Vaccination & Autism Assignment.

Some parents of children with autism are concerned that vaccines are the cause. Their concerns
center on three areas: the combination measles-mumps-rubella (MMR) vaccine; thimerosal, a
mercury-containing preservative previously contained in several vaccines; and the notion that
babies receive too many vaccines too soon.
Q. Does the MMR vaccine cause autism?
A. No. In 1998, a British researcher named Andrew Wakefi eld
raised the notion that the MMR vaccine might cause autism.
In the medical journal The Lancet, he reported the stories of
eight children who developed autism and intestinal problems
soon after receiving the MMR vaccine. Vaccination & Autism Assignment.To determine whether
Wakefi eld’s suspicion was correct, researchers performed
a series of studies comparing hundreds of thousands of
children who had received the MMR vaccine with hundreds
of thousands who had never received the vaccine. They found
that the risk of autism was the same in both groups. The
MMR vaccine didn’t cause autism. Furthermore, children
with autism were not more likely than other children to have
bowel problems.
Q. Does thimerosal cause autism?
A. No. Multiple studies have shown that thimerosal in
vaccines does not cause autism. Thimerosal is a mercurycontaining preservative that was used in vaccines to
prevent contamination. In 1999, professional groups called
for thimerosal to be removed from vaccines as a precaution.
Unfortunately, the precipitous removal of thimerosal from
all but some multidose preparations of infl uenza vaccine
scared some parents.  Vaccination & Autism Assignment.Clinicians were also confused by the recommendation.

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Since the removal of thimerosal, six studies have been
performed to determine whether thimerosal causes autism.
Again, hundreds of thousands of children who received
thimerosal-containing vaccines were compared to hundreds
of thousands of children who received the same vaccines free
of thimerosal. The results were clear: The risk of autism was
the same in both groups. Vaccination & Autism Assignment.
For the latest information on all vaccines, visit our Web site at vaccine.chop.edu
2509_VEC Info sheet on Autism.indd 1 509_VEC Info sheet on Autism.indd 1 7/9/08 10:28:16 AM /9/08 10:28:16 AM
Vaccines and Autism: What you should know
Q. Are the studies showing that neither the MMR
vaccine nor thimerosal causes autism sensitive
enough to detect the problem in small numbers
of children?
A. The studies showing that neither the MMR vaccine nor
thimerosal causes autism, called epidemiological studies, are
very sensitive. For example, epidemiological studies have
shown that a rotavirus vaccine used between 1998 and 1999
in the United States caused intestinal blockage in 1 out of
every 10,000 vaccine recipients; that measles vaccine caused
a reduction in the number of cells needed to stop bleeding
(platelets) in 1 out of every 25,000 recipients; and that an
infl uenza (swine fl u) vaccine used in the United States
in 1976 caused a type of paralysis called Guillain-Barré
Syndrome in 1 out of every 100,000 recipients. Vaccination & Autism Assignment.
About 1 out of every 150 children in the United States is
diagnosed with an autism spectrum disorder. Even if vaccines
caused autism in only 1 percent of those children – meaning
1 out of every 15,000 children – the problem would have
easily been detected by epidemiological studies.
Q. Is autism caused by children receiving too
many vaccines too soon?
A. Several facts make it very unlikely that babies are
overwhelmed by too many vaccines given too early in life.
First, before they are licensed, new vaccines are always tested
alone or in combination with existing vaccines. These studies
determine whether new vaccines alter the safety and effi cacy
of existing vaccines and, conversely, whether existing vaccines
affect the new vaccine. These studies, called concomitant use
studies, are performed every time a new vaccine is added to
the existing vaccination schedule.
Second, although the number of vaccines has increased
dramatically during the past century, the number of
immunological components in vaccines has actually
decreased. Vaccination & Autism Assignment.One hundred years ago, children received just
one vaccine, for smallpox. The smallpox vaccine contained
about 200 immunological components. Today, with advances
in protein purifi cation and recombinant DNA technology,
the 14 vaccines given to young children contain only about
150 immunological components.
Third, the immunological challenge from vaccines is minuscule
compared to what babies typically encounter every day. The
womb is sterile, containing no bacteria, viruses, parasites or
fungi. But when babies leave the womb and enter the world,
they are immediately colonized by trillions of bacteria that
live on the linings of their nose, throat, skin and intestines.
Each bacterium contains between 2,000 and 6,000
immunological components. And babies often make an
immune response to these bacteria to prevent them from
entering the bloodstream and causing harm. The challenge
that vaccines present is tiny in comparison to that from the
environment. Vaccination & Autism Assignment.
Fourth, children have an enormous capacity to respond to
immunological challenges. Susumu Tonegawa, a molecular
biologist who won a Nobel Prize for his work, showed that
people have the capacity to make between 1 billion and 100
billion different types of antibodies. Given the number of
immunological components contained in modern vaccines,
a conservative estimate would be that babies have the
capacity to respond to about 100,000 different vaccines at
once. Although this sounds like a huge number, when you
consider the number of challenges that babies face from
bacteria in their environment, it’s not.
Here’s another way to understand the difference in scale
between immunological challenges from vaccines and natural
challenges from the environment. The quantity of bacteria
that live on body surfaces is measured in grams (a gram
is the weight of about one-fi fth of a teaspoon of water).
The quantity of immunological components contained in
vaccines is measured in micrograms or nanograms (millionths
or billionths of a gram).
Q. If I am concerned that vaccines cause autism,
what is the harm in delaying or withholding
vaccines for my baby?
A. All of the evidence shows that vaccines don’t cause autism,
so delaying or withholding vaccines will not lessen the risk of
autism; it will only increase the period of time during which
children are at risk for vaccine-preventable diseases. Several of
these diseases, like chickenpox, pertussis (whooping cough)
and pneumococcus (which causes bloodstream
infections, pneumonia and meningitis) are still fairly
common. Delaying or withholding vaccines only increases
the time during which children are at unnecessary risk for
severe and occasionally fatal infections.
Autism References
Bailey A, LeCouteur A, Gottesman I, et al. Autism as a
strongly genetic disorder: evidence from a British twin
study. Psychol Med. 1995;25:63-77.
Bauman M. Autism: clinical features and neurological
observations. In: Tager-Flusberg H, ed. Neurodevelopmental
Disorders. Cambridge, MA: The MIT Press;1999:383-399.
Chess S, Fernandez P, Korn S. Behavioral consequences of
congenital rubella. J Pediatr. 1978;93:699-703.
Folstein S, Rutter M. Infantile autism: a genetic study of 21
twin pairs. J Child Psychol Psychiatry. 1977;18:297-321.
International Molecular Genetic Study of Autism
Consortium (IMGSAC). A genomewide screen for autism:
strong evidence for linkage to chromosomes 2q, 7q,
and 16p. Am J Hum Genet. 2001;69:570-581.
Moessner R, Marshall CR, Sutcliffe JS, et al. Contribution
of SHANK-3 mutations to autism spectrum disorder.
Am J Hum Genet. 2007;81:1289-1297.
Rodier PM. The early origins of autism. Sci Am. 2000;
282:56-63.
Strömland K, Nordin V, Miller M, Akerström B, Gillberg
C. Autism in thalidomide embryopathy: a population study.
Dev Med and Child Neurol. 1994;36:351-356.
Wassink TH, Piven J, Vieland VJ, et al. Evidence supporting
WNT2 as an autism susceptibility gene. Am J Med Genet.
2001;105:406-413.
MMR Vaccine References
Dales L, Hammer SJ, Smith NJ. Time trends in autism
and in MMR immunization coverage in California. JAMA.
2001;285:1183-1185.
Davis RL, Kramarz P, Bohlke K, et al. Measles-mumpsrubella and other measles-containing vaccines do not
increase the risk for infl ammatory bowel disease: a casecontrol study from the Vaccine Safety Datalink project.
