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Although child vaccination rates remain high, some parental concern persists that vaccines might cause autism. Three specific hypotheses have been proposed: (1) the combination measles-mumps-rubella vaccine causes autism by damaging the intestinal lining, which allows the entrance of encephalopathic proteins; (2) thimerosal, an ethylmercury-containing preservative in some vaccines, is toxic to the central nervous system; and (3) the simultaneous administration of multiple vaccines overwhelms or weakens the immune system. We will discuss the genesis of each of these theories and review the relevant epidemiological evidence.
A worldwide increase in the rate of autism diagnoses—likely driven by broadened diagnostic criteria and increased awareness—has fueled concerns that an environmental exposure like vaccines might cause autism. Theories for this putative association have centered on the measles-mumps-rubella (MMR) vaccine, thimerosal, and the large number of vaccines currently administered. However, both epidemiological and biological studies fail to support these claims.
On 28 February 1998, Andrew Wakefield, a British gastroenterologist, and colleagues  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.  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 , ~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.  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 .
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.  (table 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.
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.
Additional population-based studies considered the relationship between MMR vaccine and the “new variant” form of autism proposed by Wakefield et al. —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).
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.
Four retrospective, observational studies addressed the relationship between MMR vaccine and autism.
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 . A further analysis of this cohort revealed no vaccine-associated cases of autism among 1.8 million children . 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.
Thimerosal—50% ethylmercury by weight—is an antibacterial compound that has been used effectively in multidose vaccine preparations for >50 years  (thimerosal is not contained in live-virus vaccines, such as MMR). In 1997, the US Food and Drug Administration Modernization Act mandated identification and quantification of mercury in all food and drugs; 2 years later, the US Food and Drug Administration found that children might be receiving as much as 187.5 μg of mercury within the first 6 months of life. Despite the absence of data suggesting harm from quantities of ethylmercury contained in vaccines, in 1999, the American Academy of Pediatrics and the Public Health Service recommended the immediate removal of mercury from all vaccines given to young infants . Wide-spread and predictable misinterpretation of this conservative, precautionary directive, coupled with a public already concerned by a proposed but unsubstantiated link between vaccination and autism, understandably provoked concern among parents, which led to the birth of several antimercury advocacy groups. However, because the signs and symptoms of autism are clearly distinct from those of mercury poisoning, concerns about mercury as a cause of autism were—similar to those with MMR vaccine—biologically implausible ; children with mercury poisoning show characteristic motor, speech, sensory, psychiatric, visual, and head circumference changes that are either fundamentally different from those of or absent in children with autism. Consistent with this, a study performed by scientists at the Centers for Disease Control and Prevention years later showed that mercury in vaccines did not cause even subtle signs or symptoms of mercury poisoning .
Despite the biological implausibility of the contention that thimerosal in vaccines caused autism, 7 studies—again descriptive or observational—were performed (table 2). Four other studies have been reviewed in detail elsewhere  but are not discussed here because their methodology is incomplete and unclear and, thus, cause difficulty in drawing meaningful conclusions.
Three ecological studies performed in 3 different countries compared the incidence of autism with thimerosal exposure from vaccines. In each case, the nationwide removal of thimerosal—which occurred in 1992 in Europe and in 2001 in the United States—allowed robust comparisons of vaccination with thimerosal-containing and thimerosal-free products, as follows:
Four cohort studies that examined thimerosal exposure and autism have been performed, as follows:
When studies of MMR vaccine and thimerosal-containing vaccines failed to show an association with autism, alternative theories emerged. The most prominent theory suggests that the simultaneous administration of multiple vaccines overwhelms or weakens the immune system and creates an interaction with the nervous system that triggers autism in a susceptible host. This theory was recently popularized in the wake of a concession by the Vaccine Injury Compensation Program with regard to the case of a 9-year-old girl with a mitochondrial enzyme deficiency whose encephalopathy, which included features of autism spectrum disorder, was judged to have worsened following the receipt of multiple vaccines at age 19 months . Despite reassurances by the Centers for Disease Control and Prevention that the Vaccine Injury Compensation Program’s action should not be interpreted as scientific evidence that vaccines cause autism, many in the lay press and the public have not been reassured.
The notion that children might be receiving too many vaccines too soon and that these vaccines either overwhelm an immature immune system or generate a pathologic, autism-inducing autoimmune response is flawed for several reasons:
Twenty epidemiologic studies have shown that neither thimerosal nor MMR vaccine causes autism. These studies have been performed in several countries by many different investigators who have employed a multitude of epidemiologic and statistical methods. The large size of the studied populations has afforded a level of statistical power sufficient to detect even rare associations. These studies, in concert with the biological implausibility that vaccines overwhelm a child’s immune system, have effectively dismissed the notion that vaccines cause autism. Further studies on the cause or causes of autism should focus on more-promising leads.
Potential conflicts of interest. P.A.O. is a coinventor and patent coholder of the rotavirus vaccine Rotateq and has served on a scientific advisory board to Merck. J.S.G.: no conflicts.