The Wakefield studies

Two studies have been cited by those claiming that the MMR vaccine causes autism. Both studies are critically flawed.

First study

In 1998, Andrew Wakefield and colleagues published a paper in the journal The Lancet. Wakefield's hypothesis was that the measles, mumps and rubella (MMR) vaccine caused a series of events that include intestinal inflammation, entrance into the bloodstream of proteins harmful to the brain, and consequent development of autism. In support of his hypothesis, Dr. Wakefield described 12 children with developmental delay — eight had autism. All of these children had intestinal complaints and developed autism within one month of receiving MMR.

The Wakefield paper published in 1998 was flawed for two reasons:

1. About 90% of children in England received MMR at the time this paper was written. Because MMR is administered at a time when many children are diagnosed with autism, it would be expected that most children with autism would have received an MMR vaccine, and that many would have received the vaccine recently. The observation that some children with autism recently received MMR is, therefore, expected. However, determination of whether MMR causes autism is best made by studying the incidence of autism in both vaccinated and unvaccinated children. This wasn't done.
2. Although the authors claim that autism is a consequence of intestinal inflammation, intestinal symptoms were observed after, not before, symptoms of autism in all eight cases.

This study was subsequently retracted; in scientific terms, this means that the paper is not part of the scientific record because it was found to be based on scientific misconduct. In this case, the studies were deemed fraudulent and data misrepresented.

Second study

In 2002, Wakefield and coworkers published a second paper examining the relationship between measles virus and autism. The authors tested intestinal biopsy samples for the presence of measles virus from children with and without autism. Seventy-five of 91 children with autism were found to have measles virus in intestinal biopsy tissue as compared with only 5 of 70 patients who didn't have autism. On its surface, this was a concerning result. However, the second Wakefield paper was also critically flawed for the following reasons:

1. Measles vaccine virus is live and attenuated. After inoculation, the vaccine virus probably replicates (or reproduces itself) about 15 to 20 times. Measles vaccine virus is likely to be taken up by specific cells responsible for virus uptake and presentation to the immune system (termed antigen-presenting cells or APCs). Because all APCs are mobile, and can travel throughout the body (including the intestine), it is plausible that a child immunized with MMR would have measles virus detected in intestinal tissues using a very sensitive assay. To determine if MMR is associated with autism, one must determine if the finding is specific for children with autism. Therefore, children with or without autism must be identical in two ways. First, children with or without autism must be matched for immunization status (i.e., receipt of the MMR vaccine). Second, children must be matched for the length of time between receipt of MMR vaccine and collection of biopsy specimens. Although this information was clearly available to the investigators and critical to their hypothesis, it was specifically omitted from the paper.
2. Because natural measles virus is still circulating in England, it would have been important to determine whether the measles virus detected in these samples was natural measles virus or vaccine virus. Although methods are available to distinguish these two types of virus, the authors chose not to use them.
3. The method used to detect measles virus in these studies was very sensitive. Laboratories that work with natural measles virus (such as the lab where these studies were performed) are at high risk of getting results that are incorrectly positive. No mention is made in the paper as to how this problem was avoided.
4. As is true for all laboratory studies, the person who is performing the test should not know whether the sample is obtained from a case with autism or without autism (blinding). No statements were made in the methods section to assure that blinding occurred.

Studies showing that MMR vaccine does not cause autism

Several studies have been performed that disprove the notion that MMR causes autism.

Brent Taylor and co-workers

In 1999, Brent Taylor and co-workers examined the relationship between receipt of MMR and development of autism in an excellent, well-controlled study. Taylor examined the records of 498 children with autism or autism-like disorder.

Cases were identified by registers from the North Thames region of England before and after the MMR vaccine was introduced into the United Kingdom in 1988. Taylor then examined the incidence and age at diagnosis of autism in vaccinated and unvaccinated children. He found that:

1. The percentage of children vaccinated was the same in children with autism as in other children in the North Thames region.
2. No difference in the age of diagnosis of autism was found in vaccinated and unvaccinated children.
3. The onset of symptoms of autism did not occur within two, four, or six months of receiving the MMR vaccine.