Arch Pediatr Adolesc Med. 2001;155:354-359.
DeStefano F, Bhasin TK, Thompson WW, Yeargin-Allsopp
M, Boyle C. Age at fi rst measles-mumps-rubella
vaccination in children with autism and school-matched
control subjects: a population-based study in metropolitan
Atlanta. Pediatrics. 2004;113:259-266. Vaccination & Autism Assignment.
DeStefano F, Chen RT. Negative association between MMR
and autism. Lancet. 1999;353:1986-1987.
Farrington CP, Miller E, Taylor B. MMR and autism:
further evidence against a causal association.
Vaccine. 2001;19:3632-3635.
Fombonne E, Chakrabarti S. No evidence for a new
variant of measles-mumps-rubella-induced autism.
Pediatrics. 2001;108:E58.
Fombonne E, Cook EH Jr. MMR and autistic enterocolitis:
consistent epidemiological failure to fi nd an association.
Mol Psychiatry. 2003;8:133-134.
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;46:572-579.
Kaye JA, del Mar Melero-Montes M, Jick H. Mumps,
measles, and rubella vaccine and the incidence of autism
recorded by general practitioners: a time trend analysis.
BMJ. 2001;322:460-463.
Madsen KM, Hviid A, Vestergaard M, et al. A populationbased study of measles, mumps and rubella vaccination and
autism. N Engl J Med. 2002;347:1477-1482.
References
All of the evidence shows that vaccines
don’t cause autism, so delaying or
withholding vaccines will not lessen the
risk of autism; it will only increase the
period of time during which children are
at risk for vaccine-preventable diseases.

2509_VEC Info sheet on Autism.indd 2-3 509_VEC Info sheet on Autism.indd 2-3 7/9/08 10:28:16 AM /9/08 10:28:16 AM
Vaccines and Autism: What you should know
Q. Are the studies showing that neither the MMR
vaccine nor thimerosal causes autism sensitive
enough to detect the problem in small numbers
of children?
A. The studies showing that neither the MMR vaccine nor
thimerosal causes autism, called epidemiological studies, are
very sensitive. For example, epidemiological studies have
shown that a rotavirus vaccine used between 1998 and 1999
in the United States caused intestinal blockage in 1 out of
every 10,000 vaccine recipients; that measles vaccine caused
a reduction in the number of cells needed to stop bleeding
(platelets) in 1 out of every 25,000 recipients; and that an
infl uenza (swine fl u) vaccine used in the United States
in 1976 caused a type of paralysis called Guillain-Barré
Syndrome in 1 out of every 100,000 recipients. Vaccination & Autism Assignment.
About 1 out of every 150 children in the United States is
diagnosed with an autism spectrum disorder. Even if vaccines
caused autism in only 1 percent of those children – meaning
1 out of every 15,000 children – the problem would have
easily been detected by epidemiological studies.
Q. Is autism caused by children receiving too
many vaccines too soon?
A. Several facts make it very unlikely that babies are
overwhelmed by too many vaccines given too early in life.
First, before they are licensed, new vaccines are always tested
alone or in combination with existing vaccines. These studies
determine whether new vaccines alter the safety and effi cacy
of existing vaccines and, conversely, whether existing vaccines
affect the new vaccine. These studies, called concomitant use
studies, are performed every time a new vaccine is added to
the existing vaccination schedule.
Second, although the number of vaccines has increased
dramatically during the past century, the number of
immunological components in vaccines has actually
decreased. One hundred years ago, children received just
one vaccine, for smallpox. The smallpox vaccine contained
about 200 immunological components. Today, with advances
in protein purifi cation and recombinant DNA technology,
the 14 vaccines given to young children contain only about
150 immunological components.
Third, the immunological challenge from vaccines is minuscule
compared to what babies typically encounter every day. The
womb is sterile, containing no bacteria, viruses, parasites or
fungi. But when babies leave the womb and enter the world,
they are immediately colonized by trillions of bacteria that
live on the linings of their nose, throat, skin and intestines.
Each bacterium contains between 2,000 and 6,000
immunological components. And babies often make an
immune response to these bacteria to prevent them from
entering the bloodstream and causing harm. The challenge
that vaccines present is tiny in comparison to that from the
environment.
Fourth, children have an enormous capacity to respond to
immunological challenges. Susumu Tonegawa, a molecular
biologist who won a Nobel Prize for his work, showed that
people have the capacity to make between 1 billion and 100
billion different types of antibodies. Given the number of
immunological components contained in modern vaccines,
a conservative estimate would be that babies have the
capacity to respond to about 100,000 different vaccines at
once. Although this sounds like a huge number, when you
consider the number of challenges that babies face from
bacteria in their environment, it’s not.
Here’s another way to understand the difference in scale
between immunological challenges from vaccines and natural
challenges from the environment. The quantity of bacteria
that live on body surfaces is measured in grams (a gram
is the weight of about one-fi fth of a teaspoon of water).
The quantity of immunological components contained in
vaccines is measured in micrograms or nanograms (millionths
or billionths of a gram).
Q. If I am concerned that vaccines cause autism,
what is the harm in delaying or withholding
vaccines for my baby?
A. All of the evidence shows that vaccines don’t cause autism,
so delaying or withholding vaccines will not lessen the risk of
autism; it will only increase the period of time during which
children are at risk for vaccine-preventable diseases. Several of
these diseases, like chickenpox, pertussis (whooping cough)
and pneumococcus (which causes bloodstream
infections, pneumonia and meningitis) are still fairly
common. Delaying or withholding vaccines only increases
the time during which children are at unnecessary risk for
severe and occasionally fatal infections. Vaccination & Autism Assignment.
Autism References
Bailey A, LeCouteur A, Gottesman I, et al. Autism as a
strongly genetic disorder: evidence from a British twin
study. Psychol Med. 1995;25:63-77.
Bauman M. Autism: clinical features and neurological
observations. In: Tager-Flusberg H, ed. Neurodevelopmental
Disorders. Cambridge, MA: The MIT Press;1999:383-399.
Chess S, Fernandez P, Korn S. Behavioral consequences of
congenital rubella. J Pediatr. 1978;93:699-703.
Folstein S, Rutter M. Infantile autism: a genetic study of 21
twin pairs. J Child Psychol Psychiatry. 1977;18:297-321.
International Molecular Genetic Study of Autism
Consortium (IMGSAC). A genomewide screen for autism:
strong evidence for linkage to chromosomes 2q, 7q,
and 16p. Am J Hum Genet. 2001;69:570-581.
Moessner R, Marshall CR, Sutcliffe JS, et al. Contribution
of SHANK-3 mutations to autism spectrum disorder.
Am J Hum Genet. 2007;81:1289-1297.
Rodier PM. The early origins of autism. Sci Am. 2000;
282:56-63.
Strömland K, Nordin V, Miller M, Akerström B, Gillberg
C. Autism in thalidomide embryopathy: a population study.
Dev Med and Child Neurol. 1994;36:351-356.
Wassink TH, Piven J, Vieland VJ, et al. Evidence supporting
WNT2 as an autism susceptibility gene. Am J Med Genet.
2001;105:406-413.
MMR Vaccine References
Dales L, Hammer SJ, Smith NJ. Time trends in autism
and in MMR immunization coverage in California. JAMA.
2001;285:1183-1185.
Davis RL, Kramarz P, Bohlke K, et al. Measles-mumpsrubella and other measles-containing vaccines do not
increase the risk for infl ammatory bowel disease: a casecontrol study from the Vaccine Safety Datalink project.
Arch Pediatr Adolesc Med. 2001;155:354-359.
DeStefano F, Bhasin TK, Thompson WW, Yeargin-Allsopp
M, Boyle C. Age at fi rst measles-mumps-rubella
vaccination in children with autism and school-matched
control subjects: a population-based study in metropolitan
Atlanta. Pediatrics. 2004;113:259-266.
