a small subset of the children in Montreal’s schools, the authors committed a serious selection bias.
■ LBPSB includes a Center of Excellence in Autism, so its high rates of PDD are likely influenced by the fact that it is the only totally inclusive school board of the Province of Quebec and has a very high ratio of integration of students with PDD into regular classes. Many families of children with PDD often seek to enroll them in LBPSB resulting in an overestimate of true PDD rates in Montreal as a whole.
■ Fombonne et al. chose to study MMR coverage rates, rather than the number of MMR vaccines received. He ignored the fact that autism rates increased following a doubling of the MMR exposure after 1996 when a second MMR shot was added to the schedule and chose to emphasize that a rise in PDD rates coincided with a decline in MMR coverage.
■ Fombonne also ignored the possible effect of mass measles immunization campaigns in Quebec that delivered a second dose of measles to a large number of infants and children throughout 1996. The subsequent rise in PDD shortly after that campaign is clearly depicted in their figures.
■ MMR coverage data was taken from the city of Quebec, rather than from Montreal, where the PDD data was gathered. MMR data “were available through N. Bouliane, of the Direction de Santé Publique de la Capitale Nationale,” the authors wrote. But the “Capitale Nationale” refers to Quebec City, not Montreal, some 265 kilometers away. Ms. Bouliane confirmed that the MMR vaccination rates were from the Quebec City.
■ Published MMR vaccine surveys from Montreal show that rates among children 24 to 30 months old did not fall during the period in question, but actually increased from 85.1% in 1983 (Baumgarten) to 88.8% in 1996-97 (Valiquette) to 96% in 2003-04 (Health Department Survey).
■ This suggests that in Montreal, PDD prevalence and MMR vaccination rates were in fact increasing in tandem during the study period.
■ F. Edward Yazbak, MD, FAAP, wrote to Pediatrics to protest, and said that “Readers deserve to know why the authors compared developmental data from a specific group of children in Montreal with MMR vaccination data from the city of Quebec, some distance away.”
■ In response, Dr. Fombonne failed to address the criticisms when he wrote to the editor of Pediatrics that, “This person (Yazbak) is known to pursue the MMR-autism agenda at all costs in order to 'demonstrate' a link he strongly believes in. All controlled epidemiological research thus far has concluded to the absence of such a link."
■ The Editor of Pediatrics, Jerold F. Lucey, also wrote to Dr. Yazbak, and stated that “I believe the evidence of no link between MMR and Autism is sufficient. It's not worth publishing more on this subject.”
■ Dr. Yazbak subsequently stated: “I found and reported a glaring error in the paper. The rates of autism in Montreal have as much to do with MMR vaccination rates in Quebec City as pollution in Los Angeles with Diesel buses in Chicago. The lead author refused to respond to my criticism concerning that simple geographic fact and the editor was unable to force him to do so.”
The criticisms of Fombonne are numerous and cover the most basic questions of study design, data quality, data interpretation and consistency. Furthermore, Fombonne’s ad hominem attacks on his critics undermine his personal credibility. The single most ‘glaring error’ reported by Dr Yazbak, i.e. that “The rates of autism in Montreal have as much to do with MMR vaccination rates in Quebec City as pollution in Los Angeles with Diesel buses in Chicago”, undermines any of the conclusions drawn by the authors. That simple failure to match exposures and outcome is sufficient by itself to render its conclusions worthless.
9) “MMR vaccination and febrile seizures: evaluation of susceptible subgroups and long-term prognosis.
Authors: M. Vestergaard et al.
Publication & Date: Journal of the American Medical Association, July 21, 2004
Abstract online at: http://www.ncbi.nlm.nih.gov/pubmed/15265850
Details: MMR vaccination increases the rate of febrile seizures, though it is not known if the rate varies according to personal or family history of seizures, perinatal factors, or socioeconomic status, and little is known about the long-term outcome of febrile seizures following vaccination. The authors conducted a population-based cohort study of all children born in Denmark between January 1, 1991, and December 31, 1998, who were alive at 3 months. 537,171 children were followed up until December 31, 1999. While this study did not measure autism, its main outcomes studied were incidence of first febrile seizure, recurrent febrile seizures, and subsequent epilepsy.
Results: A total of 439,251 children (82%) received MMR vaccination and 17,986 of them developed febrile seizures at least once; 973 of these febrile seizures occurred within 2 weeks of MMR vaccination. The rate ratio (RR) of febrile seizures increased during the 2 weeks following MMR vaccination - (RR 2.75, or 175% more likely) and, after that period, were close to the observed RR for non-vaccinated children. The RR did not vary significantly in subgroups of children that had been defined by their family history of seizures, perinatal factors, or socioeconomic status. At 15 to 17 months, the risk difference of febrile seizures within 2 weeks following MMR vaccination was 1.56 per 1000 children overall, 3.97 per 1000 for siblings of children with a history of febrile seizures, and 19.47 per 1000 for children with a personal history of febrile seizures. Children with febrile seizures following MMR vaccinations had a slightly increased rate (19%) of recurrent febrile seizures (RR, 1.19) but no increased rate of epilepsy compared with children who were non-vaccinated at the time of their first febrile seizure.
