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Autism and chronic disease: Little evidence for
vaccines as a contributing factor
Author
Jan E Drutz, MD
Section Editor
Teresa K Duryea, MD
Deputy Editor
Mary M Torchia, MD
Last literature review for version 17.2: May 1, 2009 | This topic last updated:
September 23, 2008
INTRODUCTION — Since the 1980s, there appears to have been an increase in the number of
cases of autism diagnosed in the United States and other parts of the world [1-6]. Rates of autistic
spectrum disorders in studies from the late 1990s are consistently greater than 10 per 10,000
compared to four to five per 10,000 in previous decades [7].
This real or perceived increase in autism cases has occurred at a time when there has been a
significant increase in the number of recommended childhood vaccines. In the search for a causal
relationship, parents of autistic children and some professionals have identified a temporal
association between immunizations and the onset of more evident symptoms of autism in the
second year of life [8]. It has been suggested that certain vaccines (eg, measles, mumps, and
rubella, MMR) and vaccine constituents (eg, thimerosal) play a role in the development of autism
[9-14]. Vaccines and vaccine constituents have also been linked with the development of other
chronic diseases such as multiple sclerosis [15-17] and diabetes [18,19].
Research to prove or disprove a possible relationship between the various components of
recommended childhood vaccines and chronic diseases such as autism is ongoing. However, to
date, no scientific linkage has been established. The evidence for and against an association
between vaccines and autism and chronic disease will be presented here. The evidence for and
against an association between thimerosal and autism and chronic disease is discussed separately.
(See "Autism and chronic disease: Little evidence for thimerosal as a contributing factor").
The clinical features and diagnosis of autism spectrum disorders are discussed separately. (See
"Clinical features of autism spectrum disorders" and see "Diagnosis of autism spectrum
disorders").
APPARENT INCREASE IN AUTISM — In the past decades, there appears to have been an
increase in the number of cases of autism diagnosed in the United States and other parts of the
world [1-6]. Much attention was generated when the California Department of Developmental
Services reported a 210 percent increase in the number of persons with autism between 1987 and
1998 [1]. Adequate explanation for the increase was not clear, though there was speculation that
changes in diagnostic criteria and an increased awareness of the conditions among health-care
providers and developmental specialists may have been contributing factors. Subsequent reports
analyzing data from cohorts of children with autism from regional developmental centers in
California reached opposite conclusions about whether the apparent rise in cases of autism were
attributable to changes in diagnostic criteria, misclassification, or in-migration to a generous
service system [20,21]. (See "Clinical features of autism spectrum disorders", section on
Epidemiology).
Comparing studies with different case definitions, methods of case finding, and sample populations
is problematic unless there is rigorous control for these variables [22]. Systematic reviews of the
epidemiologic studies of autism have found evidence that changes in case definition and increased
awareness account for much of the increased prevalence [23-25]
POSSIBLE ASSOCIATION BETWEEN AUTISM AND MMR — The real or perceived increase in
autism cases occurred at a time when the number of recommended childhood vaccines also
increased (to include Haemophilus influenza type b (Hib), hepatitis B, varicella, and pneumococcal
vaccines, as well as a second dose of the MMR vaccine). (See "Standard childhood
immunizations"). In the search for a causal relationship, parents of autistic children and some
professionals identified a temporal association of immunizations with the onset of more evident
symptoms of autism in the second year of life [8].
In addition to the temporal association, concern about a potential association between autism and
MMR vaccine comes primarily from two reports describing a link between MMR vaccine,
gastrointestinal complaints, and autism [9,26]. The first report described chronic enterocolitis in
children with neuropsychiatric dysfunction, including autism [9]. The second report described
increased presence of persistent measles virus in the intestinal tissue of children with
developmental disorders compared to controls [26]. Taken together, these reports describe a
phenotype of autism that involves gastrointestinal symptoms, is associated with the persistence of
persistent measles virus, and accounts for the apparent increase in the incidence of autism [27].
Enterocolitis and regression — The potential association between MMR, enterocolitis, and
autism was first reported in a study of 12 children who were consecutively referred to a pediatric
gastroenterology unit in the United Kingdom for evaluation of abdominal pain, diarrhea, and loss
of acquired skills following previously normal development [9]. Nine of these children were
ultimately diagnosed with autism or an autistic spectrum disorder (ASD), and eight of the nine had
lymphoid nodular hyperplasia on endoscopy. The onset of symptoms in six of these children was
associated with recent injection of MMR vaccine, according to the child's parent(s) or physician.
