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TheOldGeek1</NOBR>

Sent: 12/30/2003 4:06 PM

The prion article was pretty technical, but this one should be comprehensible for just about everyone.

From Pharmacotherapy

Autism and Measles-Mumps-Rubella (MMR) Vaccination: A Challenge for Pharmacoepidemiology

Posted 12/19/2003

David C. G. Skegg, M.B., D.Phil.

Childhood autism was first described 60 years ago,[1] but this distressing condition has attracted increasing attention recently. It is a pervasive developmental disorder defined by the presence of abnormal or impaired development appearing before the age of 3 years and by a characteristic type of abnormal functioning in the three areas of social interaction, communication, and restricted, repetitive behavior.[2, 3] The parents of autistic children usually recognize that their child has been unusual since birth or early life, but sometimes they describe a setback or regression after a period of apparently normal development.[4] Today it is common to refer to an autistic spectrum of disorders, which includes related conditions such as Asperger's syndrome.[4]

Although the causes of autism are not understood, there is strong evidence for a neurobiologic basis with an important genetic component.[5] In a British twin study, 60% of monozygotic pairs, but no dizygotic pairs, were concordant for autism; 92% of monozygotic pairs were concordant for a broader spectrum of related cognitive or social abnormalities, compared with only 10% of dizygotic pairs.[6] Epidemiologic surveys show a higher prevalence of autism in boys, and an association with intellectual disability in many cases.[7] The reported prevalence is highest in the most recent surveys, but this could reflect changes in diagnostic criteria and in recognition of the autistic spectrum (as awareness has increased and services have improved).[7, 8]

Autism became a center of controversy in 1998, when an article in The Lancet ignited concerns about vaccine safety. The authors described 12 children who had chronic enterocolitis associated with a regressive developmental disorder.[9] After a period of apparent normality, these children were said to have lost acquired skills, including communication. In nine patients the behavioral diagnosis was autism. The authors suggested that they were describing a unique disease process, which they later called autistic enterocolitis.[10] By 2001 they claimed to have found similar colonic lesions in over 150 children with autism, in whom the main gastrointestinal presentation was abdominal pain with either constipation or diarrhea.[10]

The most worrisome feature of The Lancet article was a suggestion that the autistic syndrome was precipitated by measles-mumps-rubella (MMR) vaccination.[9] This conclusion was based mainly on the fact that, in eight patients, the onset of behavioral problems was linked, by either the parents or the child's physician, with MMR vaccination. For these eight children the average time from vaccination to first behavioral symptoms was reported to be 6.3 days. The article was published as an "early report" and was accompanied by a critical commentary.[11] Nevertheless, it caused great consternation among parents and some health professionals. Although the authors acknowledged in their article that they had not proved an association between MMR vaccination and the proposed syndrome,[9] there were adverse comments about the safety of the MMR vaccine at the press conference that launched the publication.[12]

Few issues in health care are as emotive as the safety of vaccines to be administered to children. Even when official bodies offer reassuring advice,[13] there is a common tendency to suspect a cover-up. The Lancet authors' observations were highlighted in the media in many countries, including the United States. The media attention was most frenetic in the United Kingdom, where an earlier controversy about the safety of pertussis vaccination interrupted a successful vaccination program and led to epidemics of whooping cough.[14]

Autism tends to appear at around the age when children receive their vaccinations. The onset is usually gradual, so it is difficult to see how parents could reliably link the start of the condition with an event such as administration of a vaccine. Several correspondents pointed out that the uncontrolled series of clinical cases discussed in The Lancet article had not established a temporal association with MMR vaccination, let alone a causal relationship.[15]

In a subsequent letter to The Lancet, the lead author marshaled different evidence in support of his hypothesis. He presented a graph showing trends in recorded autism in California and London, England, and concluded that in both places a marked rise had occurred in the years after MMR vaccination was introduced.[16] The letter was actually a response to a detailed analysis of trends in autism in relation to MMR vaccination in London; the authors concluded that an apparent increase in the incidence of autism in successive birth cohorts could not be related to the introduction of MMR vaccination or to vaccine coverage.[17] Subsequently data from the General Practice Research Database (GPRD) were used to address the same question for children from the United Kingdom.[18] The researchers found that the incidence of autism among boys (as recorded by family physicians) had increased rapidly during years when the prevalence of MMR vaccination had been virtually constant. In another study, the striking increase in the caseload of children with autism in successive birth cohorts in California could not be explained by trends in MMR vaccination.[19]

