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Danish study finds no correlation between autism and the MMR
vaccine. The abstract of the study is available through the
following link to the New England Journal of Medicine web
site:
http://content.nejm.org/cgi/content/abstract/347/19/1477
The following link to bmj.com provides a more lengthy summary of
the study and its findings:
http://bmj.com/cgi/content/full/325/7373/1134/a
(Please note: The following article, written in April of 2002, contains
excellent background information on the subject of MMR and autism.)
Children's Hospital of Philadelphia
VACCINE EDUCATION CENTER NEWSLETTER
April 5, 2002
In This Issue:
- Vaccines
and autism
- The
"Wakefield" studies
- Studies
showing that MMR vaccine does not cause autism
- Studies
on the etiology of autism
- Summing
up
- References
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VACCINES AND AUTISM Andrew
Wakefield is soon to embark on a multi-city tour to promote his
idea that the MMR vaccine causes autism. Media coverage surrounding
this tour may increase parents' fears about the vaccine and parents
may come to you with questions. This issue may be used as a resource
for talking points. It provides a concise summary of:
- The
studies used to support the hypothesis that MMR causes autism
- The
studies that refute this hypothesis
other investigations into the causes of autism
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THE
"WAKEFIELD" STUDIES: STUDIES HYPOTHESIZING THAT MMR CAUSES
AUTISM
Those who claim that MMR causes autism often cite two papers by
Andrew Wakefield and colleagues. This section summarizes those studies
and lists their critical flaws.
The first Wakefield paper
In 1998, Andrew Wakefield and colleagues published a paper in the
Lancet titled "Ileal-lymphoid-nodular hyperplasia, non-specific
colitis, and pervasive developmental disorder in children."(1)
Wakefield's hypothesis was that the MMR vaccine causes a series
of events that include intestinal inflammation, loss of intestinal
barrier function, entrance into the bloodstream of encephalopathic
proteins, and consequent development of autism. In support of his
hypothesis, Dr. Wakefield described 12 children with neurodevelopmental
delay (8 with autism). All of these children had gastrointestinal
complaints and developed autism within 1 month of receiving MMR.
Critical flaws
- 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.
- Although
the authors claim that autism is a consequence of gastrointestinal
inflammation, gastrointestinal symptoms were observed after,
not before, symptoms of autism in all 8 cases.
- Children
with autism were claimed to have low levels of circulating
immunoglobulin A (IgA). However, levels reported were within
the normal range for that age group.
- Intestinal
nodular hyperplasia (like enlarged tonsils in young children)
is considered to be a variant of normal.
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The second Wakefield paper
In 2002, Wakefield and coworkers published a 2nd paper examining
the relationship between measles virus and autism.(2)
The authors tested intestinal biopsy samples for the presence of
measles virus genome from children with and without autism. Measles
virus genome was detected by reverse-transcriptase polymerase chain
reaction (RT-PCR) and in situ hybridization. 75 of 90 children with
autism were found to have measles virus genome in intestinal biopsy
tissue as compared with only 5 of 70 control patients.
Critical flaws
- Measles
vaccine virus is live and attenuated. After inoculation,
the vaccine virus probably replicates 15-20 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). Macrophages,
B cells, and dendritic cells (DC) are different types of
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 genome
detected in intestinal tissues using a very sensitive assay
(such as RT-PCR). 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 the biopsy specimen. Although
this information was clearly available to the investigators
and critical to their hypothesis, it was specifically omitted
from the paper.
- Because
natural measles virus is still circulating in England, it
would have been important to determine whether the measles
virus genome detected in these samples was natural measles
virus or vaccine virus. Although primers are available to
distinguish these two types of virus, the authors chose
not to use them.
- RT-PCR
is a very sensitive assay. Laboratories that work with natural
measles virus (such as the lab where these studies were
performed) are at high risk of getting false positive results.
No mention is made in the paper as to how this problem was
avoided.
- 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 or a control (blinding). Because no statement
is made in the method section, it is unclear that blinding
of samples occurred.
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STUDIES SHOWING THAT MMR VACCINE DOES NOT CAUSE AUTISM
Four studies have been performed to refute a causal association
between receipt of MMR and autism.