DeStefano F, Chen RT. Negative association between MMR
and autism. Lancet. 1999;353:1986-1987. Vaccination & Autism Assignment.
Farrington CP, Miller E, Taylor B. MMR and autism:
further evidence against a causal association.
Vaccine. 2001;19:3632-3635.
Fombonne E, Chakrabarti S. No evidence for a new
variant of measles-mumps-rubella-induced autism.
Pediatrics. 2001;108:E58.
Fombonne E, Cook EH Jr. MMR and autistic enterocolitis:
consistent epidemiological failure to fi nd an association.
Mol Psychiatry. 2003;8:133-134.
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;46:572-579.
Kaye JA, del Mar Melero-Montes M, Jick H. Mumps,
measles, and rubella vaccine and the incidence of autism
recorded by general practitioners: a time trend analysis.
BMJ. 2001;322:460-463.
Madsen KM, Hviid A, Vestergaard M, et al. A populationbased study of measles, mumps and rubella vaccination and
autism. N Engl J Med. 2002;347:1477-1482.
References
All of the evidence shows that vaccines
don’t cause autism, so delaying or
withholding vaccines will not lessen the
risk of autism; it will only increase the
period of time during which children are
at risk for vaccine-preventable diseases.
2
3
2509_VEC Info sheet on Autism.indd 2-3 509_VEC Info sheet on Autism.indd 2-3 7/9/08 10:28:16 AM /9/08 10:28:16 AM
Peltola H, Patja A, Leinikki P, Valle M, Davidkin I, Paunio
M. No evidence for measles, mumps and rubella vaccineassociated infl ammatory bowel disease or autism in a 14-year
prospective study. Lancet. 1998;351:1327-1328.
Taylor B, Miller E, Farrington CP, et al. Autism and measles,
mumps and rubella vaccine: no epidemiological evidence for
a causal association. Lancet. 1999;353:2026-2029.
Wakefi eld AJ, Murch SH, Anthony A, et al. Ileal-lymphoidnodular hyperplasia, non-specifi c colitis, and pervasive
developmental disorder in children. Lancet. 1998;351:637-641. Vaccination & Autism Assignment.
Wilson K, Mills E, Ross C, McGowan J, Jadad A. Association
of autistic spectrum disorder and the measles, mumps and
rubella vaccine: a systematic review of current epidemiological
evidence. Arch Pediatr Adolesc Med. 2003;157:628-634.
Thimerosal References
Andrews N, Miller E, Grant A, Stowe J, Osborne V, Taylor B.
Thimerosal exposure in infants and developmental disorders:
a retrospective cohort study in the United Kingdom does not
support a causal association. Pediatrics. 2004;114:584-591.
Fombonne E, Zakarian R, Bennett A, Meng L, McLeanHeywood D. Pervasive developmental disorders in Montreal,
Quebec, Canada: prevalence and links with immunizations.
Pediatrics. 2006;118:E139-150.
Heron J, Golding J. Thimerosal exposure in infants and
developmental disorders: a prospective cohort study in the
United Kingdom does not support a causal association.
Pediatrics. 2004;114:577-583.
Hviid A, Stellfeld M, Wohlfahrt J, Melbye M. Association
between thimerosal-containing vaccine and autism. JAMA.
2003;290:1763-1766.
Madsen KM, Lauritsen MB, Pedersen CB, et al.
Thimerosal and the occurrence of autism: negative
ecological evidence from Danish population-based data.
Pediatrics. 2003;112:604-606.
Schechter R, Grether J. Continuing increases in autism
reported to California’s developmental services system:
mercury in retrograde. Arch Gen Psychiatry. 2008;65:19-24.
Stehr-Green P, Tull P, Stellfeld M, Mortenson PB,
Simpson D. Autism and thimerosal-containing vaccines:
lack of consistent evidence for an association.
Am J Prev Med. 2003;25:101-106. Vaccination & Autism Assignment.
Verstraeten T, Davis RL, DeStefano F, et al. Study of
thimerosal-containing vaccines: a two-phased study of
computerized health maintenance organization databases.
Pediatrics. 2003;112:1039-1048.
Immunological Capacity Reference
Offi t PA, Quarles J, Gerber MA, et al. Addressing parents’
concerns: do multiple vaccines overwhelm or weaken the
infant’s immune system? Pediatrics. 2002;109:124-129.

There has been enormous debate regarding the possibility of a link between childhood vaccinations and
the subsequent development of autism. This has in recent times become a major public health issue with
vaccine preventable diseases increasing in the community due to the fear of a ‘link’ between vaccinations
and autism.We performed a meta-analysis to summarise available evidence from case-control and cohort
studies on this topic (MEDLINE, PubMed, EMBASE, Google Scholar up to April, 2014). Eligible studies
assessed the relationship between vaccine administration and the subsequent development of autism or
autism spectrum disorders (ASD). Two reviewers extracted data on study characteristics, methods, and
outcomes. Vaccination & Autism Assignment.Disagreement was resolved by consensus with another author. Five cohort studies involving
1,256,407 children, and five case-control studies involving 9920 children were included in this analysis.
The cohort data revealed no relationship between vaccination and autism (OR: 0.99; 95% CI: 0.92 to 1.06)
orASD (OR: 0.91; 95%CI: 0.68 to 1.20), orMMR(OR: 0.84; 95%CI: 0.70 to 1.01), or thimerosal(OR: 1.00; 95%
CI: 0.77 to 1.31), or mercury (Hg) (OR: 1.00; 95% CI: 0.93 to 1.07). Similarly the case-control data found no
evidence for increased risk of developing autism or ASD following MMR, Hg, or thimerosal exposure when
grouped by condition (OR: 0.90, 95% CI: 0.83 to 0.98; p = 0.02) or grouped by exposure type (OR: 0.85, 95%
CI: 0.76 to 0.95; p = 0.01). Findings of this meta-analysis suggest that vaccinations are not associated with
the development of autism or autism spectrum disorder. Furthermore, the components of the vaccines
(thimerosal or mercury) or multiple vaccines (MMR) are not associated with the development of autism
or autism spectrum disorder.
© 2014 Elsevier Ltd. All rights reserved.
1. Introduction
Over the past several years much concern has been raised
regarding the potential links of childhood vaccinations with the
development of autism and autistic spectrum disorders (ASD). The
vaccinations that have received the most attention are the measles,
mumps, rubella (MMR) vaccine and thimerosal-containing vaccines such as the diphtheria, tetanus, pertussis (DPT or DT) vaccine.
A rising awareness of autism incidence, prevalence, and the postulated causation of childhood vaccinations has led to both an
increased distrust in the trade-off between vaccine benefit outweighing potential risks and an opportunity for disease resurgence. Vaccination & Autism Assignment.
This is especially concerning given the factthatthe CDC reported 17
measles outbreaks in the U.S. in 2011 and NSW, Australia also saw
a spike in its measles notifications from late 2011 to mid-July 2012
[1,2]. Vaccine-preventable diseases clearly still hold a presence in
∗ Corresponding author. Tel.: +61 2 47 341 373; fax: +61 2 47 343 432.
E-mail address: guy.eslick@sydney.edu.au (G.D. Eslick).
modern day society and the decision to opt out of MMR or other
childhood vaccination schedules because of concerns regarding the
development of autism should be properly evaluated with available evidence. To date there have been no quantitative data analysis
pooling cohort and case-control studies that have assessed the relationship between autism, autistic spectrum disorder and childhood
vaccinations.
This meta-analysis aims to quantitatively assess the available data from studies undertaken in various countries regarding
autism rates and childhood vaccination so that the relationship
between these two, whatever its significance, can be adequately
substantiated. Vaccination & Autism Assignment.
