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Editorial

MMR, autism and inflammatory bowel disease: responding to patient concerns using an evidence-based framework

There is no convincing evidence that the MMR vaccine is associated with autism or IBD

MJA 2001; 175: 127-128

In 1993, a group of researchers led by Andrew Wakefield at the Royal Free Hospital, London, suggested an association between both wild and vaccine measles viruses and inflammatory bowel disease (IBD), based on a small case series of children with Crohn's disease.1 In 1998, the same researchers reported another series of 12 children, and described an apparently new syndrome of an unusual type of IBD associated with developmental disorders such as (but not limited to) autism.2 They suggested that measles-mumps-rubella (MMR) vaccine may cause IBD, resulting in decreased intestinal absorption of essential vitamins and nutrients and possibly leading to developmental disorders such as autism. Wakefield has also expressed the opinion (without any scientific evidence) that such perturbations are less likely if the components of MMR are given separately, spaced several months apart.

Measles remains one of the most severe infectious childhood diseases (Box), and the current vaccine is 95% effective. Yet parents worry about sensational media reports of possible links between vaccines and a variety of medical conditions. Autism and IBD (Box) and their alleged relationship to MMR vaccine have recently been highlighted in the media.  

Epidemiological evidence

Expert groups around the world have expressed the opinion that the suggested associations between the MMR vaccine, IBD and autism are weak and the studies flawed. The studies at the Royal Free Hospital1,2 were conducted on highly selected patients referred for gastrointestinal ailments. The studies had no controls, were unblinded and were not designed to test aetiology or harm. There were multiple potential sources of bias. For example, the association between vaccination and autism was based primarily on parental recall — parents are likely to link changes in behaviour with memorable events such as vaccination, thereby introducing "recall" bias. Such a case-series analysis is unable to determine causal links. Moreover, the onset of autism and MMR vaccination may appear to be associated in time because the average age at which parents report concerns about child development is 18-19 months and most children receive MMR vaccine before their second birthday.

In contrast to Wakefield and colleagues' two small, poorly designed studies,1,2 large, well designed epidemiological studies have shown no association between MMR vaccine and autism. These include a UK population-based study of the vaccination status of 498 children with autism,6 a study of the rates of IBD and autism among 6100 French schoolchildren,7 and an examination of trends in the incidence of autism and MMR vaccine coverage over time in California3 and in UK general practices.4 Similarly, a Finnish study of 1.8 million children over 14 years that looked at adverse events after MMR vaccination did not document a single case of autism or IBD as a consequence of MMR vaccination.8  

Virological evidence

In their 1993 study, Wakefield and colleagues reported identification of measles virus in bowel tissue of patients with Crohn's disease.1 Other laboratory studies using similar methodology have not found measles virus in patients with IBD. In fact, one group suggested that the reported "measles virus" represented a cross-reaction with another protein structurally similar to certain measles antigens.9 More sensitive testing methods have not revealed any evidence of measles virus in the gut of patients with Crohn's disease or ulcerative colitis.10

Recently, Wakefield and O'Leary presented data to the Immunisation Safety Committee of the US Institute of Medicine suggesting that measles virus has been detected by very sensitive polymerase chain reaction (PCR) methods in the gut of selected autistic children.11 These data have not been published in the peer-reviewed scientific literature. Kawashima and colleagues in Japan have published a study reporting the detection of measles virus by PCR in peripheral mononuclear cells of individuals with autism and bowel disease. However, these findings have not been replicated by other laboratories, and most studies have found no evidence for the presence of measles virus in the gut in inflammatory disease.11 Interestingly, there was no mention of detection of vaccine viruses in the bowel or brain tissues of any patients in the 1998 study of Wakefield and colleagues,2 in contrast with their 1993 report.1  

Level of evidence

Wakefield's studies provide very weak (National Health and Medical Research Council Level IV) evidence for harm or causation relating to the MMR vaccine.12 The "Bradford Hill" criteria for causation13 are poorly fulfilled by Wakefield's studies.1,2 Specifically, there is no estimate of the strength of association, no evidence of a dose-response relationship or temporal sequence, no consistent findings from other investigators, no coherence with established facts, and poor specificity of association.14

In addition to there being no evidence to support a causal relationship between MMR and autism, Wakefield's proposal that the vaccine components of MMR be given separately is unsupported by any evidence. Indeed, giving these vaccines separately has many disadvantages. First, children will receive some components later than recommended, risking exposure and infection in the intervening time. Second, there are additional injections and some may be omitted, or viral interference may reduce vaccine effectiveness if components are given separately but too close together. Except for monovalent rubella, these vaccines are not currently available separately in Australia, and requests to give them separately should be strenuously resisted.  

Consensus about the safety of MMR by expert groups

The World Health Organization rejects an association between MMR and autism, and "strongly endorses the use of MMR . . . vaccine on the grounds of its convincing record of safety and efficacy".15 In 1998, a meeting of the British Medical Research Council and a group of national and international experts concluded that there was "no evidence to indicate any link between MMR vaccination and bowel disease or autism".16 In April 2001, the Institute of Medicine released its report Immunization safety review: measles-mumps-rubella vaccine and autism,11 which concluded that the available evidence rejects a causal association between MMR and autism, although recommending that further research into the issue be conducted because of public concern.

