Is there a connection between MMR vaccination and onset of autism?

April 2001

WASHINGTON, D.C. – Vaccines are the heroes of infectious diseases – an effective way to prevent and conquer diseases that cripple and kill. Their reputation has been tarnished by people who question their necessity and implicate them as a cause of severe adverse events.

Pediatricians are caught in the middle. How do they defend these infectious disease heroes to parents who think vaccines do more harm than good?

A look at history, as well as current research, may help pediatricians when they talk with parents who are trying to decide whether to vaccinate their children.

Early vaccines

The 1950s and '60s were times of great optimism in America. Antibiotics, better sanitation, pesticides, vaccines and other efforts made considerable improvements in public health. Vaccines especially held great promise in the microbial war.

One of the biggest heroes was polio vaccine. After decades of frightening epidemics of poliomyelitis, Jonas Salk, MD, developed a killed-virus vaccine in 1955, which was 90% effective and safe. Two years later, Albert Sabin, MD, began large trials of oral polio vaccine (OPV). By 1961, children were lining up at churches, schools and clinics to receive vaccine-coated sugar cubes.

To many, it felt downright un-American not to receive polio vaccine, especially when it was so successful. Before the vaccines were used, 13,000 to 20,000 cases of paralytic polio were reported annually. In 1965, there were 61.

Measles vaccine was licensed in 1963. Before the vaccine, 500,000 cases of measles were reported annually, but the incidence was believed to be in the millions, according to the CDC. Following licensure, the incidence of measles dropped to fewer than 100 cases a year.

Then in 1976, swine flu came to America. Public health officials were concerned that this strain of influenza – A/New Jersey/H1N1 — was similar to one that caused the 1918 influenza pandemic, which killed more than 21 million people. Officials recommended widespread vaccination to prevent a pandemic. But the vaccine was associated with severe adverse events, including Guillain-Barré syndrome. However, in retrospect, there have been some questions about the relationship.

"Swine flu threw ice water on the previously warm relationship between public health and individual rights," explained Laurie Garrett, PhD, in her book The Coming Plague.

As the diseases they conquered disappeared, vaccines came under fire. The public questioned whether they were safe, whether they were effective and whether they were still needed.

By the time anecdotal reports linked the whole-cell pertussis component of the diphtheria-tetanus-pertussis (DTP) vaccine to seizures and brain damage, parents were ready to believe a causal relationship, despite little evidence. In the early 1980s, concerns about DTP's safety peaked after the television program "DPT: Vaccine Roulette" and publication of the book, A Shot in the Dark.

Scientific confirmation of the allegations was lacking. No data supported a causal relationship between the vaccine and sudden infant death syndrome or infantile spasms. Mild reactions, such as fever and fussiness, were common, but moderate reactions, such as inconsolable crying, limpness and pallor, were rare.

Despite the findings of studies, parents believed that DTP vaccine caused their child's developmental problems. Those beliefs were articulated by Barbara Loe Fisher, president and cofounder of the National Vaccine Information Center (formerly Dissatisfied Parents Together) and author of A Shot in the Dark. Fisher says the DTP vaccine harmed her son. "Both Chris and I know he was lucky compared to the children who have suffered vaccine reactions and been left quadriplegic, profoundly mentally retarded, epileptic or have died," Fisher told the IOM's Vaccine Safety Committee, which is currently investigating a possible link between autism and measles vaccine.

DTP vaccine was even linked to autism, although in 1990, the IOM said there was no scientific evidence to back this claim.

Now the measles vaccine is in the public's crosshairs.

The Wakefield study

Parents and some physicians — most notably Andrew Wakefield, MD, a gastroenterologist — think that the measles component of the measles-mumps-rubella (MMR) vaccine triggered the development of autism in their children.

Wakefield and his colleagues at the Royal Free Hospital and School of Medicine in London published a study in The Lancet in 1998 in which they found intestinal abnormalities, ranging from lymphoid nodular hyperplasia to aphthoid ulceration in 12 autistic children, according to the report.

Regressive autism is a term used to describe a subset of autistic children who appear to be developing normally, but who then stop progressing.

Wakefield theorized that the vaccine led to the malabsorption of vitamin B12, which is important for central nervous system development, and that this deficiency was a contributing factor to the development of autism.

Parents of 8 of the study children associated the onset of behavioral symptoms with receipt of MMR vaccine.

In March, Wakefield discussed his research at the IOM Immunization Safety Review Committee meeting. He said the children suffered gastrointestinal (GI) symptoms, including abdominal pain, diarrhea and bloating. Several were atopic and had food intolerances. Since his first study, Wakefield said that he has "scoped more than 150 children" with autism and has found the same results.

Several studies since 1998 that looked at the possible relationship between MMR vaccine and autism failed to support Wakefield's findings.