Madsen and colleagues

One of the best studies was performed by Madsen and colleagues in Denmark between 1991 and 1998 and reported in the New England Journal of Medicine. The study included 537,303 children representing 2,129,864 person-years of study. Approximately 82% of children had received the MMR vaccine. The group of children was selected from the Danish Civil Registration System, vaccination status was obtained from the Danish National Board of Health, and children with autism were identified from the Danish Central Register. The risk of autism in the group of vaccinated children was the same as that in unvaccinated children. Furthermore, 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 autism.

Subsequent studies and meta-analysis have corroborated the findings that the MMR vaccine does not cause autism.

Watch as Dr. Offit talks about vaccines and autism in this short video, part of the Talking about Vaccines with Dr. Paul Offit video series.

Other information on the causes of autism

Genetics

One of the best ways to determine whether a particular disease or syndrome is genetic is to examine the incidence in identical and fraternal twins. Using a strict definition of autism, among twins in which one has been diagnosed with autism, approximately 60% of the time an identical twin is also diagnosed, and 0% of the time is a fraternal twin diagnosed with autism. Using a broader definition of autism (i.e., autistic spectrum disorder), these rates rise to approximately 92% in identical twins and about 10% of the time when the twins are fraternal. Therefore, autism clearly has a genetic basis.

"Home-movie" studies

Clues to the causes of autism can be found in studies examining when the symptoms of autism are first evident. Perhaps the best data examining when symptoms of autism are first evident are the "home-movie" studies. These studies took advantage of the fact that many parents take movies of their children during their first birthday (before they have received the MMR vaccine).

Home movies from children who were eventually diagnosed with autism and those who were not diagnosed with autism were coded and shown to developmental specialists. Investigators were, with a very high degree of accuracy, able to separate autistic from non-autistic children at 1 year of age. These studies found that subtle symptoms of autism were present earlier than some parents had suspected, and that receipt of the MMR vaccine did not precede the first symptoms of autism. Other investigators extended the home-movie studies of 1-year-old children to include videotapes of children taken at 2 to 3 months of age.

Timing of first symptoms

Using a sophisticated movement analysis, videos from children eventually diagnosed with autism or not diagnosed with autism were coded and evaluated for their capacity to predict autism. Children who were eventually diagnosed with autism were predicted from movies taken in early infancy. This study supported the hypothesis that very subtle symptoms of autism are present in early infancy and argues strongly against vaccines as a cause of autism.

Structural abnormalities of the nervous system

Toxic or viral insults to the fetus that cause autism, as well as certain central nervous system disorders associated with autism, support the notion that autism is likely to occur in the womb. For example, children exposed to thalidomide during the first or early second trimester were found to have an increased incidence of autism. Thalidomide was a medication that used to be prescribed to pregnant women to treat nausea. However, autism occurred in children with ear, but not arm or leg, abnormalities. Because ears develop before 24 days gestation, and arms and legs develop after 24 days gestation, the risk period for autism following receipt of thalidomide must have been before 24 days gestation. In support of this finding, Rodier and colleagues found evidence for structural abnormalities of the nervous system in children with autism. These abnormalities could only have occurred during development of the nervous system in the womb.

Natural rubella infection

Similarly, children with congenital rubella syndrome are at increased risk for development of autism. Risk is associated with exposure to rubella before birth but not after birth.

Conclusions

The following studies all support the fact that autism occurs during development of the nervous system early in the womb:

• The genetics of autism
• The timing of the first symptoms of autism (home-movie studies)
• The relationship between autism and the receipt of the MMR vaccine
• Structural abnormalities of the nervous system of children with autism
• Thalidomide and natural rubella infection

Unfortunately, for current and future parents of children with autism, the controversy surrounding vaccines has caused attention and resources to focus away from a number of promising leads.

