Abstract

It has been suggested that vaccination against measles, mumps, and rubella (MMR) is a cause of

autism.

We conducted a retrospective cohort study of all children born in Denmark from January 1991

through December 1998. The cohort was selected on the basis of data from the Danish Civil

Registration System, which assigns a unique identification number to every live-born infant and

new resident in Denmark. MMR-vaccination status was obtained from the Danish National

Board of Health. Information on the children's autism status was obtained from the Danish

Psychiatric Central Register, which contains information on all diagnoses received by patients in

psychiatric hospitals and outpatient clinics in Denmark. We obtained information on potential

confounders from the Danish Medical Birth Registry, the National Hospital Registry, and

Statistics Denmark.

Of the 537,303 children in the cohort (representing 2,129,864 person-years), 440,655 (82.0

percent) had received the MMR vaccine. We identified 316 children with a diagnosis of autistic

disorder and 422 with a diagnosis of other autistic-spectrum disorders. After adjustment for

potential confounders, the relative risk of autistic disorder in the group of vaccinated children, as

compared with the unvaccinated group, was 0.92 (95 percent confidence interval, 0.68 to 1.24),

and the relative risk of another autistic-spectrum disorder was 0.83 (95 percent confidence

interval, 0.65 to 1.07). There was no association between the age at the time of vaccination, the

time since vaccination, or the date of vaccination and the development of autistic disorder.

This study provides strong evidence against the hypothesis that MMR vaccination causes autism.

Keywords MMR vaccine, autism.

INTRODUCTION

1

The vaccination against measles, mumps, and rubella (MMR) controversy refers to claims

that autism is caused by the MMR vaccine against measles, mumps, and rubella. The scientific

consensus is that no credible scientific evidence links the vaccine to autism, and that the

vaccine's benefits greatly outweigh its risks.

Claims of a connection between the vaccine and autism were initially raised in a 1998

paper in the respected British medical journal The Lancet. After it was discovered that Andrew

Wakefield, the paper's lead author, had received major funding from British trial lawyers seeking

evidence, ten of the paper's twelve coauthors retracted its interpretation of an association

between MMR vaccine and autism. It was also discovered that Wakefield had previously filed

for a patent on a rival vaccine using technology that lacked scientific credibility, and that

Wakefield knew but did not publish test results that contradicted his theory by showing that no

measles virus was found in the children tested. In 2009 The Sunday Times reported that

Wakefield had manipulated patient data and misreported results in his 1998 paper, creating the

appearance of a link with autism. A special court convened in the United States to review claims

under the National Vaccine Injury Compensation Program ruled on 12 February 2009 that

parents of autistic children are not entitled to compensation in their contention that certain

vaccines caused autism in their children

MMR VACCINE

The MMR vaccine is a mixture of three live attenuated viruses, administered via injection for

immunization against measles, mumps and rubella (also called German measles).

- Measles - this can cause ear infections, pneumonia, fits and encephalitis (inflammation of

the brain). Sometimes it can be fatal.

- Mumps - this can cause meningitis, which can result in deafness. It may cause

inflammation of the pancreas, leading to pain, nausea and vomiting. In boys it can

damage the testicles and cause infertility.

- Rubella - this is also known as German measles and is usually a minor illness. However,

it's harmful to pregnant women. If you become infected during the first 10 weeks of

pregnancy, it's very likely to cause problems in your unborn baby. These include heart

damage, blindness, deafness and brain damage. It can also lead to miscarriage. If you

2

become infected with rubella between 10 and 16 weeks, your baby may still be harmed

but the risk is smaller.(1)(2)

Evidence suggests that almost everyone who has had a successful immunization is protected

against these diseases for life. The vaccine has been around for 30 years and is used in over 100

countries. More than 500 million doses have been given. It is generally administered to children

around the age of one year, with a second dose before starting school (i.e. age 4/5). The second

dose is not a booster; it is a dose to produce immunity in the small number of persons (2-5%)

who fail to develop measles immunity after the first dose. In the United States, the vaccine was

licensed in 1971 and the second dose was introduced in 1989. It is widely used around the world;

since introduction of its earliest versions in the 1970s, over 500 million doses have been used in

over 60 countries. As with all vaccinations, long-term effects and efficacy are subject to

continuing study. The vaccine is sold by Merck as M-M-R II, GlaxoSmithKline Biologicals as

Priorix, Serum Institute of India as Tresivac, and sanofi pasteur as Trimovax.

Although children usually recover from measles, mumps or rubella, each illness can be

unpleasant and have serious consequences.