The authors of the report hypothesized that the MMR vaccine introduced a series of events,
including colitis, intestinal inflammation, increased intestinal permeability, and absorption of
encephalopathic proteins into the bloodstream that eventually entered the brain and caused
autism [9].
Limitations of the report include the small number of patients, the lack of a control group, and
potential selection bias [28]. Subsequent review of the children's histories revealed that behavioral
symptoms preceded the gastrointestinal symptoms in all cases [29]. In addition, age-appropriate
levels of immunoglobulin A (IgA) were described as "abnormal." Finally, like childhood tonsillar
hypertrophy, ileal and colonic lymphoid hyperplasia is a normal variant [29].
Since 90 percent of children in Great Britain had received MMR vaccine at the time of this report,
and since autism is typically diagnosed at about the same age as the recommended dose for
vaccine administration, it is not surprising that children with a diagnosis of autism/ASD had
received a recent dose of the vaccine [29]. Thus, the temporal association is not necessarily
causal.
The authors clearly state that their report "did not prove an association between measles, mumps,
and rubella vaccine and the syndrome described" [9]. However, they did raise the possibility of a
link between the two, an interpretation that contributed to a lack of confidence in the MMR
vaccination program [30]. Ten of the 13 authors of the report describing the possible association
between gastrointestinal disease and developmental regression [9] have published a statement
retracting that interpretation [31].
Persistent intestinal measles virus — A second study compared the presence of persistent
measles virus in the intestinal tissue of 91 children with developmental disorders, including
autism, and 70 controls [26]. Persistent measles virus particles were more prevalent among the
children with developmental disorders (82 versus 7 percent). The authors concluded that the data
confirm an association between the presence of measles virus and gut pathology in children with
developmental disorder.
This study and its conclusions have been criticized and contradicted [27-29,32,33]. The criticisms
include a number of methodologic flaws [29]:
It is plausible that in the natural course of response to the live-attenuated measles
vaccine, including the virus being taken up by antigen-presenting cell, that measles
virus genome could be detected in the intestine and other body tissues, particularly
with a very sensitive assay (as was used).
Information about whether and when cases and controls had received the MMR vaccine
was not reported; such information is critical in determining whether the MMR vaccine
causes autism [32].
It was not determined whether the virus genome that was detected was from vaccine
virus or natural measles virus (which is still circulating in England).
Measures to prevent false-positive results from natural measles virus contamination in
the laboratory were not described, nor was blinding of the laboratory personnel.
LACK OF EVIDENCE FOR ASSOCIATION BETWEEN AUTISM AND MMR
Biologic mechanisms — One of the criteria for establishing causality is that there is a coherent
explanation that accounts for the findings (ie, a plausible biologic mechanism) [34]. Decreased
viral immunity, caused by the MMR vaccine, has been proposed as a mechanism for the
association between MMR and ASD [10]. However, there is insufficient evidence to support this
view [28,35].
Autoimmunity, persistent GI measles virus [26,36], and opioid excess [9] have been proposed to
explain the association between MMR, bowel disease, and autism/ASD [28]. However, evidence to
support these mechanisms is lacking:
Characteristic markers for immune injury or inflammation are not present in patients
with autism [28,37].
Although there is support for persistent CNS measles vaccine virus causing
neuropsychiatric dysfunction in immunocompromised individuals as a possible
mechanism [38,39], the presence of vaccine-strain measles virus mRNA has not been
demonstrated in the CNS or other tissues of healthy individuals [28].
Using PCR technology, several investigators have reported the presence of measles
virus in intestinal or blood samples of children with autism spectrum disorders
[26,36,40]. However, subsequent studies using highly sensitive and specific assays and
enhanced laboratory techniques failed to detect measles virus nucleic acids in the white
blood cells of children with autism who had received MMR vaccine, suggesting that the
findings in the earlier studies may have been false positives [41-43].