The Autism Science Foundation is a non-profit organization that follows the developments related to autism; in particular, making sure that the studies are scientifically sound. Their website provides up-to-date information about what is known about the causes of autism.

Resources

The Vaccine Education Center has compiled the following resources addressing concerns surrounding vaccine safety as it relates to autism. These materials are based on the scientific findings of many scientists studying hundreds of thousands of children on multiple continents. The one clear and consistent finding is that vaccines do not cause autism.

Print materials

• Vaccines and Autism: What you should know – English  | Spanish
• Thimerosal: What you should know - English | Spanish
• Too many vaccines: What you should know - English | Spanish
• Aluminum in vaccines: What you should know - English  | Spanish
• Vaccine ingredients: What you should know - English | Spanish
• Recommended immunization schedule: What you should know - English | Spanish
• The Facts About Childhood Vaccines – English| Spanish
• Vaccine Safety and Your Child booklet – English | Spanish

Webpages

• Vaccine Safety References

Videos

• Do Vaccines Cause Autism?
• Is the MMR Vaccine Safe?
• Pediatricians Discuss Vaccines, Pregnancy, Development & Autism
• Are Combination Vaccines Safe?
• Do Babies Get Too Many Vaccines?
• How Are Vaccines Tested Before They Can Be Given to Kids?
• How Do You Know Whether a Vaccine Has Been Tested Long Enough?

References

DeStefano, R., T.T. Shimabukuro, The MMR vaccine and autism, Ann Rev Virol (2019) 6: 1.1-1.16.
Autism is a developmental disability that can cause significant social, communication, and behavioral challenges. A report published in 1998, but subsequently retracted by the journal, suggested that measles, mumps, and rubella (MMR) vaccine causes autism. However, autism is a neurodevelopmental condition that has a strong genetic component with genesis before one year of age, when MMR vaccine is typically administered.

Hviid A, Hansen JV, Frisch M, Melbye M. Measles, mumps, rubella vaccination and autism. Ann Int Med 2019; epub ahead of print.
The authors evaluated the relationship between receipt of MMR vaccine and the development of autism in more than 650,000 Danish children born between 1999 and 2010. During the study period, about 6,500 children were diagnosed with autism. The authors found no increased risk of autism in those who received one or two doses of MMR vaccine compared with those who didn’t. The authors also found that MMR vaccine did not increase the risk of autism in children with specific risk factors such as maternal age, paternal age, smoking during pregnancy, method of delivery, gestational age, 5-minute APGAR scores, low birthweight, head circumference, and sibling history of autism. Further, by evaluating specific time periods after vaccination, the authors found no evidence for a regressive phenotype triggered by vaccination. The authors concluded that MMR vaccination did not increase the risk for autism or trigger autism in susceptible children.

Jain A, Marshall J, Buikema A, et al. Autism occurrence by MMR vaccine status among US children with older siblings with and without autism. JAMA 2015;313(15):1534-1540.
The authors evaluated about 100,000 younger siblings who did or did not receive an MMR vaccine when the older sibling had been diagnosed with autism spectrum disorder (ASD). For children with or without older siblings with ASD, there were no differences in the adjusted relative risks of ASD between no doses of MMR, one dose of MMR or two doses of MMR. The authors concluded that receipt of MMR vaccine was not associated with increased risk of ASD even among children whose older siblings had ASD, and, therefore, were presumed to be at higher risk for developing this disorder.

Taylor LE, Swerdfeger AL, Eslick GD. Vaccines are not associated with autism: an evidence-based meta-analysis of case-control and cohort studies. Vaccine 2014;32:3623-3629.

