August 2001
MMR and Autism:Causality or Coincidence?
By ERIC STRONG
Jeana and Darrell Smith always loved children. For years they tried unsuccessfully to have children of their own,
before eventually Jeana became pregnant with identical twins. Born full term, and without any of the complications
often expected in a multiple birth, their sons Jacob and Jesse seemed perfect in every way. At three months of age,
the two children received their first DTP, polio, and H. influenza vaccines. From that day, Jacob's life became
riddled with ear and upper respiratory infections. Despite his near constant state of illness and the endless barrage
of antibiotics given to him, Jacob continued to meet every developmental milestone within the normal range, right along
with Jesse.
At 16 months of age, the twins received their first MMR vaccine. Although they had received the recommended dosage of
Tylenol to prevent fever, over the following 24 hours, both had temperatures of 100 degrees and seemed lethargic.
Whereas Jesse quickly got better and resumed his previous level of activity, Jacob began exhibiting strange behaviors.
He was no longer excited when his father returned home from work. He became preoccupied with certain toys, meticulously
studying the way their wheels would spin. Any attempt to interrupt or distract him was met with great resistance.
Whereas his brother Jesse would be constantly chattering, Jacob lacked the ability to express even the simplest needs
and wants. Despite reassurances from their pediatrician, Jeana and Darrell Smith were sure that something was wrong
with their child.
Finally, after much frustration and anguish, the Smiths learned why Jacob was so different - he was autistic.
- Adapted from the testimony of Jeana Smith to the United States House of Representatives' Committee on Government
Reform, April 6, 2000.1
Autism
In today's world of movies and mass media, the word autism often conjures up a specific picture in most people's minds.
Many will often think of Dustin Hoffman's character in the movie Rain Man - a man unable to communicate with or even
understand the world around him. With recent media publicity surrounding speculated links between a number of vaccines
and autism, public awareness of this crippling condition has further increased. Despite our familiarity however, the
history of autism is surprisingly short.
Leo Kanner wrote the first scientific description of the entity we now know as autism in 1943.2 He reported a series
of children with marked disturbances of affect and language. They made poor eye contact when spoken to, had an inability
to form relationships with other people, had a dread of change in daily routine, and showed delayed language development,
often with echolalia and pronoun reversal. Originally, the disease was thought to be a result of dysfunction family
dynamics - the product of cold parents who were overdemanding of the child, despite showing little genuine interest in
him. This theory has since been proven untrue.3
The basic clinical description of autism that we currently use has changed little from Kanner’s original description,
although it has been formalized to some extent. As defined today, autism comprises the following:4
| 1. | Deficits in Social Interaction - Autistic children have poor peer relationships and have an inability to show reciprocity in those relationships. |
| 2. | Deficits in Communication - Autistic children have a delay in the development of language, an overuse of repetitive language, and an inability to develop imaginative play. |
| 3. | Deficits in Behavior - Autistic children demonstrate abnormal motor movements (i.e. rocking, hand flapping), have an excessive need for routine, and have a consuming preoccupation with a few idiosyncratic areas of interest. |
Often what one hears referred to as autism is actually a heterogeneous group of at least six distinctive entities
collectively known either as pervasive developmental disorders or the autistic spectrum disorders.5 Classic childhood
autism is one, along with less common entities such as the Rett’s and Asperger’s syndromes. Despite the official
differentiation between these diseases, in clinical practice there is much overlap between them, and the distinction
is often arbitrary, leading many clinicians to actually prefer the simpler term autism to describe any child exhibiting
the constellation of abnormalities above.
There is currently no definitive evidence supporting a clear etiology of autism, however, theories are plentiful. A
genetic predisposition6-8, a perinatal insult9,10, defects in embryogenesis11, and
neurobiochemical12-14 and neuroanatomical15,16
causes have all been suggested. Of greater debate than autism’s possible etiologies are the current trends in its
incidence. A 1993 review of 16 studies concerning the epidemiology of typical childhood autism revealed an overall
prevalence ranging from 3.3 to 16 per 10,000 children, with no evidence of an increase over time.17 However, anecdotal
stories and public opinion have consistently stressed that autism is on the rise - not just a gradual rise, but rather
an astounding rise. Whether this impression is based on an increased awareness of autistic disorders, changes in the
diagnostic criteria, better reporting methods, or a true trend is currently unclear.18,19 What is clear however, was
that as of 1998, no scientist had offered a logical, science-based explanation for a true rise in autistic pathology.
