Autism and Andrew Wakefield
THE "WAKEFIELD" STUDIES: STUDIES HYPOTHESIZING THAT MMR CAUSES AUTISM
Paul Offit, M.D., FAAP, Chief of Infectious Diseases and Director of the
Vaccine Education Center at Children's Hospital of Philadelphia. Those
who claim that MMR causes autism often cite two papers by Andrew Wakefield
and colleagues. This section summarizes those studies and lists their
The first Wakefield paper
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
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
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.
second Wakefield paper
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
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.
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.
STUDIES SHOWING THAT MMR VACCINE DOES NOT CAUSE AUTISM
studies have been performed to refute a causal association between receipt
of MMR and autism.
The first Taylor paper
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
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
remained the same.
British Medical Journal paper
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.
second Taylor paper
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
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
have focused on the genetics of autism and the timing of the first symptoms
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),
one twin has autism, approximately 92% of monozygotic and 10% of dizygotic
twins have autism. (7,8) Therefore, autism clearly has a genetic basis.
of development of 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
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)
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.
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)
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.
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
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.
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.
of 1)the genetics of autism, the timing of the first symptoms of autism
(home-movie studies), 3)the relationship between autism and the receipt
of the MMR vaccine, 4)the histopathology of the central nervous system
of children with autism, and 5)thalidomide, natural rubella infection,
fragile X syndrome, and tuberous sclerosis all support the fact
that autism occurs during development of teh central nervous system early
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.
Wakefield, A.J., et al.Ileal-lymphoid-nodular hyperplasia, non-specific
colitis, and pervasive developmental disorder in children Lancet 351:
V., et al. Potential viral pathogenic mechanism for new variant inflammatory
bowel disease. Journal of Clinical Pathology: Molecular Pathology 55:1-6,
B., et al. Autism and measles, mumps, and rubella vaccine: no epidemiological
evidence for a causal association. Lancet 353:2026-2029,1999.
L., et al. Time trends in autism and in MMR immunization coverage in
California. JAMA 285:1183-1185, 2001
J.A., et al. Mumps, measles, and rubella vaccine and the incidence of
autism recorded by general practitioners: a time trend analysis. Brit
Med J 322:460-463, 2001.
B., et al. Measles, mumps, and rubella vaccination and bowel
problems or developmental regression in children with autism: population
study. Brit Med J 324:393-396, 2002.
A., et al. Autism as a strongly genetic disorder: evidence from a British
twin study. Psychol Med 25:63-77, 1995.
S., et al. Infantile autism: a genetic study of 21 twin pairs. J Child
Psychol Psychiatry 18:297-321, 1977.
Adrien, J., et al. Blind ratings of early symptoms of autism based upon
family home movies. J Am Acad Child Adolesc Psychiatry 32:617-626, 1993.
J., et al. Early symptoms in autism from family home movies: evaluation
and comparison between 1st and 2nd year of life using I.B.S.E. scale.
Acta Paedopsychiatrica 55:71-75, 1992.
J., et al. Autism and family home movies: preliminary findings. J Autism
Devel Disorders 21:43-49, 1991.
J., et al. Early recognition of children with autism: a study of first
birthday home videotapes. J Autism Devel Disorders 24:247-257, 1994.
A.E., et al. Symptoms of pervasive developmental disordeers as observed
in prediagnostic home videos of infants and toddlers. J Pediatr 132:500-504,
P., et al. Movement analysis in infancy may be useful for the early
diagnosis of autism.Proc Natl Acad Sci USA 95:13982-13987, 1998. http://www.ncbi.nlm.nih.gov/pubmed/9811912
K., et al. Autism in thalidomide embropathy: a population study.In Devel
Med Child Neurol 36:351-356, 1994.
P., et al. Embryological origin for autism: developmental anomalies
of the cranial nerve motor nuclei. J Comp Neurol 370:247-261, 1996.
R.B., R. Lajoie, J. Mendelson, and L. Pinsky. Congenital rubella and
language disorders. Lancet 2:978, 1971.
R.B., L. Pinsky, J. Mendelson, and R. Lajoie. Can language disorder
not due to peripheral deafness be an isolated expression of prenatal
rubella? Pediatrics 52:296-299, 1973.
C.N., and L. Swisher. Congenital rubella and autistic behavior.
N Engl J Med 293:198, 1975.
M. Behavioral consequences of congenital rubella. J Pediatr 94:678-679,
E.Y., and B. MacMahon. Viral exposure and autism. Am J Epidemiol 109:628-638,
S., P. Fernandez, and S. Korn. Behavioral consequences of congenital
rubella. J Pediatr 93:699-703, 1978.
S. Autism in children with congenital rubella. J Autism Child Schizo
Last Updated: 10/30/2013