Authors’ Conclusions: MMR was associated with a transient increased rate of febrile seizures but the risk difference was small even in high-risk children. The long-term rate of epilepsy was not increased in children who had febrile seizures following vaccination compared with children who had febrile seizures of a different etiology.
WHAT THE COCHRANE REVIEW SAID
■ The rate of febrile seizures was significantly higher during the first week after vaccination (RR 2.46) and second week (RR 3.17) but not thereafter. Overall, MMR was associated with a higher risk of febrile seizures (RR 1.1).
■ These are plausible conclusions given that MMR is a viral live attenuated vaccine. There appeared to be no association with a family history of febrile seizures but there was a four-fold increase in risk of seizures within the first two weeks after MMR in siblings of children with epilepsy and a 19% increase in the risk of a second febrile seizure.
■ Overall, this was a well-reported, powerful study with credible conclusions as all possible efforts to account for confounders were made. This was the only cohort study judged to have a low probability of bias.
■ This study failed to provide descriptions of all outcomes monitored.
WHAT CRITICS SAID
■ This was one of the best constructed studies reviewed by Cochrane and carried the lowest risk of bias of all 14 cohort studies. And though the paper did not look at autism, it did find that the risk of febrile seizures more than tripled (RR 3.17) in the second week after MMR vaccination.
■ This study’s findings were consistent with other studies showing that MMR vaccination increases the risk of febrile seizures, causing them in 10-to-20-per-10,000 injections, and in 220-per-10,000 children with a previous history of febrile seizures.
■ In1994, a panel of the Institute of Medicine, writing about measles vaccine and brain injury or inflammation, concluded: “The National Childhood Encephalopathy Study, a case-control study described in detail in Chapter 5, reported a significant association between measles vaccination and onset of either convulsions or encephalopathy within 7 to 14 days of receiving the vaccine.”
■ MMR vaccine, when combined with varicella (chicken pox) live-virus vaccine into the 4-in-1 combination ProQuad shot, doubles the risk of seizures in children, compared with two separate MMR and chicken pox vaccines, a CDC study found. The CDC's Advisory Committee on Immunization Practices had recommended the vaccines be administered as separate shots, but subsequently voted to not recommend a preference between ProQuad and giving separate MMR and varicella vaccines. 
■ The MMR vaccine, (as well as DTP), is recognized by the US Department of Health and Human Services as a known cause of “encephalopathy” (brain disease) in a small subset of children. Acute encephalopathy induced by MMR exposure in children 18 months and older is associated not only with seizures, but can also cause a "decreased level of consciousness."
■ "A significantly decreased level of consciousness" induced by MMR exposure is indicated by the presence of at least one of the following clinical signs for at least 24 hours or greater:
1) Decreased or absent response to environment (responds, if at all, only to loud voice or painful stimuli).
Meanwhile “Many children with autism have a reduced sensitivity to pain, but are abnormally sensitive to sound, touch, or other sensory stimulation,”according to the National Institute of Neurological Disorders and Stroke (NINDS).
(2) Decreased or absent eye contact (does not fix gaze upon family members or other individuals).
“Children with autism often avoid eye contact with other people.”
3) Inconsistent or absent responses to external stimuli (does not recognize familiar people or things)."
“A baby with autism may be unresponsive to people or become indifferent to social engagement.”
■ In Bailey Banks v HHS, the Federal Vaccine Court ruled that Bailey’s case of Pervasive Developmental Disorder – Not Otherwise Specified (PDD-NOS) was a direct result of his development of acute disseminated encephalomyelitis (ADEM), a neurological disorder characterized by inflammation of the brain and spinal cord and damage to the myelin sheath, a fatty coating that insulates nerve fibers in the brain. Symptoms of ADEM include seizures. The judge ruled that Bailey’s ADEM was caused by his MMR immunization, “leading inexorably from vaccination to Pervasive Developmental Delay.”
Verstergaard et al. was more effectively designed than most other MMR safety studies. This analysis, however, did not explicitly include autism as an outcome. Nevertheless, did find an increased risk of febrile seizure following MMR, a finding that is consistent with other studies of MMR. The similarities between the Bailey Banks case--one in which the U.S. government conceded that a febrile seizure after MMR resulted in brain inflammation and an autism spectrum disorder--and the findings reported in this paper are striking. The dismissal of concerns over an adverse event like a febrile seizure highlights the casual and careless manner in which potentially crucial evidence is interpreted.