The Wakefield Hypothesis
In the early 1990’s, a group of physicians from the Royal Free Hospital in London began investigating a theory behind
the etiology of Crohn’s disease, a form of inflammatory bowel disease (IBD). Led by Dr. Andrew Wakefield, they
speculated that submucosal inflammation of the intestinal wall, in the form of a vasculitis, was an initiating event
in the development of Crohn’s disease. Furthermore, they hypothesized that this vasculitis was more specifically a
result of persistent viral infection of the mesenteric microvascular endothelium. Dr. Wakefield and his colleagues
centered their attention on the measles virus as the source of that infection. A 1993 study by this group demonstrated
that measles virus could be identified in the biopsy specimens of 10 Crohn’s patients using in situ hybridization.
20 The same group confirmed this finding by the use of a novel protocol for immunogold electron microscopy
in 1995.21
These studies were followed in 1998 by the paper that initiated the autism/MMR controversy.22 In this paper,
the Wakefield group examined children who had a history of both a pervasive developmental disorder and gastrointestinal
symptoms suggestive of inflammatory bowel disease. In 8 of the 12 children, the onset of behavioral abnormalities had
been linked to MMR vaccination by either the parents or the child’s pediatrician. The MMR vaccine, typically given at
about 12 months of age, actually contains 3 separate vaccines: measles, mumps, and rubella. The measles component is a
live, attenuated virus, one which is still capable of infecting a host (turning on the host’s immune system in the
process), but has been artificially rendered non-pathogenic, so that it can no longer cause disease. However, when
dealing with live, attenuated viral vaccines, there are occasions, although exceedingly rare, in which the vaccine’s
non-pathogenic strain reverts back to a wild-type strain, sometimes with the ability to cause the very disease it was
meant to prevent. All of this data suggested to the Wakefield group a possible causal relationship between the MMR
vaccine, inflammatory bowel disease, and the development of autism. Dr. Wakefield proposed the following sequence of
events following the MMR vaccinations:
| 1. | MMR vaccination |
| 2. | Chronic measles infection |
| 3. | Immune-mediated vasculitis |
| 4. | Focal ischemia and intestinal inflammation with ulceration of the overlying epithelium |
| 5. | Gastrointestinal symptoms and macroscopic features of the bowel which mimic Crohn’s disease |
| 6. | Increased permeability of the gut wall to exogenous peptides |
| 7. | Circulating toxic peptides interfere with neuroregulation and brain development |
| 8. | Development of clinical autism |
Based on his case reports, Wakefield suggested that this entire process could take anywhere from several weeks to as
little as 24 hours.
The findings of Wakefield’s 1998 study, as well as his autism/MMR hypothesis were widely reported in the media, and
public concern over the vaccine’s safety sprung up overnight. As a consequence of public, political, and academic
pressures, a number of studies were quickly designed and conducted over the following years to investigate this claim.
Supporting Evidence:
Without doubt, the most frequently quoted supporting evidence for a link between MMR and autism has been Wakefield’s
original 1998 paper.22 As mentioned above, this study involved 12 children with an autistic disorder and
with possible Crohn’s disease, who had been specifically referred to the Wakefield group. They were admitted to the
hospital for 1 week, during which time they underwent a barrage of diagnostic tests, including ileocolonoscopy with
biopsy, barium enema, MRI scans of the head, EEG, lumbar puncture, a handful of screens for hereditary metabolic disease,
and formal developmental assessment. Following these tests, none of the 12 had findings consistent with a recognized
organic pathology that could explain their autistic disease. However, 8 of the children had colonic and rectal mucosal
abnormalities including granularity, patchy erythema, lymphoid hyperplasia and aphthoid ulceration. In 9 children,
lymphoid nodular hyperplasia was found in the terminal ileum. Also, as discussed above, the autistic symptoms in 8
children were anecdotally linked to MMR vaccination. Of note, colonic pathology, ileal pathology, and temporal
association with vaccination appeared to occur in the children independently of one another.
The inherent limitations of this study and the dubious leaps in logic in Wakefield’s conclusions are numerous.23
First, the study in question is a case series. Case series studies have no controls and have no blinding of
investigators. Although they often serve an important purpose in suggesting a possible exposure/disease link, they
are far from scientific proof. Second, the subjects were composed of 12 children with known pathology whom were
specifically referred to the Wakefield group, a group widely recognized to actively investigate a proposed link between
measles infection and inflammatory bowel disease. The degree of selection bias present is enough in itself to call into
question any conclusions from the findings. Third, recall bias may also have played a significant role. It is often
impossible to precisely date the onset of symptoms in an insidious, progressive disease such as autism. Parents and
pediatricians may make an unintentional, but inaccurate, temporal association between the perceived onset and an unusual
event, such as a post-vaccination reaction. Fourth, the presence of neurotoxic peptides in these subjects is entirely
speculative - no such toxins have been identified in autistic children. Fifth, in several of the 12 cases, behavioral
changes preceded GI symptoms, despite the final conclusion that GI pathology leads to a disruption in neuroregulatory
mechanisms. It seems counterintuitive that the symptoms of the effect should precede the symptoms of the cause. Lastly,
the rate at which these pathological changes are proposed to progress seems implausible. There are no known
infection-induced vasculitides in which symptoms of the vasculitis occur anywhere near as little as 24 hours after
exposure to the infectious agent.