2. Methods
2.1. Study protocol
We followed the Preferred Reporting Items for Systematic
Reviews and Meta-Analyses (PRISMA) guidelines to conduct our
review and analysis [3,4]. The PRISMA guidelines have been
http://dx.doi.org/10.1016/j.vaccine.2014.04.085
0264-410X/© 2014 Elsevier Ltd. All rights reserved.
reviews and include a four-phase flow diagram as well as a checklist of 27 items deemed necessary for transparent reporting of
results of meta-analyses.Asystematic search ofthe databases Medline (from 1950), PubMed (from 1946), Embase (from 1949), and
Google Scholar (from 1990) through to March 2014, to identify
relevant articles was completed. The following combinations or
search terms were used to search all databases: vaccine;immunise; Vaccination & Autism Assignment.
immunisation; autism; autistic; Asperger; pervasive developmental disorder and PDD. The search strategy was peer reviewed by
two independent experts prior to implementation. The reference
lists of relevant articles were also searched for appropriate studies.
No language restrictions were used in either the search or study
selection. A search for unpublished literature was not performed.
2.2. Eligibility criteria
This review included retrospective and prospective cohort studies and case-control studies published in any language looking at
the relationship between vaccination and disorders on the autistic
spectrum. No limits were placed on publication date, publication
status, or participant characteristics. Studies were included that
looked at either MMR vaccination, cumulative mercury (Hg) or
cumulative thimerosal dosage from vaccinations to ensure all proposed causes of ASD or regression were investigated. Outcome
measures included development of any condition on the autistic
spectrum as well as those specifically looking at regressive phenotype. Papers that recruited their cohort of participants solely from
the Vaccine Adverse Event Reporting System (VAERS) in the United
States were not included due to its many limitations and high risk
of bias including unverified reports, underreporting, inconsistent
data quality, absence of an unvaccinated control group and many
reports being filed in connection with litigation [5,6]. We excluded
studies that did not meet the inclusion criteria. Vaccination & Autism Assignment.
2.3. Study selection
Two authors (LT, AS) independently reviewed the abstracts and
methods of returned results to assess for eligibility for inclusion.
Disagreements between reviewers were resolved by consensus
with the third author (GE).
2.4. Data collection process
Data was extracted manually by one author (LT) which was
subsequently reviewed by another author (GE). Where data on
multiple endpoints was available, the longest duration between
exposure and measurement of outcome was used. Where data
on multiple doses of mercury were available, the data used was
that when the largest dose was given. Where data was provided
adjusted for confounding variables, the result that was adjusted
for the most variables was included. Duplicate publications were
determined and excluded by juxtaposing authors’ names, sample
sizes of treatment and control groups, and subsequent odds and
risk ratios.
2.5. Data items
Information was extracted from each paper on (1) study design;
(2) country of study; (3) sample sizes (including total number of
participants, and number of participants in each treatment arm); Vaccination & Autism Assignment.
(4) intervention (including type, dose and timing of vaccination);
(5) outcome measure (including development of autistic disorder, other autistic spectrum disorder, or autistic disorder with
regression); (6) and measures of effect (including calculated odds
and risk ratios and the confounding variables for which they were
adjusted).
2.6. Risk of bias in individual studies
Risk of bias was assessed independently by two authors (LT,
AS) using the appropriate Newcastle-Ottawa scale (NOS) [7] with
disagreements resolved by consensus with the other author (GE).
The NOS scale has three components assessing studies on participant selection, comparability, and outcome/exposure assessment.
A study is awarded stars for items within each category for a maximum of nine stars. We decided to rate studies as low risk of bias
if they received nine stars, moderate risk of bias if they received
seven or eight stars, and high risk of bias if they received less.
2.7. Statistical analysis
Pooled odds ratios and 95% confidence intervals were calculated
for the effect of vaccinations on the development of autism using
a random effects model [8]. Vaccination & Autism Assignment. For both case-control and cohort studies, an overall pooled odds ratio was calculated. Subsequently we
divided the data and performed subgroup analyses to investigate
risk of developing either autism alone or ASD alone after MMR, Hg,
or thimersal exposure. In addition we performed subgroup analyses by exposure type investigating the individual likelihood of
developing autism or ASD depending on whether the participants
Potentially relevant
studies identiied and
screened for retrieval
(n=929)
Studies excluded after inspection
of abstracts (n=769)
Studies retrieved for more
detailed evaluation
(n=160)
Potentially appropriate
studies to be included in
the meta-analysis (n=12)
Studies included in metaanalysis (n=5)
Studies with usable
information, by outcome
(n=5)
Studies excluded for having no
cohort data (n=148)
Studies excluded for not meeting
inclusion criteria (n=7)
Studies withdrawn, by outcome
(n=0)

Please cite this article in press as: Taylor LE, et al. Vaccines are not associated with autism: An evidence-based meta-analysis of casecontrol and cohort studies. Vaccine (2014), http://dx.doi.org/10.1016/j.vaccine.2014.04.085
ARTICLE IN PRESS G Model
JVAC153661–7
L.E. Taylor et al. / Vaccine xxx (2014) xxx–xxx 3
had received the MMR vaccine, the measles vaccine alone, or had
exposure to thimerosal or Hg.
We tested heterogeneity with Cochran’s Q statistic, with p < 0.10 indicating heterogeneity, and quantified the degree of heterogeneity using the I 2 statistic, which represents the percentage of the total variability across studies which is due to heterogeneity. I values of 25, 50 and 75% corresponded to low, moderate and high degrees of heterogeneity, respectively [9]. We quantified publication bias using the Egger's regression model where effect estimates are graphed against sample size and symmetry of the resultant funnel plot is assessed. This approach assumes that larger studies will produce results nearer the average and smaller studies will be spread on both sides of the average, which is useful to detect bias in meta-analyses that are later contradicted by large trials [10]. In addition,Rosenthal's fail-safe number was calculated to assess publication bias, which calculates the number of additional 'positive' or 'negative' studies that would be required to change the outcome of the meta-analysis [11]. All analyses were performed with Comprehensive Meta-Analysis (version 2.0), Biostat, Englewood, NJ (2005). Vaccination & Autism Assignment. 3. Results 3.1. Study selection The search of Medline, PubMed, and Embase returned 519, 718, and 1133 results, respectively. After adjusting for duplicates, 1112 papers in total remained, 953 were excluded immediately on inspection of the abstracts as they clearly did not meet inclusion criteria, leaving 159 papers whose methods sections were analysed in more detail to determine suitability. No unpublished relevant studies were obtained. Five additional papers were found on examination of relevant reference lists. A further 111 were identified as having no possible case-control or cohort data and were excluded, leaving 46 papers to which the inclusion criteria were applied (Fig. 1). A total of five case-control studies and five cohort studies were identified for inclusion in the review. 3.2. Study characteristics All five cohort studies selected for inclusion were retrospective cohort studies published in English (Table 1). The total sample evaluated among these cohort studies consisted of 1,256,407 children. Two studies [12,13] had data looking specifically at MMR vaccination, two [14,15] had data specifically on cumulative Hg dosage, while one [16] had two data sets looking specifically at thimerosal exposure. All studies looked at the development of autism or other ASD among large populations as the defined outcome, with the exception of one [13] that investigated specifically the development of the regressive phenotype of autism compared to non-regressive autism. Vaccination & Autism Assignment. The five case-control studies were published in English and investigated a total sample of 9920 children (Table 2). Four of the five studies had data specifically on MMR vaccination [17–21] and subsequent risk of autism or ASD, two of the five studies had data on the monovalent measles vaccine [18,20], and one study had three data sets investigating cumulative Hg/thimerosal exposure and subsequent risk of developing autism, ASD, or autism with regressive phenotype [22]. 