SOME FINAL REMARKS FROM CRITICS OF EPIDEMIOLOGICAL
STUDIES ON MMR AND AUTISM
(The following quotes were part of official presentations made on February 9, 2004 to the Vaccine Safety Committee of the Institute of Medicine.)
“The current genetic research estimates that no more than 10% of all autistic cases are genetic in origin. Simply put, the remainder 90% of autistic cases is sporadic with a non-genetic etiology. I tend to think that the sporadic form is by and large an “acquired” subset involving autoimmunity. This subset is likely triggered by a virus, possibly measles virus or MMR vaccine. Based upon our experimental research, it is plausible to postulate that an atypical measles infection that does not produce a typical measles rash but manifests neurological symptoms might be etiologically linked to autoimmunity in autism. The source of measles virus could potentially be MMR vaccine or a mutant measles strain, but more research is necessary to establish either of these two possibilities.” -- Vijendra K. Singh, Ph.D., Research Associate Professor of Neuroimmunology, Utah State University, an international expert in the autoimmune causes of autism.
”Half of Dr. Wakefield’s theory has been proven correct and accepted in the medical community. Hundreds of children with regressive autism and GI dysfunction have been scoped and clinicians are seeing the inflammatory bowel disease he first described.” -- (Frmr) U.S. Representative Dave Weldon, MD (R-FL).
“In light of encephalopathy, presenting in children as autistic regression closely following MMR vaccination. The findings confirm a highly significant statistical association between the presence of measles virus RNA in cerebral-spinal fluid and autistic regression following MMR vaccination.” -- Jeff Bradstreet, MD, Director, International Child Development Resource Center.
 Demicheli V, Jefferson T, Rivetti A, Price D. Vaccines for measles, mumps and rubella in children. Cochrane Database of Systematic Reviews 2005, Issue 4. Art. No.: CD004407. DOI: 10.1002/14651858.CD004407.pub2.
 “Immunization Safety Review: Vaccines and Autism,” Immunization Safety Review Committee Board on Health Promotion and Disease Prevention INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES, THE NATIONAL ACADEMIES PRESS Washington, D.C. Online at: http://www.nap.edu/catalog.php?record_id=10997
 Kreesten Meldgaard Madsen, M.D., Anders Hviid, et. al. “A Population-Based Study of Measles, Mumps, and Rubella Vaccination and Autism.” New England Journal of Medicine, November 7, 2002.Online at: http://content.nejm.org/cgi/content/full/347/19/1477
 Correspondence, “Measles, Mumps, and Rubella Vaccination and Autism.” Spitzer W. O., Mullins M. E., Wakefield A. J., Noble K. K., Miyasaka K., Madsen K. M., Campion E. W. - N Engl J Med 2003; 348:951-954, Mar 6, 2003.
 Goldman,GS and Yazbak, FE., Journal of American Physicians and Surgeons 2004;9(3):70-75.
 Carol Stott, Ph.D.; Mark Blaxill; Andrew J. Wakefield, M.B., “MMR and Autism in Perspective: the Denmark Story.” Commentary, Journal of American Physicians and Surgeons 2004;9(3):89-91.
 F. Edward Yazbak, MD, FAAP TL Autism Research, Falmouth, Massachusetts
 “Immunization Safety Review: Vaccines and Autism,” Immunization Safety Review Committee Board on Health Promotion and Disease Prevention INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES, THE NATIONAL ACADEMIES PRESS Washington, D.C. Online at: http://www.nap.edu/catalog.php?record_id=10997
 Frank DeStefano, et al.., “Age at first measles-mumps-rubella vaccination in children with autism and school-matched control subjects: a population-based study in metropolitan Atlanta.” Pediatrics, 2004 Feb; 113(2):259-66. Abstract online at: www.ncbi.nlm.nih.gov/pubmed/14754936?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum
 Dr Andrew J Wakefield MB,BS., FRCS., FRCPath and Dr Carol Stott PhD. Letter - “Response to: D'Souza et al.. No evidence of persisting measles virus in peripheral blood mononuclear cells from children with autism spectrum disorder. Pediatrics. 2006;118:1664-75. Online at http://www.parentingbanter.com/archive/index.php/t-47590.html
 B. Taylor, et al.. “Autism and measles, mumps, and rubella vaccine: no epidemiological evidence for a causal association.” Lancet, 1999 Jun 12;353(9169):2026-9. Abstract online at: http://www.ncbi.nlm.nih.gov/pubmed/10376617?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum
 Hideo Honda, Yasuo Shimizu, and Michael Rutter, “No effect of MMR withdrawal on the incidence of autism: a total population study.” J Child Psychol Psychiatry. 2005 Jun;46(6):572-9. Online at: http://www.ncbi.nlm.nih.gov/pubmed/15877763
 Andrew J Wakefield FRCS FRCPath and Carol M Stott PhD, “Commentary: Japanese study is the strongest evidence yet for a link between MMR and autism.” Thoughtful House, Austin, TX. - Online at: http://www.thoughtfulhouse.org/pr/No-effect-of-MMR-withdrawal-on-the-incidence-of-autism.php.