In view of considerable epidemiological evidence on the safety of MMR vaccine, we believe that Wakefield's small, unsubstantiated case series should be seen in correct perspective, and that parents and healthcare professionals should be reassured that there is no evidence that the MMR vaccine is associated with autism or IBD.

C Raina MacIntyre
 Senior Lecturer

Peter B McIntyre
 Deputy Director
National Centre for Immunisation Research and Surveillance of Vaccine
Preventable Diseases, Children's Hospital, Westmead, NSW.
rainamAToptusnet.com.au

  1. Wakefield AJ, Pittilo RM, Sim R, et al. Evidence of persistent measles virus infection in Crohn's disease. J Med Virol 1993; 39: 345-353.
  2. Wakefield AJ, Murch SH, Anthony A, et al. Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet 1998; 351: 637-641.
  3. Dales L, Hammer SJ, Smith NJ. Time trends in autism and in MMR immunization coverage in California. JAMA 2001; 285: 1183-1185.
  4. Kaye JA, del Mar Melero-Montes M, Jick H. Mumps, measles, and rubella vaccine and the incidence of autism recorded by general practitioners: a time trend analysis. BMJ 2001; 322: 460-463.
  5. Fombonne E. The epidemiology of autism: a review. Psychol Med 1999; 29: 769-786.
  6. Taylor B, Miller E, Farrington CP, et al. Autism and measles, mumps, and rubella vaccine: no epidemiological evidence for a causal association. Lancet 1999; 353: 2026-2029.
  7. Fombonne E, Du Mazaubrun C, Cans C, Grandjean H. Autism and associated medical disorders in a French epidemiological survey. J Am Acad Child Adolesc Psychiatry 1997; 36: 1561-1569.
  8. Patja A, Davidkin I, Kurki T, et al. Serious adverse events after measles-mumps-rubella vaccination during a fourteen-year prospective follow-up. Pediatr Infect Dis J 2000; 19: 1127-1134.
  9. Iizuka M, Chiba M, Yukawa M, et al. Immunohistochemical analysis of the distribution of measles related antigen in the intestinal mucosa in inflammatory bowel disease. Gut 2000; 46: 163-169.
  10. Afzal MA, Armitage E, Ghosh S, et al. Further evidence of the absence of measles virus genome sequence in full thickness intestinal specimens from patients with Crohn's disease. J Med Virol 2000; 62: 377-382.
  11. Institute of Medicine. Immunization safety review: measles-mumps-rubella vaccine and autism. Washington, DC: National Academy Press, 2001. Available at: <http://books.nap.edu/html/mmr> (Accessed 4 July 2001).
  12. Levine M, Walter S, Lee H, et al. Users' guides to the medical literature. IV. How to use an article about harm. Evidence-Based Medicine Working Group. JAMA 1994; 271: 1615-1619.
  13. Wilkinson L. Sir Austin Bradford Hill: medical statistics and the quantitative approach to prevention of disease. Addiction 1997; 92: 657-666.
  14. Halsey NA, Hyman SL. Measles-mumps-rubella vaccine and autistic spectrum disorder: report from the New Challenges in Childhood Immunizations Conference convened in Oak Brook, Illinois, June 12-13, 2000. Pediatrics 2001; 107(5): 1-23.
  15. World Health Organization. Statement on the use of MMR vaccine. Available at: <http://www.who.int/vaccines-diseases/safety/hottop/mmrstatement.htm> Accessed 4 July 2001.
  16. Medical Research Council. Report from the Working Party on MMR. London: MRC, 1998.

©MJA 2001
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Measles, inflammatory bowel disease and autism
    Measles

    Measles is virtually universal among unimmunised children in all countries: 99.9% of unimmunised people will contract measles, 90% before the age of 20. One in every 5000-10000 cases results in death from the acute effects of the disease. Worldwide, there were 888000 deaths due to measles in 1998, more than the number due to breast or skin cancer, homicide or violence.

    Inflammatory bowel disease (IBD)

    IBD is a group of chronic inflammatory disorders of the small and large bowel, the commonest being ulcerative colitis and Crohn's disease. The cause of IBD is not understood, but both an immune mechanism and a genetic predisposition are probably involved. IBD is relatively rare, with an incidence of 6-8 cases per 100000 population for ulcerative colitis and 2 cases per 100000 for Crohn's disease. It usually occurs in people aged between 15 and 30 years, but can occur in children.

    Autism

    Autism is a developmental disorder that is usually identified between the ages of 18 months and three years. Four times more common in boys than girls, autism occurs in all racial and social groups. Autistic children and adults typically have difficulties in verbal and non-verbal communication, social interactions and leisure or play activities. A single cause of autism has not been identified, but current research implicates neurodevelopmental, genetic and environmental factors. The sex differential suggests a strong genetic component.

    Many children have some features of autism but do not fulfil all the diagnostic criteria. There has been an apparent increase in the incidence of autism in recent decades. In the United States the rate increased from 44/100000 births in 1980 to 208/100000 births in 1994,3 while in the United Kingdom the rate increased from 3/100000 births in 1988 to 21/100000 births in 1999.4 This has been attributed largely to changing case definitions and classifications (which now include less severe forms of the disease) and improved recognition.5 The discrepancy between the US and UK rates may be evidence of inconsistent case definitions. It is uncertain how much, if any, of the increased incidence is independent of diagnostic practice.

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