3.3. Risk of bias within studies 3.3.1. Cohort studies Using the NOS, two studies were rated as having low risk of bias [14,16], two as moderate risk [12,15], and one was rated as having a high risk of bias [13]. Specific ratings for each study are included in Table 1. Bias encompassed in the assessment of the study by Uchiyama included selection bias due to recruitment of all participants from a private clinic, poor definition and inadequate description of assessment of regression, and a lack of controlling for comparability between the "MMR Generations" and "pre- and postMMR Generations". The study by Madsen also has the potential for bias as a result of investigating MMR vaccination status as opposed to a cumulative dosage of thimerosal or Hg. As the Hg or thimerosal dosage in vaccinations varies, there is a degree of fluctuation in the amount of exposure to the individuals within a population studied. In contrast, when using the binary system of vaccinated versus nonvaccinated in a population with such high immunisation coverage to investigate the risk of ASD, the unvaccinated group is at much higher risk of being non-representative of the larger population for many additional reasons thus creating bias. We have continued to include itin our meta-analysis despite risk of bias as it still provides valuable evidence for the question ofthe increased risk of autism or ASD in the vaccinated population compared to those unvaccinated, despite bias affecting the implications that can be drawn about the causal nature of the relationship. Follow-up periods for each of the cohort studies varied with time periods of 5 years (at least 3 years of data per individual) [13], 8 years (at least 2 years of data per individual) [15], 8 years [12], 11 years (at least 2 years of data per individual) [14], and individuals followed from 1 to 11 years [16]. The mean length of follow-up of the five cohort studies is 8.6 years, with the range being 5 years to 11 years. Vaccination & Autism Assignment. This meta-analysis of five case-control and five cohort studies has found no evidence for the link between vaccination and the subsequent risk of developing autism or autistic spectrum disorder. ORDER A CUSTOM-WRITTEN PAPER HERE   Subgroup analyses looking specifically at MMR vaccinations, cumulative mercury dosage, and thimerosal exposure individually were similarly negative, as were subgroup analyses looking specifically at development of autistic disorder versus other autistic spectrum disorder. Four of the five cohort studies included in this review investigated very large populations and were of sound methodology, which is of great importance as our review question has implications at the population level, and thus required such data for optimal applicability. Vaccination & Autism Assignment. The current meta-analysis is the only quantitative analysis of pooled data on the topic. In the process of searching the literature 12 systematic reviews were identified and reference lists searched for additional data [24–35]. Eleven of the 12 identified reviews shared the current conclusion that there was no evidence for a link between vaccination and autistic spectrum disorder, advocating continuation of current immunisation practices. The only review to suggest that a link could not be excluded was that by Ratajczak [32] looking into the aetiology of autism and concluded that it is Of specific mention, a 2012 Cochrane review examining five RCTs, one controlled clinicaltrial, 27 cohort studies, 17 case-control studies, five time-series trials, one cross-over trial, two ecological studies, and six self-controlled case series studies looked at the effectiveness of the MMR vaccination and its associated adverse effects [25]. Congruent with our current study,this review found no qualitative evidence for a link between the MMR vaccination and autism. As every treatment has the possibility of adverse events, those found to be associated to MMR vaccination included aseptic meningitis, febrile seizures and thrombocytopenic purpura in specific populations. Many conditions were found to be unlikely to be associated with vaccination, one of which was autism. Publication bias was not found in the study, which may be due to the important public health nature of the question. While we thought it more important to include only studies that strictly adhered to a case-control or cohort study protocol and drew it's participants from reliable sources, we recognise that there does exist data from VAERS that reported positive results, however, due to the aforementioned reasons these papers were excluded. It could be considered that duplicate data may be influencing the results as two of the five cohort studies were performed at the population level in Denmark with a crossover of birth cohorts. While the two studies looked at different interventions (one MMR and the other thimerosal-containing vaccines) the outcome data was the same, so while being an interesting comparison to one another, may not provide completely individual results to contribute to this meta-analysis. However, a sensitivity analysis ofthese studies from Denmark did not change the overall result. An important strength ofthis meta-analysis is the length offollow-up ofthe cohort studies, with an average of 8.6 years. In conclusion, this meta-analysis provides no evidence of a relationship between vaccination and autism or autism spectrum disorders and as such advocate the continuation of immunisation programs according to national guidelines. Vaccination & Autism Assignment. As with any treatment or behaviour, one must weigh the benefits and risks to determine their course forward. While at the level of the individual avoidance of immunisation may be seen as conferring lower risk by avoiding possible associated adverse events, the increase in parents deciding to take this course of action has substantially decreased 'herd immunity' among populations, subsequently increasing the risk of catching potentially more serious infectious diseases. Thus the risk incurred by not immunising a child is increasing substantially as levels of immunisation coverage fall. In regards specifically to the fear of a child developing autism following immunisation, the data consistently shows the lack of evidence for an association between autism, ASD and vaccination, regardless of whether the intervention was the MMR vaccine itself or one of its components, providing no reason to avoid immunisation on these grounds. Autism and ThimerosalContaining Vaccines: Lack of Consistent Evidence for an Association This study was prompted by findings reported to the Institute of Medicine by Blaxill in July 2001, which showed increases in autism incidence in California in association with increases in the use of thimerosal-containing vaccines during the 1990s. Vaccination & Autism Assignment.To further examine the plausibility of this finding, this study took advantage of the cessation of thimerosal use in Denmark and Sweden in 1992 to conduct a before and after comparison of the incidence or case numbers of autism. In both countries, autism increases throughout the years 1987-1999, contrary to the decrease in autism that would be expected after 1992 if thimerosal exposure was related to autism. The increasing trend for autism is most notable in Denmark where the number of autism cases rises substantially even after the discontinuation of thimerosal use. The results were published in the American Journal of Preventive Medicine (Aug 2003; 25(2):101-6). Vaccination & Autism Assignment. Ecological Cohort Published in American Journal of Preventive Medicine, August 2003 Autism Thimerosal Screening Study The Vaccine Safety Datalink (VSD) was used to screen for possible associations between exposure to thimerosal-containing vaccines and a variety of renal, neurologic and developmental problems. In the first phase of this study, CDC used data from the two VSD managed care organizations (MCOs) with automated outpatient data (where more subtle effects of mercury toxicity might be seen). The CDC and VSD researchers found statistically significant associations between thimerosal and two neurodevelopmental disorders - language delays and tics. However, the associations were weak and were not consistent between the two MCOs. No association was shown with autism. In the second phase of the investigation, CDC investigators examined data from a third MCO with similar available automated vaccination and outpatient databases to see if these findings could be replicated. Analyses of these data using the same methods as with the first two MCOs did not confirm results seen in the first