Brent Taylor, MD, also of the Royal Free Hospital, did not find epidemiological evidence for a causal association in a study published in The Lancet one year after Wakefield's. In his population-based study, Taylor identified almost 500 children with autism, and noted when they received the MMR vaccine and when they were diagnosed with autism. The researchers found no temporal association between autism onset and time of MMR vaccination. In addition, developmental regression was not clustered in the months following vaccination.

Most recently, Loring Dales, MD, and colleagues, found similar results to Taylor's when they looked at autistic children in California. "Essentially no correlation was observed between the secular trend of early childhood MMR immunization rates in California and the secular trend in numbers of children with autism enrolled in California's regional service enter system," the researchers wrote in the Journal of the American Medical Association.

Autism

The etiology of autism is unknown, and parents of autistic children are left with more questions than answers. "Parents inevitably try to make sense out of it [the diagnosis]," explained Fred Volkmar, MD, professor of child psychiatry, pediatrics and psychology at Yale Child Study Center. "So, parents will say, 'Gee, this happened right after his sibling was born or right after his grandfather died.'"

Since a child is within a couple of months of being vaccinated anytime in the first 12 months of life, it is easy for a parent to link a vaccination to the event. "There is a natural tendency to want to make sense out of the autism. I think that has to be kept in mind," Volkmar said.

When pressed by the committee, Volkmar said that he has encountered a few parents who thought the symptoms started after receipt of MMR vaccine. "One does see — in my experience not commonly — parents who link the autism with the receipt of vaccine."

In most cases, he said, parents are aware that the child is not developing at the same level as his or her peers. More than 50% of parents are worried in the first year of the child's life. By age 2, 90% of parents have expressed concern about the child's development.

Parents often complain about delays in language development. They worry that the child may be deaf or socially deviant. Unfortunately, Volkmar said, delays in diagnosis are still common.

Incidence

No one knows how many people have autism or similar disorders. Studies done overseas indicate there may be as many as 1:500 children, according to the CDC. Many people think there is an epidemic of autism caused, in part, by the distribution of MMR vaccine, but this is difficult to prove because of the unknown incidence. However, the increase may be due to a change in diagnostic criteria, and some children receiving an autistic designation to obtain needed school services, said Lou Danielson, PhD, director, research to practice division, Office of Special Education Programs, Department of Education.

Most experts believe that autism has a genetic basis for autism, and it probably begins in the womb. Research supports this idea. Examinations of the brains of autistic children have found reduced cell size and an increase in the number of nerve cells bilaterally in the hippocampus, amygdala, entorhinal cortex, mamillary body, medial septal nucleus and anterior cingulate gyrus, according to Thomas Kemper, MD, who also spoke before the IOM committee.

These are parts of the limbic system, which is important for processing information, learning, memory, emotion and behavior – all areas affected by autism.

In addition, "we noticed that the brains are unusually large," said Kemper, professor, department of neurology, anatomy and pathology, Boston University School of Medicine.

Researchers have also found abnormalities in the cerebellum where the number of Purkinje cells is reduced. "Virtually everyone who has looked at the cerebellum has found a reduction of Purkinje cells," Kemper said. "Whatever caused the reduction of Purkinje cells must have occurred before 30 weeks [gestation], probably when the neural tube was being developed," he added.

What these abnormalities mean in terms of developing autism is uncertain, but studies suggest that they modulate the child's emotions, language development and the ability to create mental images. In addition, these abnormalities likely affect cognition and attention.

Like Volkmar, Kemper did not seem to think the MMR vaccine played a role in the development of autism. "I suppose it's conceivable," he finally said. "But any insult, I suppose would make your brain smaller not larger."

Marie Bristol-Power, PhD, special assistant for autism, Office of the Director, National Institute for Child Health & Development (NICHD), agreed with Kemper that the autistic brain would probably be smaller rather than larger, if the assault was due to infection or vaccination. There are probably many factors that lead to autism, she said.

"We look at autism not as a single disorder, but as a class of disorders with the idea that there are a variety of causes likely, which makes it unlikely that there will be any silver bullet found," she told the IOM committee.

A variety of etiology has been implicated in autism: genetic, infectious, neurologic, metabolic, immunologic and environmental, she said.

"There is strong evidence that there is a genetic basis in autism. At this point it seems unlikely that it would be a single-gene disorder, probably multiple genes that interact in a complex way," she explained. "Not a single gene disorder, but a genetic susceptibility that is somehow conferred. And the question then becomes what genes are responsible, and then, what other dynamics are needed to precipitate autism in a susceptible individual."

That is what researchers are trying to determine. "The original insult does appear to occur during gestation," she said. "No autopsy studies of brains from individuals with autism have demonstrated an immune pathology."