A case-control study evaluated the presence of measles virus RNA (with PCR) and/or
inflammation in bowel tissue and the temporal relation between MMR administration
and onset of ASD and/or gastrointestinal (GI) disturbances in 23 children with GI
disturbances and ASD and 9 children with isolated GI disturbances [44]. The presence
of measles virus RNA was assayed in three laboratories, including the one from which
the findings suggesting a link between MMR and autism were reported [9]. The
laboratories were blinded to the diagnosis. The results were consistent across
laboratories: measles virus RNA was detected in one patient in each group. The timing
of MMR, onset of GI disturbances, and onset of autism was not consistent with MMR
vaccine as a trigger of GI disturbances or ASD.
Another case-control study found no differences in the excretion of opioid peptides in
the urine of children with ASD or controls [45]. Cerebrospinal beta-endorphins in
patients with autism are not consistently elevated [46-48]. Nor do social and
stereotypic behaviors in children with ASD improve with administration of opioid
antagonists [49-51].
Persistent measles infection or abnormally persistent immune response to MMR is another
mechanism that has been proposed to explain an association between MMR and autism. Support
for this hypothesis was lacking in a case-control study in which measles virus and measles
antibody were measured in 98 children (aged 10 to 12 years) with ASD, 52 children with special
needs without ASD, and 90 typically developing children [52]. Measles virus nucleic acid was
detected in peripheral blood mononuclear cells of one child with ASD and two typically developing
children. Antibody response did not differ between cases and controls and there was no correlation
between antibody levels and autism symptoms.
Epidemiologic studies — To determine whether the MMR vaccine actually causes autism, it is
necessary to compare the relative risk of developing autism among children who did and did not
receive the MMR vaccine [29,32]. Such epidemiologic methods have been used to detect
associations between the swine flu vaccine and Guillain-Barre syndrome [53], the Rotashield
vaccine and intussusception [54], and the MMR vaccine and idiopathic thrombocytopenic purpura
[55]. In contrast, several large epidemiologic studies have failed to detect an association between
MMR vaccine and autism [3,56-62]. As examples:
The incidence of autism among vaccinated and unvaccinated children was compared in
a retrospective cohort study of all children born in Denmark between January 1991 and
December 1998 [3]. Among the 537,303 children in the cohort, 838 (<1 percent) had
autism or ASD, and 82 percent had received the MMR vaccine. After adjustment for
potential confounders, the relative risk of autism among the vaccinated children was
0.92 (95% CI, 0.68-1.24), and the relative risk of ASD among the vaccinated children
was 0.83 (95% CI, 0.65-1.07). In addition to the lack of association between MMR
vaccine and autism/ASD, no association was found between the age at the time of
vaccination, the time since vaccination, or the date of vaccination and the development
of autism or ASD.
A population-based study from the United Kingdom investigated the incidence of autism
before and after the introduction of MMR vaccine in 1988 [56]. Although there was a
steady increase in the number of cases of autism by year of birth, there was no sudden
change in the trend after the introduction of the MMR vaccine. Moreover, there was no
difference in the age of diagnosis of autism between the cases vaccinated before or
after 18 months of age and those never vaccinated. The analysis failed to support a
causal relationship between receipt of the MMR vaccine and subsequent development of
autism [56]. A similar retrospective analysis in the United States came to the same
conclusion [2].
In a population-based study from Montreal, rates of ASD increased as MMR vaccination
coverage decreased [62]. In addition, the rate of increased prevalence of ASD was
similar before and after the introduction of a second dose of MMR vaccine to the routine
childhood immunization schedule [62].
A population-based case-control study in the United States, which hypothesized that
earlier age at vaccination might be associated with an increased risk for autism, failed
to detect such an association [57].
A matched case-control study using the UK General Practice Research Database found
no association between receipt of the MMR vaccine and autism or pervasive
developmental disorder [61].
After the introduction of the MMR vaccine in Finland in 1982, a countrywide surveillance
program was established to determine the incidence and nature of serious adverse
events [58-60]. Among children who received the vaccine between 1982 and 1986,
there was no clustering of hospitalizations for autism related to MMR administration;
nor was there an increase in cases of encephalitis or aseptic meningitis [58]. Among 31
children who reported gastrointestinal symptoms after the vaccine, no cases of ASD
were reported or identified; mean follow-up was 9.25 years (range of 1.3 to 15.1 years)
[60].