The authors conducted a meta-analysis of case-control and cohort studies that examined the relationship between the receipt of vaccines and development of autism. Five cohort studies involving more than 1.2 million children and five case-control studies involving more than 9,000 children were included in the analysis. The authors concluded that vaccinations, components of vaccines (thimerosal), and combination vaccines (MMR) were not associated with the development of autism or autism spectrum disorder.

Hornig M, Briese T, Buie T, et al. Lack of association between measles virus vaccine and autism with enteropathy: a case-control study. PLoS ONE 2008;3(9):e3140.
The authors evaluated children with GI disturbances with and without autism to determine if those with autism were more likely to have measles virus RNA or inflammation in bowel tissues and to determine if autism or GI symptoms related temporally to receipt of MMR.  The authors found no differences between patients with and without autism relative to measles virus presence in the ileum and cecum or GI inflammation. GI symptoms and autism onset were unrelated to the receipt of MMR vaccine.

Uchiyama T, Kurosawa M, Inaba Y. MMR-vaccine and regression in autism spectrum disorders: negative results presented from Japan. J Autism Dev Disord 2007;37:210-217.
MMR vaccination was only utilized in Japan between 1989 and 1993, given as a single dose between 12 and 72 months of age.  The authors examined the rate of autism spectrum disorders (ASD) involving regressive symptoms in children who did or didn’t receive MMR during that period. No significant differences were found in the incidence of ASD regression between those who did or didn’t receive an MMR vaccine.

Afzal MA, Ozoemena LC, O’Hare A, et al. Absence of detectable measles virus genome sequence in blood of autistic children who have had their MMR vaccination during the routine childhood immunization schedule of UK. J Med Virol 2006;78:623-630.
Investigators obtained blood from 15 children diagnosed with autism with developmental regression and a documented previous receipt of MMR vaccine. Measles virus genome was not present in any of the samples tested. The authors concluded that measles vaccine virus was not present in autistic children with developmental regression.

Honda H, Shimizu Y, Rutter M. No effect of MMR withdrawal on the incidence of autism: a total population study. J Child Psychol Psychiatry 2005;46(6):572-579.
MMR vaccination was only utilized in Japan between 1989 and 1993, given as a single dose between 12 and 72 months of age. The authors found that while MMR vaccination rates declined significantly in the birth cohort of years 1988 through 1992 (~70% in 1988, < 30% in 1991 and < 10% in 1992), the cumulative incidence of ASD up to age 7 years increased significantly. The authors concluded that withdrawal of MMR in countries where it is still being used will not lead to a reduction in the incidence of ASD.

Smeeth L, Cook C, Fombonne E, et al. MMR vaccination and pervasive developmental disorders: a case-control study. The Lancet 2004;364:963-969.
The authors reviewed a major United Kingdom database for patients diagnosed with autism or other pervasive developmental disorders (PDD) over a 28-year period and similarly aged patients without those diagnoses to determine if the receipt of MMR vaccination was associated with an increased risk of autism or other PDD. They found no association between MMR vaccine and risk of autism or other PDD.

Madsen KM, Hviid A, Vestergaard M, et al. A population-based study of measles, mumps, and rubella vaccination and autism. N Engl J Med 2002;347(19):1477-1482.
The authors conducted a retrospective review of all children (> 500,000) born in Denmark between 1991 and 1998 to determine if a link existed between receipt of MMR vaccine and diagnosis of autism or autism spectrum disorders. No association was found between ages at the time of vaccination, the time since vaccination, or the date of vaccination and the development of autistic disorder.

Taylor B, Miller E, Farrington CP, et al. Autism and measles, mumps, and rubella vaccine: no epidemiological evidence for a causal association. The Lancet 1999;353:2026-2029.
The authors determined whether the introduction of MMR vaccine in the United Kingdom in 1988 affected the incidence of autism by examining children born between 1979 and 1998. They found no sudden change in the incidence of autism after introduction of MMR vaccine and no association between receipt of the vaccine and development of autism.

Reviewed by Lori Handy, MD, MSCE, on February 05, 2024