phase. The results were published in Pediatrics (Nov 2003; 112(5): 1039-48). Presented at the July 2001 IOM Meeting: Thimerosal-Containing Vaccines and Neurodevelopmental Outcomes Cohort Published in Pediatrics, November 2003 Language Delay; Speech   Delay; ADHD 1 Draft: Last updated – January 30, 2009 Study Description Study Design Estimated Publication Date Study Objective(s) Thimerosal Neurological Developmental Disorders (NDD) Follow-up Study The Thimerosal Follow-Up Study examines more rigorously the hypotheses that increasing exposure to thimerosal is associated with neurodevelopmental disorders. In contrast to the Thimerosal Screening Study, which utilized ICD-9 codes, the Thimerosal Follow-Up Study will objectively measure the neurodevelopmental disorders of interest by bringing children aged 7 to 9 years into a health clinic for a three-hour objective assessment by staff trained to administer neuropsychological test batteries. The results of the study should be significantly less vulnerable to the introduction of health care seeking bias and will assist in the interpretation of the results obtained in the Thimerosal Screening Study. Vaccination & Autism Assignment. The study found only a few statistically significant associations between exposure from thimerosal and neuropsychological functioning. The weight of the evidence from this study does not support an association between early ethyl mercury exposure from thimerosal-containing vaccines and/or immunoglobulins and neuropsychological functioning at ages 7 to 10 years. The results published in New England Journal of Medicine (2007 Sep 27;357(13):1281-92). 2001 IOM Recommendation: Thimerosal 4 Cohort Published in New England Journal of Medicine, September 2007 Language Delay; Speech Delay; ADHD Italy Thimerosal NDD Study CDC funded this follow-up study in Italy that compares neuropsychological outcomes of children at ages 10-12 years who were randomly assigned to receive one of two forms of diphtheria-tetanus-acellular pertussis vaccine (DTaP) in the first year of life, one containing thimerosal and the other containing 2-phenoxyethanol. As a result, children who received the thimerosal-containing DTaP vaccines had a higher cumulative exposure to thimerosal (137.5 micrograms of ethylmercury) in their first year compared to the other form of DTaP (62.5 micrograms of ethylmercury) during the same age range. Ten years after vaccination, the two groups were tested in school on 24 neuropsychological outcomes. The overall results of the study do not support neurological or developmental harm to children resulting from thimerosal exposure. Vaccination & Autism Assignment. This strong study adds to the body of scientific evidence that thimerosal in vaccines is not harmful to children. The results are published in Pediatrics (2009 Feb:123(2): 475- 482). 2001 IOM Recommendation: Thimerosal 2 Clinical Trial Published: Pediatrics, February 2009 Language Delay; Speech Delay; ADHD 2 Draft: Last updated – January 30, 2009 Study Description Study Design Estimated Publication Date Study Objective(s) VSD Thimerosal and Autism Case Control Study Exposure to thimerosal has been hypothesized to be associated with the risk for autism. Preliminary results from the VSD Thimerosal Screening Study published in 2003 did not find an association between thimerosal exposure and autism risk and recent ecological studies have not found a correlation between thimerosal content of vaccines and autism rates. Autism, however, can be difficult to diagnose and the studies to date have relied on computerized clinical or administrative databases in which the validity of the autism diagnoses have not been fully validated. Vaccination & Autism Assignment.The Thimerosal and Autism Study is a case-control study conducted in three U.S. MCOs. Data collection began in 2005 and took three years to complete. In this study, children who were diagnosed with autism were matched with control children. The autism diagnosis of the case samples was confirmed by a standardized clinical assessment protocol. Vaccination histories and information on other potential confounding factors were confirmed by reviewing the medical records for all children. In addition, the mothers of both cases and matched controls were interviewed. The IOM Immunization Safety Review Committee recommended such a study in 2001. 2001 IOM Recommendations: Thimerosal 1 & 4 Casecontrol January 2010 Autism Trends in Diagnosis Rates for Autism and ADHD at Hospital Discharge in the Context of Other Psychiatric Diagnoses Data from the Healthcare Cost and Utilization Project (HCUP) were used for descriptive analyses of secular trends of diagnosed psychiatric disorders between 1989 and 2000. Vaccination & Autism Assignment.The HCUP Nationwide Inpatient Sample (NIS) approximates a 20% sample of U.S. community hospitals as defined by the American Hospital Association (AHA). The AHA defines community hospitals as "all nonfederal, short-term, general and other specialty hospitals, excluding hospital units of hospital institutions." Psychiatric disorders were coded using the International Classification of Diseases, 9th edition (ICD-9) (27). Disorders were associated with a hospital discharge if they were coded as the primary or secondary diagnosis for that discharge. For each disorder or set of disorders, three sets of rates were calculated. The rate of hospital discharges associated with each disorder was calculated for each calendar year as a function of the total number of hospital discharges for that year. Average rates were calculated across all years of the study period by year of age. Differences in trends in diagnosis were examined for each period. The results were published in January 2005 in the journal Psychiatric Services (January 2005 56:56-62). Vaccination & Autism Assignment. 2001 IOM Recommendation: Thimerosal 3 Ecological Cohort Published in Psychiatric Services, January 2005 Autism; ADHD 3 Draft: Last updated – January 30, 2009 MMR and Autism Research Agenda Study Description Study Design Estimated Publication Date Study Objective(s) Denmark MMR/ Autism Study CDC has an ongoing cooperative agreement with the Danish Medical Research Council. This cooperative agreement supports a collaborative research program with Danish researchers and provides opportunities for CDC to pursue causes of birth defects and developmental disabilities through Denmark's unique public health data infrastructure. The Danish study, which followed more than 500,000 children, over 7 years, found no association between the MMR vaccination and autism. The results were published in the New England Journal of Medicine (2002; 347:1477- 82). 2001 IOM Recommendations: MMR/Autism 1, 2, 5, 6 Cohort Published in New England Journal of Medicine November 2002 Autism Metropolitan Atlanta Developmental Disabilities Surveillance Program (MADDSP) CDC conducted this study using data collected through the Metropolitan Atlanta Developmental Disabilities Surveillance Program (MADDSP). This case-control study examined the possible relationship between exposure to the MMR vaccine and autism. Cases are children with a diagnosis of autism spectrum disorder according to DSM-IV criteria that were between the ages of 3-10 years of age in 1996 and identified through MADDSP. Controls are matched 3:1 with cases based on school system, birth date and gender. Vaccination & Autism Assignment.Developmental and immunization histories were collected from education records. The study found that the overall distribution of ages at MMR vaccination among children with autism was similar to that of matched control children; most case and control children were vaccinated between 12 and 17 months of age. The results were published in Pediatrics (Feb 2004; 113(2):259-66). 