The first Taylor paper
In 1999, Brent Taylor and coworkers examined the relationship between
receipt of MMR and development of autism in an excellent, well-controlled
study(3) 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 the following:
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; and 3) the onset of "regressive"
symptoms of autism did not occur within 2, 4, or 6 months of receiving
the MMR vaccine.
The JAMA paper
In 2001, Nathalie Smith and coworkers examined the relationship between
the increase in the number of cases of autism in California and receipt
of the MMR vaccine.(4) The
percentage of children immunized with MMR vaccine between 1980 and
1994 was compared with the incidence of autism during the same period.
Although a dramatic increase in the incidence of children with autism
was reported, the percentage of children that received MMR vaccine
remained the same.
The British Medical Journal paper
In a study that supported the findings in the JAMA paper, Hershel
Jick and coworkers examined the incidence of autism in England between
1988 and 1993 and compared this with MMR immunization rates.(5)
Although the incidence of autism increased, MMR immunization rates
remained the same.
The second Taylor paper
A second study by Brent Taylor and coworkers examined the relationship
between MMR vaccine and "new variant autism" (Wakefield's
claim that autism is associated with inflammation of the small intestine).(6)
Children with autism diagnosed between 1979 and 1998 were examined.
The authors compared the number of children with autism and intestinal
symptoms before 1988 and after 1988 (MMR was introduced into England
in 1988). There was no difference. They concluded that there was,
therefore, no evidence for "new variant autism" and provided
further evidence that MMR vaccine was not associated with autism.
STUDIES ON THE ETIOLOGY OF AUTISM
Studies have focused on the genetics of autism and the timing of the
first symptoms of autism.
Genetics of autism
One of the best ways to determine whether a particular disease or
syndrome is genetic is to examine the incidence in identical (monozygotic)
and fraternal (dizygotic) twins. Using a strict definition of autism,
when one twin has autism, 60% of monozygotic and 0% of dizygotic twins
have autism. Using a broader definition of autism (i.e. autistic spectrum
disorder), when one twin has autism, approximately 92% of monozygotic
and 10% of dizygotic twins have autism. (7,8)
Therefore, autism clearly has a genetic basis.
Timing of development of autism
- Autism
symptoms are present before 1 year of age
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 shown
to blinded neurodevelopmental specialists. Investigators
were, with a very high degree of accuracy, able to separate
autistic from non-autistic children at one year of age.(9-13)
These studies found that subtle symptoms of autism are present
earlier than some parents had suspected, and that receipt
of the MMR vaccine did not precede the first symptoms of
autism.
- Autism
symptoms are present before 4 months of age
Other investigators extended the home-movie studies of one-year-old
children to include videotapes of children taken at 2-3
months of age. 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.(14)
- This
study supported the hypothesis that very subtle symptoms
of autism are present in early infancy and argue strongly
against vaccines as a cause of autism.
- Evidence
that autism occurs in utero
Toxic or viral insults in utero as well as certain central
nervous system disorders are associated with an increase
in the incidence of autism.
For example, children exposed to thalidomide during the
first or early second trimester were found to have an increased
incidence of autism.(15)
However, autism occurred in children with ear, but not arm
or leg, abnormalities. Because arms and legs develop after
24 weeks gestation, the risk period for autism following
receipt of thalidomide must be before 24 weeks gestation.
In support of this finding, Rodier and colleagues(16)
found evidence for structural brainstem abnormalities in
children with autism. These abnormalities could only have
occurred during brainstem development in utero.
Similarly, children with congenital rubella syndrome are
at increased risk for development of autism.(17-23)
Risk is associated with exposure to rubella prenatally,
but not postnatally.
Finally,
children with fragile X syndrome or tuberous sclerosis
are also at increased risk of developing autism.
Taken
together, these findings indicate that autism is likely
due to abnormalities of the central nervous system that
occur in utero.
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SUMMING UP
Studies of 1)the
genetics of autism, the timing of the first symptoms of autism (home-movie
studies), 2)the relationship between autism and the receipt of the
MMR vaccine, 3)the histopathology of the central nervous system
of children with autism, and 4)thalidomide, natural rubella infection,
fragile X syndrome, and tuberous sclerosis all support the fact
that autism occurs during development of the central nervous system
early in utero.
Unfortunately, for parents who will someday bear children diagnosed
with autism, the controversy surrounding vaccines has diverted attention
and resources away from a number of promising leads.
REFERENCES
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