Although these studies provided strong evidence against the notion that the increasing rates of autism were due to MMR vaccination, they did not exclude the possibility that MMR vaccination could cause autism. This hypothesis was tested directly in a study from Denmark. Researchers used that country's remarkable record keeping to link vaccination records with records of autism. The retrospective cohort study examined data from more than one-half million children born in Denmark from January 1991-December 1998.[20] Using the unique identification number assigned to each infant, they linked records of MMR vaccination status (from the National Board of Health) with records of autism (from the Danish Psychiatric Central Register, which contains information on all diagnoses in outpatient clinics as well as psychiatric hospitals). Information about potential confounding factors was obtained from three other registers. The adjusted relative risk of autism among children who had received the MMR vaccine was 0.92 (95% confidence interval 0.68-1.24). There was also no increase in the risk of other autistic-spectrum disorders. This study was highlighted in a recent systematic review, which concluded that no evidence of an association exists between MMR vaccination and autism.[21]

The feasibility of using record linkage for pharmacoepidemiologic studies in the British National Health Service was also recognized many years ago.[22] This potential has been realized through the development of computerized databases such as the GPRD.[23] In addition to the investigation described earlier,[18] the Boston Collaborative Drug Surveillance Program has used the GPRD in other studies conducted in response to The Lancet article's claims. In a nested case-control study, results showed no evidence that children with autism were more likely than other children to have defined gastrointestinal disorders before their diagnosis of autism.[24]

In this issue of Pharmacotherapy, Drs. Jick and Kaye complete additional parts of the jigsaw puzzle. As well as providing a new case-control evaluation, they show that the marked increase in the incidence rate of recorded autism among boys in British general practices from 1992-2000 was balanced closely by a decline in the rate of certain developmental disorders without a diagnosis of autism.[25] This strongly suggests that the apparent increase in the rate of autism is due primarily to changes in diagnostic practices and ascertainment. A new study from California points to the same conclusion.[26]

Five years after the controversial report in The Lancet,[9] parents and health professionals can have considerable confidence in the safety of the MMR vaccine. If vaccination did occasionally cause an unusual variant of autism, this occurrence would have to be so rare as to escape detection in well-designed epidemiologic studies. Moreover, the recent "epidemic" of diagnosed autism cannot be attributed to the MMR vaccine. Given that the controversial hypothesis proved to be an expensive false alarm, should the paper have been published at all? Although one can only condemn the media frenzy and excessive claims that stemmed from the publication, this question has to be answered in the affirmative.

The reason for this conclusion is that many adverse effects of drugs and vaccines are first recognized by astute clinicians. The process of discovery was analyzed for 18 important adverse reactions that were identified in the two decades after the thalidomide disaster.[27] In 13 of the 18 situations, the first alerts came from anecdotal reports, including single case reports in four instances. Physicians often report their suspicions in letters to medical journals, but national registries also are set up to receive reports of adverse reactions.[28, 29] Once an adverse effect is suspected, epidemiologic studies generally are required to confirm (or refute) the hypothesis, to estimate the magnitude of risk, and to identify any other factors that modify the effect.

If suspicions are not reported promptly, there may be an unacceptable delay in discovering hazards. Hence it was appropriate for the controversial hypothesis to be published. Unfortunately, its reporting in a full article in The Lancet, even though this was designated as an "early report," gave the impression that the hypothesis was based on more than a small series of anecdotal cases and the "hunches" of a few parents and physicians. Moreover, some propo-nents of the hypothesis have been reluctant to accept the reassuring findings of subsequent epidemiologic research, preferring to fuel the controversy through various channels including the news media.

The saga about MMR vaccination and autism illustrates the challenge to pharmacoepidemiologists to be able to investigate suspicions about the safety of drugs or vaccines in a timely and effective manner. There can be no doubt that studies using databases such as the GPRD, as exemplified in the article in this issue of Pharmacotherapy,[25] have a vital role to play in this task.

Reprint Address

Address reprint requests to Professor David Skegg, Department of Preventive and Social Medicine, University of Otago, P.O. Box 913, Dunedin, New Zealand; e-mail: [email protected].

--------------------------------------------------------------------David C. G. Skegg, M.B., D.Phil., from the Department of Preventive and Social Medicine, University of Otago, Dunedin, New Zealand.

New study disputes vaccine, autism link

Critics say mercury in shots led to nervous-system problems

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