 Montgomery SM et al.. Gastroenterology 1999; 116: 796-803
 Eric Fombonne, MD, “Pervasive Developmental Disorders in Montreal, Quebec, Canada: Prevalence and Links With Immunizations.” Pediatrics Vol. 118 No. 1 July 2006, pp. e139-e150 (doi:10.1542/peds.2005-2993) Online at: http://pediatrics.aappublications.org/cgi/content/full/118/1/e139.
 David M. Ayoub, MD, Monica Ruscitti, “Letter to Editor - Title: Fombonne’s errors keep vaccine-PDD hypothesis alive in Quebec.” Unpublished letter to Pediatrics, 2006.
 Sandra Caron S. “Les injections multiples en vaccination ça vaut le coup!" Available at: http://www.oiiq.org/ordres/monteregie/vol23n3/p12_14.pdf. Accessed January 1, 2007.
 Annexe 1 of "Enquête sur la couverture vaccinale des enfants de 24 à 30 mois de Montréal-Centre" by Valiquette (1998).
 Table 3 (page 20) of "Enquête sur la couverture vaccinale des enfants de 24 à 30 mois de Montréal-Centre" by Valiquette (1998)
 4 Hudson Patricia et al., Are Montreal Children adequately vaccinated? Prevention en pratique médicale. Online at: http://www.santepub-mtl.qc.ca/Publication/pdfppm/ppmjuly2005.pdf
 F. Edward Yazbak, MD, FAAP, “A Tale of Two Cities: Flawed Epidemiology.” Unpublished letter to Pediatrics. March 7, 2007. Online at: http://www.nationalautismassociation.org/library/A%20Tale%20of%20Two%20Cities%20FLAWED%20EPIDEMIOLOGY.doc.
 “Newly Released Canadian Data Links Vaccines with Pervasive Developmental Disorder - National Autism Association calls 2006 Pediatrics study fatally flawed. News Release, National Autism Association, Chicago, IL, March 7, 2007. Online at: http://www.nationalautismassociation.org/press030707.php
 “Newly Released Canadian Data Links Vaccines with Pervasive Developmental Disorder - National Autism Association calls 2006 Pediatrics study fatally flawed.” News Release, National Autism Association, Chicago, IL, March 7, 2007. Online at: http://www.nationalautismassociation.org/press030707.php
 Vestergaard M, et al., “MMR vaccination and febrile seizures: evaluation of susceptible subgroups and long-term prognosis.” JAMA. 2004 Jul 21;292(3):351-7. Online at: JAMA. 2004 Nov 3;292(17):2083; author reply 2083-4.
 M Vestergaard et al.. “MMR vaccination and febrile seizures: evaluation of susceptible subgroups and long-term prognosis.” JAMA 2004 292: 351-357. Online at: http://www.medicine.ox.ac.uk/bandolier/booth/Vaccines/MMRfebse.html
 Kathleen R. Stratton, Cynthia J. Howe, and Richard B. Johnston, Jr., “Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Casuality.” Vaccine Safety Committee, Division of Health Promotion and Disease Prevention, Institute of Medicine. National Academy Press, Washington, D.C. 1994. Online at: http://books.nap.edu/openbook.php?record_id=2138&page=R1
 Daniel J. DeNoon, “Measles-Mumps-Rubella-Chickenpox Vaccine Doubles Febrile Seizure Risk.” WebMD Health News, February 26, 2008. Online at: http://www.medicinenet.com/script/main/art.asp?articlekey=87504
 Vaccine Injury Table, National Vaccine Injury Compensation Program, Health Resources and Services Administration (HRSA), US Dept. of Health and Human Services, Washington, DC. November 10, 2008. Online at: http://www.hrsa.gov/Vaccinecompensation/table.htm
 "Autism Fact Sheet," NINDS, NIH Publication No. 06-1877.April 2006. Online at: http://www.ninds.nih.gov/disorders/autism/detail_autism.htm
 United States Court of Federal Claims - OFFICE OF SPECIAL MASTERS: Bailey Banks, by his father Kenneth Banks, petitioner v. Secretary of the Department of Health and Human Services. No. 02-0738V - Filed: 20 July 2007. Online at: http://big.assets.huffingtonpost.com/BANKS_CASE.pdf