In a population study, bowel problems and developmental regression among 473
children with autism or ASD were examined between 1979 and 1998, and related to
MMR vaccine (which was introduced in 1988) [56]. The proportion of children with
bowel symptoms or developmental regression did not change after the introduction of
the MMR vaccine. In addition, the rates of bowel problems and regression among
children who received the MMR vaccine before their parents were concerned about their
development were similar to the rates among children who received the vaccine after
their parents were concerned about their development and those who did not receive
the vaccine. These findings do not support an association between MMR vaccine and
autism.
In a total population study in Yokohama, Japan, the incidence of ASD among 31,426
children born between 1988 and 1996 increased from 48 to 117 cases per 10,000
children [63]. The increased incidence in ASD occurred despite decline in MMR
vaccination rate from 70 to 0 percent in 1993, after which MMR vaccination was
replaced with monovalent measles and rubella vaccines (mumps vaccination was
terminated because of concerns regarding aseptic meningitis as a possible side-effect).
Systematic reviews of the epidemiologic evidence also have failed to find support for an
association between the MMR vaccine and autism/ASD [28,64]. As an example, the Immunization
Safety Committee of the Institute of Medicine (IOM) reviewed evidence for an association between
MMR vaccine and autism in 2001 and 2004 and concluded that existing epidemiologic evidence
failed to reveal any causal association between the vaccine and autism [28,35]. Evidence for a
plausible biologic mechanism was fragmentary and insufficient [8,28,35].
Summary — Research to prove or disprove a possible relationship between MMR and autism is
ongoing. However, to date, no scientific linkage has been established.
The proposed biologic mechanisms that have been generated are only theoretical [35].
Multiple large, well-designed epidemiologic studies [2-5,27,56,58,65] and systematic
reviews [28,35,64] have found insufficient evidence to support an association between
the MMR vaccine and autism.
The inability to absolutely exclude an association between the MMR vaccine and autism stems
from the limitations of the scientific method [32], in which the null hypothesis (ie, that MMR
vaccine does not cause autism) can be rejected or not rejected, but cannot be accepted. Thus, in
strict adherence to the scientific method, one cannot accept the null hypothesis and conclude that
the MMR vaccine does not cause autism, because this would imply that the MMR vaccine never
causes autism, something that cannot be proven. However, in its latest review, the Immunization
Safety Review Committee of the IOM concludes that the evidence favors rejection of a causal
relationship between MMR vaccine and autism [35].
OTHER CHRONIC DISEASES — In addition to autism, other chronic diseases, including multiple
sclerosis and diabetes, have been attributed to the proximate receipt of vaccines in certain
individuals.
Multiple sclerosis — There has been a concern that onset or relapse of multiple sclerosis was
precipitated by hepatitis B or other vaccines. The relationship between multiple sclerosis and
vaccines is discussed separately. (See "Epidemiology, risk factors, and clinical features of multiple
sclerosis in adults" section on Role of immune system stimuli).
Type 1 diabetes mellitus — There have been reports of clustering of cases of type 1 diabetes
mellitus (DM) linked temporally to hemophilus influenza type b vaccine, pertussis vaccine, MMR,
and BCG vaccine [18] and concerns that the timing of the first dose of vaccine may affect the risk
of development of type 1 diabetes mellitus [19].
The studies linking type 1 diabetes mellitus and various vaccines were performed by comparing
the rates of diabetes and vaccination schedules among various countries, and searching databases
on the incidence of type 1 diabetes in various regions and then determining whether changes in
immunization occurred during the time the incidence of DM was recorded [18].
Such ecologic studies may provide the basis for a hypothesis that a vaccine is associated with a
particular disease, but do not provide evidence for the association. Many factors may affect the
rates of diabetes between various countries (eg, genetic predisposition, environmental exposures,
breastfeeding, etc). (See "Pathogenesis of type 1 diabetes mellitus").
To provide evidence of an association between a particular vaccine and diabetes mellitus, it is
necessary to compare the relative risk of developing type 1 diabetes among children who did and
did not receive the particular vaccine (as described above). Two large, population-based,
case-control studies found no association between any of the routinely recommended childhood
vaccines and an increased risk of type 1 diabetes mellitus [66,67]. Nor has an association between
type 1 diabetes and childhood vaccination been detected in large population-based cohort studies
in Sweden, Finland, and Denmark [68-70].
