On 28 February 1998, Andrew Wakefield, a British gastroenterologist, and colleagues [1
] published a paper in The Lancet
that described 8 children whose first symptoms of autism appeared within 1 month after receiving an MMR vaccine. All 8 of these children had gastrointestinal symptoms and signs and lymphoid nodular hyperplasia revealed on endoscopy. From these observations, Wakefield postulated that MMR vaccine caused intestinal inflammation that led to translocation of usually nonpermeable peptides to the bloodstream and, subsequently, to the brain, where they affected development.
Several issues undermine the interpretation by Wakefield et al. [1
] of this case series. First, the self-referred cohort did not include control subjects, which precluded the authors from determining whether the occurrence of autism following receipt of MMR vaccine was causal or coincidental. Because ~50,000 British children per month received MMR vaccine between ages 1 and 2 years—at a time when autism typically presents—coincidental associations were inevitable. Indeed, given the prevalence of autism in England in 1998 of 1 in 2000 children [2
], ~25 children per month would receive a diagnosis of the disorder soon after receiving MMR vaccine by chance alone. Second, endoscopic or neuropsychological assessments were not blind, and data were not collected systematically or completely. Third, gastrointestinal symptoms did not predate autism in several children, which is inconsistent with the notion that intestinal inflammation facilitated bloodstream invasion of encephalopathic peptides. Fourth, measles, mumps, or rubella vaccine viruses have not been found to cause chronic intestinal inflammation or loss of intestinal barrier function. Indeed, a recent study by Hornig et al. [3
] found that the measles vaccine virus genome was not detected more commonly in children with or without autism. Fifth, putative encephalopathic peptides traveling from the intestine to the brain have never been identified. In contrast, the genes that have been associated with autism spectrum disorder to date have been found to code for endogenous proteins that influence neuronal synapse function, neuronal cell adhesion, neuronal activity regulation, or endosomal trafficking [4
Although no data supporting an association between MMR vaccine and autism existed and a plausible biological mechanism was lacking, several epidemiologic studies were performed to address parental fears created by the publication by Wakefield et al. [1
] (). Fortunately, several features of large-scale vaccination programs allowed for excellent descriptive and observational studies—specifically, large numbers of subjects, which generated substantial statistical power; high-quality vaccination records, which provided reliable historical data; multinational use of similar vaccine constituents and schedules; electronic medical records, which facilitated accurate analysis of outcome data; and the relatively recent introduction of MMR vaccine in some countries, which allowed for before and after comparisons.
Studies that fail to support an association between measles-mumps-rubella vaccine and autism.
Researchers in several countries performed ecological studies that addressed the question of whether MMR vaccine causes autism. Such analyses employ large databases that compare vaccination rates with autism diagnoses at the population level.
- In the United Kingdom, researchers evaluated 498 autistic children born from 1979 through 1992 who were identified by computerized health records from 8 health districts . Although a trend toward increasing autism diagnoses by year of birth was confirmed, no change in the rates of autism diagnoses after the 1987 introduction of MMR vaccine was observed. Further, MMR vaccination rates of autistic children were similar to those of the entire study population. Also, investigators did not observe a clustering of autism diagnoses relative to the time that children received MMR vaccine, nor did they observe a difference in age at autism diagnosis between those vaccinated and not vaccinated or between those vaccinated before or after 18 months of age. These authors also found no differences in autism rates among vaccinated and unvaccinated children when they extended their analysis to include a longer time after MMR exposure or a second dose of MMR .
- Also in the United Kingdom, researchers performed a time-trend analysis using the General Practice Research Database—a high-quality, extensively validated electronic medical record with virtually complete vaccination data . More than 3 million person-years of observation during 1988–1999 confirmed an increase in autism diagnoses despite stable MMR vaccination rates.
- In California, researchers compared year-specific MMR vaccination rates of kindergarten students with the yearly autism case load of the California Department of Developmental Services during 1980–1994 . As was observed in the United Kingdom, the increase in the number of autism diagnoses did not correlate with MMR vaccination rates.
- In Canada, researchers estimated the prevalence of pervasive developmental disorder with respect to MMR vaccination in 27,749 children from 55 schools in Quebec . Autism rates increased coincident with a decrease in MMR vaccination rates. The results were unchanged when both exposure and outcome definitions varied, including a strict diagnosis of autism.
Additional population-based studies considered the relationship between MMR vaccine and the “new variant” form of autism proposed by Wakefield et al. [1
]—specifically, developmental regression with gastrointestinal symptoms. Although it is difficult to analyze such a phenomenon when it is unclear that one exists (which complicates the formulation of a case definition), conclusions may be gleaned from the data with respect to developmental regression alone (i.e., autism irrespective of coincident bowel problems).
- In England, researchers performed a cross-sectional study of 262 autistic children and demonstrated no difference in age of first parental concerns or rate of developmental regression by exposure to MMR vaccine . No association between developmental regression and gastrointestinal symptoms was observed.
- In London, an analysis of 473 autistic children used the 1987 introduction of MMR to compare vaccinated and unvaccinated cohorts . The incidence of developmental regression did not differ between cohorts, and the authors observed no difference in the prevalence of gastrointestinal symptoms between vaccinated and unvaccinated autistic children.
Two conclusions are evident from these data. First, the explicit consideration of developmental regression among autistic children does not alter the consistent independence of MMR vaccine and autism. Second, these data argue against the existence of a new variant form of autism.
Retrospective, observational studies
Four retrospective, observational studies addressed the relationship between MMR vaccine and autism.
- In the United Kingdom, 71 MMR-vaccinated autistic children were compared with 284 MMR-vaccinated matched control children through use of the Doctor’s Independent Network, a general practice database . The authors observed no differences between case and control children in practitioner consultation rates—a surrogate for parental concerns about their child’s development—within 6 months after MMR vaccination, which suggests that the diagnosis of autism was not temporally related to MMR vaccination.
- In Finland, using national registers, researchers linked hospitalization records to vaccination records in 535,544 children vaccinated during 1982–1986 . Of 309 children hospitalized for autistic disorders, no clustering occurred relative to the time of MMR vaccination.
- In Denmark, again using a national registry, researchers determined vaccination status and autism diagnosis in 537,303 children born during 1991–1998 . The authors observed no differences in the relative risk of autism between those who did and those who did not receive MMR vaccine. Among autistic children, no relationship between date of vaccination and development of autism was observed.
- In metropolitan Atlanta, using a developmental surveillance program, researchers compared 624 autistic children with 1824 matched control children . Vaccination records were obtained from state immunization forms. The authors observed no differences in age at vaccination between autistic and nonautistic children, which suggests that early age of MMR vaccine exposure was not a risk factor for autism.
Prospective observational studies
Capitalizing on a long-term vaccination project maintained by the National Board of Health, investigators in Finland performed 2 prospective cohort studies. Researchers prospectively recorded adverse events associated with MMR-vaccinated children during 1982–1996 and identified 31 with gastrointestinal symptoms; none of the children developed autism [16
]. A further analysis of this cohort revealed no vaccine-associated cases of autism among 1.8 million children [17
]. Although this cohort was analyzed using a passive surveillance system, the complete absence of an association between gastrointestinal disease and autism after MMR vaccination was compelling.