MMR Vaccine Safety

Adverse reactions, rarely serious, may occur from each component of the MMR vaccine.

10% of children develop fever, malaise and a rash 5–21 days after the first vaccination; 5%

develop temporary joint pain. Older women appear to be more at risk to joint pain, acute

arthritis, and even (rarely) chronic arthritis. Anaphylaxis is an extremely rare but serious allergic

reaction to the vaccine. The vaccine product brief lists many other adverse reactions.

The number of reports on neurologic disorders is very small, other than evidence for an

association between a form of the MMR vaccine containing the Urabe mumps strain and rare

adverse events of aseptic meningitis, a transient mild form of viral meningitis. The UK National

Health Service stopped using the Urabe mumps strain in the early 1990s due to cases of transient

mild viral meningitis, and switched to a form using the Jeryl Lynn mumps strain instead. The

Urabe strain remains in use in a number of countries; MMR with the Urabe strain is much

cheaper to manufacture than with the Jery Lynn strain, and a strain with higher efficacy along

with a somewhat higher rate of mild side effects may still have the advantage of reduced

incidence of overall adverse events.

3

The Cochrane Library review found several problems in the quality of MMR vaccine

safety studies. Its authors concluded by recommending the adoption of standardized definitions

of adverse events. The review's abstract concludes, "The design and reporting of safety outcomes

in MMR vaccine studies, both pre- and post-marketing, are largely inadequate. The evidence of

adverse events following immunisation with MMR cannot be separated from its role in

preventing the target diseases." (2)

MMR Vaccine Controversy

In February 1998, the Lancet published an article titled “Illeal-Lymphoid-Nodular Hyperplasia,

Non-Specific Colitis and Pervasive Developmental Disorder in Children,” which suggested that

MMR vaccine could contribute to the development of autism. Intense media coverage of the

article followed its publication, and many parents, particularly in the UK, refuse MMR

vaccination of their children. (3)

AUTISM

Definition

Autism is a complex disorder of the central nervous system that has the following 3 defining

core features:

- Problems with social interactions

- Impaired verbal and nonverbal communication

- A pattern of repetitive behavior with narrow, restricted interests 

Childhood autism

Children with symptoms before the age of 3 years that meet the necessary criteria* under each

section of the diagnostic triad for autism: communication difficulties, problems with social

interaction, and behavior problems such as stereotyped repetitions.

Atypical autism

4

Cases with many of the features of childhood autism but not quite meeting the required criteria

for that diagnosis, or with atypical features such as onset of symptoms after age 3 years (also

known as pervasive developmental disorder not otherwise specified).

Developmental regression

A documented deterioration in any aspect of development or reported loss of skills, however

transient.

*ICD-10 (international classification of diseases, 10th revision) and DSMIV (Diagnostic and

Statistical Manual of Mental Disorders, 4th ed). (8)

Causes of Autism

Although autism is the result of a neurologic abnormality, the cause of these problems with

the nervous system is unknown in most cases. Research findings indicate a strong genetic

component. Most likely, environmental, immunologic, and metabolic factors also influence the

development of the disorder.

- There is probably no single gene or genetic defect that is responsible for autism.

Researchers suspect that there are a number of different genes that, when combined

together, increase the risk of getting autism. In families with one child with autism, the

risk of having another child with autism is 3-8%. The concordance of autism in

monozygotic twins is 30%. A number of studies have found that first-degree relatives of

children with autism also have an increased risk of autism spectrum disorders.

- In some children, autism is linked to an underlying medical condition. Examples include

metabolic disorders (untreated phenylketonuria [PKU]), congenital infections (rubella,

cytomegalovirus [CMV], toxoplasmosis), genetic disorders (fragile X syndrome,

tuberous sclerosis), developmental brain abnormalities (microcephaly, macrocephaly,

cerebral dysgenesis), and neurologic disorders acquired after birth (lead encephalopathy,

bacterial meningitis). These medical disorders alone do not cause autism as most children

with these conditions do not have autism.

- Environmental factors and exposures may interact with genetic factors to cause an

increased risk of autism in some families.

5

Over time, many different theories have been proposed about what causes autism. Some of

these theories are no longer accepted, however.

- Emotional trauma: Some believed that emotional trauma at an early age, especially bad

parenting, was to blame. This theory has been rejected.

- Vaccines: Although the mercury preservative used in some vaccines is known to be

neurotoxic, the most recent research on this subject does not suggest a specific link

between vaccines and autism. (4)

DISCUSSION

1. Study from The Lancet

Autism became a center of controversy in 1998, when an article in The Lancet ignited

concerns about vaccine safety.