One potential mechanism for an association between vaccine administration and development of
type 1 diabetes is that the vaccines stimulate beta cell autoimmunity. However, in a prospective
cohort of children who had a first-degree relative with type 1 diabetes mellitus, development of
beta-cell autoimmunity was not associated with HBV, Hib, polio, or DTP vaccines administered
before nine months of age, time of receipt of first HBV vaccine, or median age at first HBV, Hib,
polio, or DTP vaccination [71]. In another study, vaccination against tuberculosis, smallpox,
tetanus, pertussis, rubella, and mumps had no effect on the risk of developing type 1 diabetes
[72]. On the other hand, there is some evidence that measles vaccine may decrease the risk of
diabetes mellitus [72,73]. (See "Pathogenesis of type 1 diabetes mellitus").
PROVEN BENEFITS OF VACCINES — As discussed above, there is a lack of evidence for an
association between vaccines and chronic disease [74]. On the other hand, the benefits of
vaccines are clear. As illustrated below, several infectious diseases that were once associated with
significant morbidity and mortality have been almost completely eliminated through the
development, distribution, and almost universal administration of protective vaccines:
Wild-strain poliomyelitis has been eliminated from the Western hemisphere. No case
has been reported in the United States since 1979. The last known case in the Western
hemisphere was reported in Peru in 1992. (See "Poliovirus vaccination").
The number of reported measles cases in the United States has fallen substantially
since the early 1990s, when the uniform recommendation was made that all children,
adolescents, and young adults without history of natural measles disease receive two
doses of measles vaccine. (See "Clinical presentation and diagnosis of measles").
Between 1987 (when the Hib conjugate vaccine was introduced in the United States)
and 2000, the number of invasive Hib cases in children younger than five years of age
declined by >99 percent [75,76]. (See "Microbiology, epidemiology and treatment of
Haemophilus influenzae").
With the declining incidence of these once-common infectious diseases, parents of young children
may no longer appreciate the potential severity or dire consequences of the illnesses. Parents who
lack such appreciation may be willing to forego immunizations for their children, particularly if
unproven risks (eg, autism/ASD) are highly publicized [77]. When this occurs, immunization rates
decline and outbreaks of infectious diseases, such as measles and pertussis, may occur with
significant morbidity and mortality [32,78-82].
As an example, between 35 and 100 of every 100,000 patients with measles disease develop
acute encephalitis, which has a mortality rate of 10 percent and causes neurologic damage in 25
percent of survivors [58,80,83,84]. In addition to acute encephalitis, meningitis, subacute
sclerosing panencephalitis, and acute disseminated encephalomyelitis have been reported
[58,83,85]. Even in uncomplicated cases of measles, as many as 50 percent of patients may have
EEG changes [58,86]. (See "Clinical presentation and diagnosis of measles").
SUMMARY AND CONCLUSIONS — Based upon the above discussion, several conclusions can be
drawn:
The prevalence of autism and ASD appears to have increased over the last several
decades. Much of this trend is accounted for by changes in case definition and increased
awareness of autism [24]. Whether or not the actual incidence of autism has increased
is unclear.
Multiple large, well-designed epidemiologic studies [2-5,27,56,58,65] and systematic
reviews [28,35,64] have found insufficient evidence to support an association between
the MMR vaccine and autism. In its latest review, the Immunization Safety Review
Committee of the IOM concludes that the evidence favors rejection of a causal
relationship between MMR vaccine and autism [35].
Similarly, well-designed epidemiologic studies have failed to find an association between
vaccines and multiple sclerosis or type 1 diabetes mellitus.
The administration of childhood vaccines has led to a decline in the incidence of
childhood diseases that can have severe sequelae. Withholding vaccines from a child
because of a hypothetical risk places the child at risk for actual infection that may have
actual sequelae.
Though neither specific childhood vaccines nor vaccine components, such as thimerosal, have
been proven by scientific study to have a causal relationship with the development of autism,
there is evidence that other factors, including genetics, are important in the development of
autism. These factors are discussed separately. (See "Terminology, epidemiology, and
pathogenesis of autism spectrum disorders", section on Pathogenesis).
INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients.
(See "Patient information: Childhood immunizations" and see "Patient information: Autism
spectrum disorders"). We encourage you to print or e-mail these topics, or to refer patients to our
public web site www.uptodate.com/patients, which includes these and other topics.