2001 IOM Recommendations: MMR/Autism 1, 2, 5, 6 CaseControl Published in Pediatrics, February 2004 Autism 4 Draft: Last updated – January 30, 2009 5 Study Description Study Design Estimated Publication Date Study Objective(s) Lack of Association between Measles Virus Vaccine and Autism with Enteropathy: A CaseControl Study CDC supported a case-control study to investigate the association between MMR vaccine, gastrointestinal tract disorders (GI), and autistic spectrum disorder (ASD) through examination of intestinal tissue samples for measles virus genome. The research was led by scientists at Columbia University Mailman School of Public Health and included researchers from Massachusetts General Hospital, Trinity College Dublin, and CDC. Vaccination & Autism Assignment.Laboratories evaluated bowel tissues from 25 children with autism and GI disturbances and 13 children with GI disturbances alone (controls); only 2 biopsy samples with measles virus RNA were found, one in the autism/GI group and one in the control group, showing that the presence of measles virus sequences was not associated with an autism diagnosis (autism/GI group, 4%; control, 8%). Samples were analyzed in three separate laboratories blinded to diagnosis, including one laboratory wherein the original findings suggesting a link between measles virus and autism had been reported in 1998 (Wakefield et al.). Results are inconsistent with a causal role for MMR vaccine as a trigger or exacerbator of either GI difficulties or autism, The results were published in PLoS One (September 2008; 3(9): e3140. doi:10.1371/journal.pone.0003140) 2001 IOM Recommendations: MMR/Autism 2 & 3 CaseControl Published in PLoS ONE 3(9): e3140. doi:10.1371/jou rnal.pone.0003Delay; ADHD 1 Draft: Last updated – January 30, 2009 Study Description Study Design Estimated Publication Date Study Objective(s) Thimerosal Neurological Developmental Disorders (NDD) Follow-up Study The Thimerosal Follow-Up Study examines more rigorously the hypotheses that increasing exposure to thimerosal is associated with neurodevelopmental disorders. In contrast to the Thimerosal Screening Study, which utilized ICD-9 codes, the Thimerosal Follow-Up Study will objectively measure the neurodevelopmental disorders of interest by bringing children aged 7 to 9 years into a health clinic for a three-hour objective assessment by staff trained to administer neuropsychological test batteries. The results of the study should be significantly less vulnerable to the introduction of health care seeking bias and will assist in the interpretation of the results obtained in the Thimerosal Screening Study. The study found only a few statistically significant associations between exposure from thimerosal and neuropsychological functioning. The weight of the evidence from this study does not support an association between early ethyl mercury exposure from thimerosal-containing vaccines and/or immunoglobulins and neuropsychological functioning at ages 7 to 10 years. Vaccination & Autism Assignment.The results published in New England Journal of Medicine (2007 Sep 27;357(13):1281-92). 2001 IOM Recommendation: Thimerosal 4 Cohort Published in New England Journal of Medicine, September 2007 Language Delay; Speech Delay; ADHD Italy Thimerosal NDD Study CDC funded this follow-up study in Italy that compares neuropsychological outcomes of children at ages 10-12 years who were randomly assigned to receive one of two forms of diphtheria-tetanus-acellular pertussis vaccine (DTaP) in the first year of life, one containing thimerosal and the other containing 2-phenoxyethanol. As a result, children who received the thimerosal-containing DTaP vaccines had a higher cumulative exposure to thimerosal (137.5 micrograms of ethylmercury) in their first year compared to the other form of DTaP (62.5 micrograms of ethylmercury) during the same age range. Ten years after vaccination, the two groups were tested in school on 24 neuropsychological outcomes. The overall results of the study do not support neurological or developmental harm to children resulting from thimerosal exposure. This strong study adds to the body of scientific evidence that thimerosal in vaccines is not harmful to children.Vaccination & Autism Assignment. The results are published in Pediatrics (2009 Feb:123(2): 475- 482). 2001 IOM Recommendation: Thimerosal 2 Clinical Trial Published: Pediatrics, February 2009 Language Delay; Speech Delay; ADHD 2 Draft: Last updated – January 30, 2009 Study Description Study Design Estimated Publication Date Study Objective(s) VSD Thimerosal and Autism Case Control Study Exposure to thimerosal has been hypothesized to be associated with the risk for autism. Preliminary results from the VSD Thimerosal Screening Study published in 2003 did not find an association between thimerosal exposure and autism risk and recent ecological studies have not found a correlation between thimerosal content of vaccines and autism rates. Autism, however, can be difficult to diagnose and the studies to date have relied on computerized clinical or administrative databases in which the validity of the autism diagnoses have not been fully validated. The Thimerosal and Autism Study is a case-control study conducted in three U.S. MCOs. Data collection began in 2005 and took three years to complete. In this study, children who were diagnosed with autism were matched with control children. The autism diagnosis of the case samples was confirmed by a standardized clinical assessment protocol. Vaccination histories and information on other potential confounding factors were confirmed by reviewing the medical records for all children. In addition, the mothers of both cases and matched controls were interviewed. The IOM Immunization Safety Review Committee recommended such a study in 2001. 2001 IOM Recommendations: Thimerosal 1 & 4 Casecontrol January 2010 Autism Trends in Diagnosis Rates for Autism and ADHD at Hospital Discharge in the Context of Other Psychiatric Diagnoses Data from the Healthcare Cost and Utilization Project (HCUP) were used for descriptive analyses of secular trends of diagnosed psychiatric disorders between 1989 and 2000. The HCUP Nationwide Inpatient Sample (NIS) approximates a 20% sample of U.S. community hospitals as defined by the American Hospital Association (AHA). The AHA defines community hospitals as "all nonfederal, short-term, general and other specialty hospitals, excluding hospital units of hospital institutions." Psychiatric disorders were coded using the International Classification of Diseases, 9th edition (ICD-9) (27). Vaccination & Autism Assignment.Disorders were associated with a hospital discharge if they were coded as the primary or secondary diagnosis for that discharge. For each disorder or set of disorders, three sets of rates were calculated. The rate of hospital discharges associated with each disorder was calculated for each calendar year as a function of the total number of hospital discharges for that year. Average rates were calculated across all years of the study period by year of age. Differences in trends in diagnosis were examined for each period. The results were published in January 2005 in the journal Psychiatric Services (January 2005 56:56-62). 2001 IOM Recommendation: Thimerosal 3 Ecological Cohort Published in Psychiatric Services, January 2005 Autism; ADHD 3 Draft: Last updated – January 30, 2009 MMR and Autism Research Agenda Study Description Study Design Estimated Publication Date Study Objective(s) Denmark MMR/ Autism Study CDC has an ongoing cooperative agreement with the Danish Medical Research Council. This cooperative agreement supports a collaborative research program with Danish researchers and provides opportunities for CDC to pursue causes of birth defects and developmental disabilities through Denmark's unique public health data infrastructure. Vaccination & Autism Assignment.The Danish study, which followed more than 500,000 children, over 7 years, found no association between the MMR vaccination and autism. The results were published in the New England Journal of Medicine (2002; 347:1477- 82). 2001 IOM Recommendations: MMR/Autism 1, 2, 5, 6 Cohort Published in New England Journal of Medicine November 2002 Autism Metropolitan Atlanta Developmental Disabilities Surveillance Program (MADDSP) ORDER A CUSTOM-WRITTEN PAPER HERE   CDC conducted this study using data collected through the Metropolitan Atlanta Developmental Disabilities Surveillance Program (MADDSP). This case-control study examined the possible relationship between exposure to the MMR vaccine and autism. Cases are children with a diagnosis of autism spectrum disorder according to DSM-IV criteria that were between the ages of 3-10 years of age in 1996 and identified through MADDSP. Controls are matched 3:1 with cases based on school system, birth date and gender. Developmental and immunization histories were collected from education records. The study found that the overall distribution of ages at MMR vaccination among children with autism was similar to that of matched control children; most case and control children were vaccinated between 12 and 17 months of age. The results were published in Pediatrics (Feb 2004; 113(2):259-66). Vaccination & Autism Assignment. 