Opposing Evidence:
The first research-based evidence that disputed the MMR/autism link was made public in June, 1999.24 Brent
Taylor and colleagues undertook an epidemiological study designed specifically to investigate whether or not the MMR
vaccine was causally linked to autism. They identified all known children with an autistic spectrum disorder born
between 1979 and 1998 in a section of northeast London. These 498 individuals were identified from registers at child
development centers and from records at special schools. Information extracted from these records included the age at
which they were vaccinated with MMR, the age at which autism was first diagnosed, the age at which the parents first
became concerned, and the age at which developmental regression became obvious (if it was a feature). The records were
also used to check the diagnosis of autism using the criteria of the International Classification of Diseases (ICD10).
This information was then used in multiple statistical analyses.
The results of this study were as follows:
| 1. | There was a nearly tenfold increase in the number of diagnosed cases of autism from 1979 to 1992. |
| 2. | There was no evidence of a "step-up" in 1987, the first birth cohort eligible for the MMR vaccine. |
| 3. | There was no clustering of development regression in the months after vaccination. |
| 4. | There was no difference between the age at diagnosis in vaccinated and unvaccinated children with autism. |
This study has been widely criticized by those of the Wakefield camp on several points.25 First, it has been
criticized on the basis that the form of statistical analysis used was not adequate to examine the temporal association
between an exposure and a disease in which the onset of the disease is gradual and the diagnosis is often delayed.
Taylor responded to this criticism by stating that the method was specifically suited to test the hypothesis that
Wakefield initially put forth - that the onset of autism follows immunization with MMR by hours to weeks.26
Second, it has been criticized for not accounting for older children who were immunized as part of the catch-up program
when the MMR vaccine was introduced. Once again Taylor responds by stating that such children were identified, and in
all cases in which the age of first parental concern was recorded, it preceded the vaccination. Lastly, Taylor was
criticized for minimizing a marginally positive statistical association in which there was a clustering in the number
of parents who first became concerned about their child’s behavior within 6 months following vaccination (p value = 0.03).
However, the authors regarded this as an artifact. It was the only one of 14 such analyses that detected an association.
When such a high number of analyses are completed, it is not unlikely for one to detect an association by pure chance
even though no such association exists.
Another study refuting the MMR/autism link was published in February, 2001.27 This study, led by James Kaye,
used the UK general practice research database to identify 305 children who were first diagnosed with autism between
1988 and 1999. They conducted a time trend analysis to examine the relation of autism and MMR over time, estimating
annual incidence and age specific incidence of disease and comparing it to the rates of vaccination.
Their results were as follows:
| 1. | The estimated yearly incidence of diagnosed autism increased sevenfold from 3 per 100,000 in 1988 to 21 per 100,000 in 1999. |
| 2. | The median age at diagnosis was 4.6, and did not vary significantly over time. |
| 3. | During the period studied, the prevalence of the MMR vaccination was nearly constant at approximately 97%. |
If MMR vaccination was to explain a recent rise in the number of autistic children, it seems logical to assume that rates
of MMR vaccine coverage and prevalence of autism should parallel one another. Such a trend was not demonstrated here.
The major disadvantage of the Kaye study was that the diagnosis of autism among study subjects was not confirmed from
original records.
The most recent epidemiological study comes from the California Department of Developmental Services.28 Loring
Dales and colleagues identified autistic children born between 1980 and 1994 from the CDDS regional service center
system, which provides educational and medical services for developmentally disabled children throughout the entire
state of California. They also obtained estimates of MMR immunization rates among all Californian children born during
these same years from the California Department of Health Services. When they examined this data, they determined that
among children born between 1980 and 1994, the incidence of autism increased by 373%. However, for children born over
this same period, there was only a 14% increase in vaccine coverage by age 24 months. This finding confirms the results
of the Kaye study. Such a small increase in vaccine coverage can not explain such an enormous increase in autism
incidence.