The most worrisome feature of The Lancet article was a suggestion that the autistic syndrome

was precipitated by measles-mumps-rubella (MMR) vaccination. 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

- Methods

We did a matched case-control study using the UK General Practice Research Database.

Cases were people born in 1973 or later who had first recorded diagnosis of pervasive

developmental disorder while registered with a contributing general practice between

1987 and 2001. Controls were matched on age, sex, and general practice.

- Findings

1294 cases and 4469 controls were included. 1010 cases (78·1%) had MMR vaccination

recorded before 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 0·86

(95% CI 0·68—1·09). 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.

6

- Interpretation

Our findings suggest that MMR vaccination is not associated with an increased risk of

pervasive developmental disorders. (6)

2. Study in Denmark

A 2002 retrospective cohort study of all 537,303 children born in Denmark from January

1991 through December 1998 found no statistically significant difference in risk of

autism among the 440,655 who were vaccinated with MMR. This study provided strong

evidence against the hypothesis that MMR vaccination causes autism. (9)

3. Report from London

Researchers studied 473 autistic children born in London between 1979 and 1998. When they

compared the years before the MMR vaccine was introduced and the years following its

introduction in 1988, they found no difference in the proportion of autistic children with bowel

problems or developmental regression. Based on that and earlier studies, the United Kingdom's

Committee on Safety of Medicines, which advises the government, ruled that MMR vaccine is

safe and effective and that, overall, the vaccine's benefits far outweigh any adverse effects.

Even so, parents of autistic children and some British physicians are asking that more

research be conducted and are also asking the British government to make single-dose vaccines

more available. Fears that the vaccine can cause autism and bowel disease have led to a

reduction in the number of children being vaccinated, from 85% down to as low as 65% in some

parts of the country. Health officials are concerned that low immunity could spark epidemics,

especially with measles. While this study did not address the broader issue of an association

between use of the MMR vaccine and development of autism, other studies have failed to show

such an association. (10)

CONCLUSION

7

This study provides three strong arguments against a causal relation between MMR vaccination

and autism. First, the risk of autism was similar in vaccinated and unvaccinated children, in both

age-adjusted and fully adjusted analyses. Second, there was no temporal clustering of cases of

autism at any time after immunization. Third, neither autistic disorder nor other autistic-spectrum

disorders were associated with MMR vaccination. Furthermore, the results were derived from a

nationwide cohort study with nearly complete follow-up data. (9)

Five years after the controversial report in The Lancet, 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. 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. 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.

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. (7)

REFERENCES

8

1. Bupa’s Health Information Team. Measles, Mumps, and Rubella (MMR) Vaccine. Available

at http://hcd2.bupa.co.uk/fact_sheets/html/mmr.html. Accessed January 17, 2010.

2. Wikipedia. MMR Vaccine. Available at http://en.wikipedia.org/wiki/MMR_vaccine.

Accessed January 17, 2010.

3. Immunization Action Coalition. MMR Vaccine Does Not Cause Autism. Available at

http://www.immunize.org/catg.d/p4026.pdf. Accessed January 17, 2010.

4. Cynthia R Ellis. Autism. Available at

http://www.emedicinehealth.com/autism/page18_em.htm. Accessed January 17, 2010.

5. Mayo Clinic. Autism Risk Factors. Available at

http://www.mayoclinic.com/health/autism/DS00348/DSECTION=risk-factors. Accessed

January 17, 2010.

6. Smeeth L, Cook C, Fombonne E, et al. MMR Vaccination and pervasive developmental

disorders: a case-control study.The Lancet; 364: 963-969.

7. Skegg DC, Phill D. Autism and Measles-Mumps-Rubella (MMR) Vaccination: A Challenge

for Pharmacoepidemiology. Pharmacotherapy. 2003;23(12).

8. Taylor B, Miller E, Lingam R, et al. Measles, mumps, and rubella vaccination and bowel

problems or developmental regression in children with autism: population study. BMJ

2002;324:393-396 .

9. Madsen KM, Hviid A, Vestergaard M, et al. A population-based study of measles, mumps,

and rubella vaccination and autism. New England Journal of Medicine 2002;347:1477-82.

10. Steven Fox. Measles, Mumps, Rubella Combo Safe. Available at

http://www.medscape.com/viewarticle/433133. Accessed February 8, 2010.

9

A Controversy of Measles, Mumps, and Rubella

(MMR) Vaccine and Autism

Fania Pancar Fadilla

030.06.086

Faculty of Medicine Trisakti University

Jakarta

2010

10