2001 IOM Recommendations: MMR/Autism 1, 2, 5, 6 CaseControl Published in Pediatrics, February 2004 Autism 4 Draft: Last updated – January 30, 2009 5 Study Description Study Design Estimated Publication Date Study Objective(s) Lack of Association between Measles Virus Vaccine and Autism with Enteropathy: A CaseControl Study CDC supported a case-control study to investigate the association between MMR vaccine, gastrointestinal tract disorders (GI), and autistic spectrum disorder (ASD) through examination of intestinal tissue samples for measles virus genome. The research was led by scientists at Columbia University Mailman School of Public Health and included researchers from Massachusetts General Hospital, Trinity College Dublin, and CDC. Laboratories evaluated bowel tissues from 25 children with autism and GI disturbances and 13 children with GI disturbances alone (controls); only 2 biopsy samples with measles virus RNA were found, one in the autism/GI group and one in the control group, showing that the presence of measles virus sequences was not associated with an autism diagnosis (autism/GI group, 4%; control, 8%). Vaccination & Autism Assignment.Samples were analyzed in three separate laboratories blinded to diagnosis, including one laboratory wherein the original findings suggesting a link between measles virus and autism had been reported in 1998 (Wakefield et al.). Results are inconsistent with a causal role for MMR vaccine as a trigger or exacerbator of either GI difficulties or autism, The results were published in PLoS One (September 2008; 3(9): e3140. doi:10.1371/journal.pone.0003140) 2001 IOM Recommendations: MMR/Autism 2 & 3 CaseControl Published in PLoS ONE 3(9): e3140. doi:10.1371/jou rnal.pone.0003 140 5. Epilogue As an epidemiologist I believe the data that is presented in this meta-analysis. However, as a parent of three children I have some understanding of the fears associated with reactions and effects of vaccines. My first two children have had febrile seizures after routine vaccinations, one of them a serious event. These events did not stop me from vaccinating my third child, however, I did take some proactive measures to reduce the risk of similar adverse effects. I vaccinated my child in the morning so that we were aware if any early adverse reaction during the day and I also gave my child a dose of paracetamol 30 min before the vaccination was given to reduce any fever that might develop after the injection. As a parent I know my children better than anyone and I equate their seizures to the effects of the vaccination by increasing their body temperature. For parents who do notice a significant change in their child's cognitive function and behaviour after a vaccination I encourage you to report these events immediately to your family physician and to the 'Vaccine Adverse Event Reporting System'. Author contributions Dr Guy D. Eslick had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Guy D. Eslick; acquisition of data: Luke Taylor, Amy L. Swerdfeger; analysis and interpretation of data: Guy D. Eslick; drafting of the manuscript: Luke Taylor, Amy L. Swerdfeger; critical revision of the manuscript for important intellectual content: Guy D. Eslick, Luke Taylor, Amy L. Swerdfeger; statistical analysis: Guy D. Eslick; study supervision: Guy D. Eslick. References [1] Center for Disease Control and Prevention. Morbidity and Mortality Weekly Report (MMWR). Measles- United States, 2011. Available at: http://www.cdc .gov/mmwr/preview/mmwrhtml/mm6115a1.htm?s cid=mm6115a1 w#fig1. Accessibility verified October 30, 2013. [2] NSWGovernmentHealth.MeaslesNotifications inNSWResidents.Available at: http://www0.health.nsw.gov.au/data/diseases/measles.asp. Accessibility verified October 30, 2013. [3] Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009;339:b2535. Please cite this article in press as: Taylor LE, et al. Vaccines are not associated with autism: An evidence-based meta-analysis of casecontrol and cohort studies. Vaccine (2014), http://dx.doi.org/10.1016/j.vaccine.2014.04.085 ARTICLE IN PRESS G Model JVAC153661–7 L.E. Taylor et al. / Vaccine xxx (2014) xxx–xxx 7 [4] Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 2009;339:b2700. Vaccination & Autism Assignment. [5] Varricchio F, Iskander J, Destefano F, Ball R, Pless R, Braun M, Chen RT. Understanding vaccine safety information from the Vaccine Adverse Event Reporting System. Pediatr Infect Dis J 2004;23:287–94. [6] Goodman MJ, Nordin J. Vaccine Adverse Event Reporting System reporting source: a possible source of bias in longitudinal studies. Pediatrics 2006;117:387–90. [7] Wells GA, Shea B, O'Connell D, Peterson J, Welch V, Losos M, Tugwell P. The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Non Randomised Studies in Meta-Analyses, Available from http://www.ohri.ca/ programs/clinical epidemiology/oxford.asp, (accessed July 16, 2013). [8] DerSimonian R, Laird N. Meta-analysis in clinical trials. Controlled Clin Trials 1986;7:177–88. [9] Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in metaanalyses. BMJ 2003;327:557–60. [10] Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. Br Med J 1997;315:629–34. [11] Rosenthal R. The file drawer problem and tolerance for null results. Psychol Bull 1979;85:638–41. [12] 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):1477–82. Vaccination & Autism Assignment. [13] Uchiyama T,Kurosawa M, Inaba Y. MMR-vaccine and regression in autism spectrum disorders: negative results presented from Japan. J Autism Dev Disord 2007;37:210–7. [14] Andrews N, Miller E, Grant A, Stowe J, Osborne V, Taylor B. Thimerosal exposure in infants and developmental disorders: a retrospective cohort study in the United Kingdom does not support a causal association. Pediatrics 2004;114(3):584–91. [15] Verstraeten T, Davis RL, DeStefano F, et al. Safety of thimerosal-containing vaccines: a two-phased study of computerized health maintenance organization databases. Pediatrics 2003;112(5):1039–48. [16] Hviid A, Stellfeld M, Wohlfahrt J, Melbye M. Association between thimerosalcontaining vaccine and autism. JAMA 2003;290(13):1763–6. [17] DeStefano F, Bhasin TK, Thompson WW, Yeargin-Allsopp M, Boyle C. Age at first measles–mumps–rubella vaccination in children with autism and schoolmatched control subjects: a population-based study in metropolitan Atlanta. Pediatrics 2004;113(2):259–66. [18] Mrozek-Budzyn ˙ D, Kiełtyka A, Majewska R. Lack of association between measles–mumps–rubella vaccination and autism in children: a case-control study. Pediatr Infect Dis J 2010;29(5):397–400. [19] Smeeth L, Cook C, Fombonne E, Heavey L, Rodrigues LC, Smith PG, Hall AJ. MMRvaccinationand pervasive developmental disorders: a case-control study. Lancet 2004;364:963–9. Vaccination & Autism Assignment. [20] Smeeth L, Hall AJ, Fombonne E, Rodrigues LC, Huang X, Smith PG. A casecontrol study of autism and mumps–measles–rubella vaccination using the general practice research database: design and methodology. BMC Public Health 2001;1:2. [21] Uno Y, Uchiyama T, Kurosawa M, Aleksic B, Ozaki N. The combined measles, mumps, and rubella vaccines and the total number of vaccines are not associated with development of autism spectrum disorder: the first case-control study in Asia. Vaccine 2012;30:4292–8. [22] Price CS, Thompson WW, Goodson B, et al. Prenatal and infant exposure to thimerosal from vaccines and immunoglobulins and risk of autism. Pediatrics 2010;126(4):656–64. [23] Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994;50(4):1088–101. [24] Almazrou AM. MMR vaccine and autism: is there a link? Curr Pediatr Res 2006;10(1–2):5–8. [25] Demicheli V, Rivetti A, Debalini MG, Di Pietrantonj C. Vaccines for measles, mumps and rubella in children (review). Cochrane Database Syst Rev 2012;2:CD004407, http://dx.doi.org/10.1002/14651858.CD004407.pub3. [26] Jefferson T, Price D, Demicheli V, Bianco E. Unintended events following immunization with MMR: a systematic review. Vaccine 2003;21(25–26): 3954–60. [27] Kimmel SR, Burns IT, Wolfe RM, Zimmerman RK. Addressing immunization barriers, benefits, and risks. J Fam Pract 2007;56(Suppl. 2 vaccines): S61–9. [28] Klein KC, Diehl EB. Relationship between MMR vaccine and autism. Ann Pharmacother 2004;38(7–8):1297–300. [29] Mutter J, Naumann J, Schneider R, Walach H, Haley B. Mercury and autism: accelerating evidence? Neuro Endocrinol Lett 2005;26(5):439–46. [30] Örtqvist Å, Blennow M, Carlsson R-M, et al. Vaccination of children—a systematic review. Acta Paediatr 2010;99(461):1–192. [31] Parker SK, Schwartz B, Todd J, Pickering LK. Thimerosal-containing vaccines and autistic spectrum disorder: a critical review of published original data. Pediatrics 2004;114(3):793–804. [32] Ratajczak HV. Theoretical aspects of autism: causes—a review. J Immunotoxicol 2011;8(1):68–79. [33] Rutter M. Aetiology of autism: findings and questions. J Intellect Disabil Res 2005;49(4):231–8. [34] Sengupta N, Bedford H, Elliman D, Booy R. Does the MMR triple vaccine cause autism? Evid Based Healthc Public Health 2004;8:239–45. [35] Wilson K, Mills E, Ross C, McGowan J, Jadad A. Association of autistic spectrum disorder and the measles, mumps, and rubella vaccine: a systematic review of current epidemiological evidence. Arch Pediatr Adolesc Med 2003;157(7):628–34. Vaccination & Autism Assignment. [36] Taylor B, Miller E, Lingram L, Andrews N, Simmons A, Stowe J. Measles, mumps, and rubella vaccination and bowel problems or developmental regression in children with autism: population study. BMJ 2002;324:393–6. Vaccination & Autism Assignment.