Perhaps the most convincing evidence against the Wakefield hypothesis questions the original connection between measles
infection and IBD. Although one epidemiological study from the Wakefield group in 1995 found that patients who had
received measles vaccine were at increased risk for the development of Crohn’s disease, 74% of the study cohort was lost
to follow-up.29 Furthermore, additional data from the late 1990’s failed to find such an association.
30,31 In addition, two independent, simultaneously published studies (one from the Wakefield group themselves)
failed to detect measles virus within colonic tissue of patients with IBD, despite using highly sensitive reverse
transcription PCR protocols.32,33
In summary, the vast majority of available evidence fails to detect a causal association between MMR vaccination and the
development of autism. This opinion is the same shared by the Center for Disease Control and Prevention (CDC),34
the World Health Organization (WHO),35 the American Medical Association (AMA),36 the American
Academy of Pediatrics,37 the US Institute of Medicine,38 and the UK Medical Research Council.39
Public Perception and Its Implications:
Despite the relative weakness of the 1998 Wakefield study, his suggestion that MMR might be causally linked to autism
received much media attention. Unfortunately, the media was far less interested in reporting the overwhelming voice of
opposition from the scientific community regarding the validity of this study’s results and conclusions. The net
consequence has been a significant decrease in the public’s confidence in the MMR vaccine.40 Great Britain’s
Health Education Authority reported that in 1998, 8% of British mothers believed that MMR presented a greater risk to
their children than do the diseases it protects against.40 In addition, the medical journal Pediatrics
reported in November, 2000, that nearly one quarter of parents surveyed felt that children get more immunizations than
were good for them.41 A nearly equal number were concerned that too many vaccines were weakening their
child’s immune system (despite clear and undisputed evidence that vaccines strengthen children’s immune responses).
Unfounded fear of vaccines is certainly nothing new. The anti-vaccine movement has existed as long as vaccines themselves
have. Public fear seems to have an affinity for anecdotal stories and poorly designed studies that erroneously suggest
an adverse reaction from a vaccine. The clearest example of this occurred in the 1970’s, when a series of anecdotal
case reports linked pertussis vaccination to non-specific infant brain damage, including mental retardation and seizure
disorders.42 This was yet another example of a coincidental temporal association between a vaccine and
terrible childhood conditions whose natural peak onset was at the same time they received the vaccine. The media,
the public, and uninformed physicians assumed a causal relationship, and anxiety concerning the vaccine grew overnight.
This was followed by a string of anti-pertussis movements that spread across the globe, which had a profound effect
on pertussis vaccination and disease incidence.43 In Great Britain, national immunization rates fell from
80% to 30%. As the number of susceptible children rose, three major outbreaks occurred, accounting for over 300,000
cases and at least 70 deaths.44 A large epidemiological study eventually demonstrated that while a temporal
association between pertussis vaccination and acute encephalopathy existed, the risk of long-term neurological
sequelae was so small that is was unquantifiable.45
While often such anti-vaccine sentiment is the result of the well-intentioned overzealousness of the ill-informed, it
is occasionally the result of blatant disregard for scientific truth, largely on the part of the media.46 On
September 17, 1994, Heather Whitestone was chosen as Miss America, the first ever with a disability - she was deaf.
The following day, The New York Times ran a featured story about Whitestone which stated “Miss Whitestone...lost her
hearing at 18 months because of a reaction to a diphtheria-tetanus shot.” It was not until September 26th, that the
Times published another story that correctly stated that Whitestone’s deafness was actually the result of H. influenza
type B meningitis, an illness which vaccines now prevent. Another similar story followed the 1982 airing of the
television special “DTP: Vaccine Roulette”. The program, broadcast 3 times over a local Washington DC station,
“investigated” a possible association between DTP and neurological damage. Although the program had a strong emotional
impact on parents, the scientific community quickly denounced it as an unbalanced distortion of the available medical
evidence. The American Academy of Pediatrics protested to television officials that the program’s “distortion and
total lack of balance of scientific fact ... [has caused] extraordinary anguish and perhaps irreparable harm to the
health and welfare of the nation’s children.” However, the damage to public perception was already done.
In recent years, the anti-vaccine movement has gained a new forum - the Internet.47 Misinformation circulating
on the internet may be the greatest threat to immunization programs to date. A person with a basic understanding of
computers can now misrepresent data, spread far-fetched anecdotes, and relate scientific falsehoods to anyone who will
listen. Add in a few extra dollars, and that same person can set up their own website. Given a professional
appearance, an innocent layperson can be easily misled that such a site represents a recognized authority on medical
information. One such site, “Dr.” Joseph Mercola’s Optimal Wellness Center, provides concerned parents with extensive
information on vaccinations.48 In regards to MMR and autism, his site states “...Since parents have been
repeatedly reassured by many doctors that the vaccine is safe, which they now can see is not true, it is important for
them to logically reason that they cannot trust anything they are told by doctors, particularly about vaccination, ...”