Bristol-Power mentioned studies in which blinded researchers were able to pick out the child who was likely to develop autism after viewing first birthday videos. The researchers saw differences in the way the autistic child interacted with others.

Two questions

Ezra Susser, MD, DrPH, said the debate should be separated into two questions. "Whether there is an increase of autism is one question and whether the MMR vaccine is the cause of autism in some cases is another question. And I don't think the questions necessarily have to go together. There may be an epidemic of autism, and yet, the MMR vaccine may be unrelated to it. On the other hand, there may be no change in the incidence of autism, and yet, the MMR vaccine may be the cause of some cases," said Susser, head of the division of epidemiology at the Joseph L. Mailman School of Public Health at Columbia University.

Whether the MMR vaccine is a risk factor of autism will be difficult to determine, he added, because the vaccine is used so widely in developed countries. Case-control studies, the gold standard of research, are only applicable if there are subjects who are not exposed.

However, parents of autistic children may provide science with an unvaccinated cohort of individuals who are at-risk for autism. Many parents who think MMR vaccine caused their child's autism are refusing to vaccinate subsequent children. Siblings of autistic children are at increased risk of autism. This may provide case-controls for future study, he said.

"Many parents feel that the vaccine may have been the cause of autism and are not vaccinating later-born children. I don't advocate this," Susser said. "I advocate for the vaccine. I think the risk-benefits are in favor of vaccination, but I can understand why parents are doing so. But by doing so, it creates a natural experiment. Later-born children who receive the vaccine can be compared with later-born siblings of autistic children who do not," he said.

Some people are advocating the idea that MMR vaccine was introduced in many countries, and an epidemic in autism followed. "I think that was a rather simple picture of the situation, which isn't supported by the data. If this hypothesis was true, that the introduction of the MMR had led to a sudden drastic increase in autism, then we should be seeing different things then we are seeing in the incidence and prevalence of autism," Susser continued.

"I'm willing to go that far, but I'm not willing to say that there is no epidemic of autism. In fact, I lean the other way. I think there most likely is, although as Eric [Fombonne] said, 'we're not there, yet.' And I'm also not willing to say that there is no relationship between MMR vaccine and autism. I think we just don't have enough information on that, yet. It may be a cause in some cases," he said.

Although Bristol-Power said autism has a genetic basis, she does not dismiss the MMR vaccine question out of hand. "As we look at the MMR vaccination question, I think there is a fair amount of hysteria on both sides. No one is saying that vaccination is bad or that vaccination should not be given to the majority of children.

"But is there a subgroup of children who may somehow be sensitive to a substance or substances that are not only not harmful, but are helpful to a majority of [other] children? And if so, can we identify these children?" She asked.

If they can be identified, perhaps steps can be taken to make the vaccine safer for this cohort of children, she suggested.

Wakefield and parents are asking for a "safe alternative," such as giving the vaccines separately. Public health officials say that would increase the cost, the number of doctor's visits and decrease the number of people who are vaccinated. They question the cost-effectiveness of a different approach when there is no proof that it is needed. There is no research, Wakefield's included, that says giving separate doses will eliminate the risk if there is one.

The IOM is weighing all the evidence, while agencies, such as the NIH and CDC, are conducting more studies to determine whether there is a connection between the receipt of MMR vaccine and the development of autism.

In the meantime, most experts, including Wakefield, said pediatricians should encourage MMR vaccination since the benefits of prevention outweigh the risks of vaccination.

For more information:

• Kemper TL, Bauman ML. Neuropathology of infantile autism. Journal of Neuropathology and Experimental Neurology. 1998;57:645-652.
• Bauman ML, Kemper TL. The neuroanatomy of the brain in autism. In Bauman ML, Kemper TL (eds.) The Neurobiology of Autism. Johns Hopkins University Press, Baltimore 1994. 119-145.
• Chen RT, DeStefano F. Vaccine adverse events: causal or coincidental Lancet. 1998;351:611-12.
• Dales L, Hammer SJ, Smith NJ. Time trends in autism and in MMR immunization coverage in California. JAMA. 2001;285:1183-85.
• Taylor B, Miller E, Farrington CP, et. al. Autism and measles, mumps and rubella vaccine: no epidemiological evidence for a causal association. Lancet. 1999;353:2026-29.
• Volkmar FR. Brief report: Diagnostic issues in autism. Journal of Autism and Developmental Disorders. 1996. 26:155-158.
• Volkmar FR, Cohen DJ. Disintegrative disorder or "late onset" autism. Journal of Child Psychology & Psychiatry & Allied Disciplines. 1989;30(5):717-724.
• Wakefield AJ, Murch SH, Anthony A, et al. Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet. 1998;351:637-41.