The implications of such statements circulating throughout the internet are obvious.
What exactly is the driving force behind anti-vaccine sentiment? Why are so many people convinced of the dangers of
routine immunizations, despite the overwhelming mountain of evidence that the risk of a serious reaction to a vaccine
is exceedingly small? The answers to these questions are complex and involve interplay between normal human behavior,
perception of risk, and an absent understanding of basic scientific principles. The first notion to understand is
that the public’s fear of a particular disease is largely proportional to its incidence. When diseases such as polio,
pertussis, and measles were rampant, fear of these diseases was equally rampant. If people had concerns over vaccine
safety, they were insignificant in comparison. Now that these diseases are rare in much of the Western world, people
have redirected that same fear towards the serious, but uncommon, side effects which may occasionally outnumber
wild-type disease cases. The elimination of these diseases has had another effect. Whereas before, a parent whose
child acquired a serious infectious disease could be somewhat reassured in the fact that most parent’s children were
equally afflicted, the same is no longer true. A parent whose child is that one in five thousand case who develops
autism in a given year is left to wonder what made their child different. They have a natural tendency to gravitate
towards any explanation offered, regardless of the presence or absence of a scientific basis.
A second principle in understanding fear of vaccinations is that of the power of the anecdotal case report. Although
in the scientific community such reports are often helpful in first detecting previously unknown reactions and in
stimulating new hypotheses, they are never taken as truth. Most scientists and physicians realize that an anecdote
is a far cry from scientific proof, and needs to be supported by repeated, large scale, well-designed epidemiological
studies before serving as a guideline for patient care. Unfortunately, much of the public does not understand or
fully appreciate this process. For many a layperson, a collection of anecdotes can be equated to scientific truth.
As many physicians will attest to, an argument otherwise is often met with great resistance.
A third concept is a philosophical idea that has been formally termed The Precautionary Principle. Borrowed from the
environmental movement, this principle states: “When an activity raises threats of harm to human health or the
environment, precautionary measures should be taken, even if some cause and effect relationships are not fully
established scientifically.49 The real danger of this principle lies in its rather innocuous wording - who
wouldn’t agree that its always prudent to be cautious when dealing with the unknown? However, prior applications of
this idea have led to disaster. After several studies in the 1990’s linked chlorination of public water to a possible,
negligible risk of cancer, the nation of Peru made a precautionary response. They chose to not chlorinate their
drinking water, and a subsequent epidemic of cholera led to 300,000 cases and over 3500 deaths.50 Currently,
activists are using the Precautionary Principle as a rallying cry in their fight to ban DDT throughout the world,
despite evidence that the use of DDT prevents millions of cases of malaria in Africa each year.51 Precautionary
philosophy has now entered the anti-vaccine movement, and is being used to convince laypeople to question vaccine
safety based on small, poorly designed studies or even worse, on individual anecdotes. Such philosophy also requires
statistical proof that a given vaccine does not lead to a particular adverse reaction. Unfortunately, absolute proof
of the absence of an association is simply not possible - it is an inherent and unavoidable limitation of the science
of epidemiology.
Conclusions:
No one questions that uncertainty exists concerning the separate issues of autism and vaccine safety. However, there
are several points that are certain. First, evidence currently exists both in support of and in opposition to a recent
increase in the incidence of autism. Second, it is unclear that if such a rise is present, whether it is a result of
increased recognition, changing diagnostic criteria, better reporting, or a true rise in autistic pathology. Third,
the overwhelming available scientific data fails to support a causal relationship between the MMR vaccine and autism.
Lastly, inaccurate media reporting and misinformation spread by well-intentioned laypeople have had an adverse effect
on public perception of vaccine safety.
“Falsehood flies and truth comes limping after; so that when men come to be undeceived it is too late; the jest
is over and the tale has had its effect.”
- Jonathan Swift
It is somewhat ironic that a seventeenth century author could so clearly summarize the difficulties that the
scientific community faces in educating the public about vaccine safety. When scientific truth generate less
excitement than fiction, it is likely to lose in the race of public acceptance and understanding. To counterbalance
this trend, physicians and other members of the scientific community have a duty to actively provide education on
issues of vaccine safety. Information within medical journals must be stressed over information within media
reporting. Solid epidemiological studies must be stressed over anecdote. Logic and reason must be stressed over
emotion. It is a challenging task, but not an impossible one, and although an old problem, it is one that can be
overcome with continued vigilance and perseverance.
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