The following Web sites from the US Centers for Disease Control and Prevention (CDC), the United
Kingdom's Department of Health, and Australian National Centre for Immunisation Research and
Surveillance (NCIRS) provide additional information about vaccines and autism and diabetes. They
include sections on frequently asked questions that may be helpful when discussing these issues
with parents.
www.cdc.gov/nip/vacsafe/concerns/autism
www.cdc.gov/nip/vacsafe/concerns/Diabetes
www.mmrthefacts.nhs.uk
www.ncirs.usyd.edu.au/facts/f-diabetes.html
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REFERENCES
1.
Department of Developmental Services. Changes in the population of persons with
autism and pervasive developmental disorders in California's developmental services
system: 1987 through 1998. A Report to the Legislature. California Health and Human
Services, March 1, 1999. Available at: www.dds.ca.gov/Autism/pdf/
autism_report_1999.pdf (Accessed on January 18, 2006).
2.
Dales, L, Hammer, SJ, Smith, NJ. Time trends in autism and in MMR immunization
coverage in California. JAMA 2001; 285:1183.
3.
Madsen, KM, Hviid, A, Vestergaard, M, et al. A population-based study of measles,
mumps, rubella vaccine and autism. N Engl J Med 2002; 347:1477.
4.
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.
5.
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.
6.
Yeargin-Allsopp, M, Rice, C, Karapurkar, T, et al. Prevalence of autism in a US
metropolitan area. JAMA 2003; 289:49.
7.
Fombonne, E. Epidemiologic trends in rates of autism. Mol Psychiatry 2002; 7 Suppl
2:S4.
8.
McCormick, MC. The autism "epidemic": impressions from the perspective of
immunization safety review. Ambul Pediatr 2003; 3:119.
9.
Wakefield, AJ, Murch, SH, Anthony, A, et al. Ileal-lymphoid-nodular hyperplasia,
non-specific colitis, and pervasive developmental disorder in children. Lancet 1998;
351:637.
10.
Wakefield, AJ, Montgomery, SM. Autism, viral infection and measles-mumps-rubella
vaccination. Isr Med Assoc J 1999; 1:183.
11.
Bernard, S, Enayati, A, Redwood, L, et al. Autism: a novel form of mercury poisoning.
Med Hypotheses 2001; 56:462.
12.
Bernard, S, Enayati, A, Roger, H, et al. The role of mercury in the pathogenesis of
autism. Mol Psychiatry 2002; 7 Suppl 2:S42.
13.
Geier, MR, Geier, DA. Thimerosal in childhood vaccines, neurodevelopment disorders
and heart disease in the United States. J Am Physicians Surg 2003; 8:6.
14.
Geier, MR, Geier, DA. Neurodevelopmental disorders after thimerosal-containing
vaccines: a brief communication. Exp Biol Med (Maywood) 2003; 228:660.
15.
Iniguez, C, Mauri, JA, Larrode, P, et al. [Acute transverse myelitis secondary to hepatitis
B vaccination]. Rev Neurol 2000; 31:430.
16.
Herroelen, L, de Keyser, J, Ebinger, G. Central-nervous-system demyelination after
immunisation with recombinant hepatitis B vaccine. Lancet 1991; 338:1174.
17.
Marshall, E. A shadow falls on hepatitis B vaccination effort. Science 1998; 281:630.
18.
Classen, JB, Classen, DC. Clustering of cases of type 1 diabetes mellitus occurring 2-4
years after vaccination is consistent with clustering after infections and progression to
type 1 diabetes mellitus in autoantibody positive individuals. J Pediatr Endocrinol Metab
2003; 16:495.
19.
Classen, DC, Classen, JB. The timing of pediatric immunisation and the risk of insulindependent diabetes mellitus. Infectious Dis Clin Practice 1997; 6:449.
20.
Byrd, RS, Segman, M, Bono, M. Report to the Legislature on the principal findings from
the epidemiology of autism in California: a comprehensive pilot study. University of
California, Davis, M.I.N.D. Institute, October 17, 2002. Available at:
www.ucdmc.ucdavis.edu/mindinstitute/newsroom/study_final.pdf (Accessed on March
8, 2006).
21.
Croen, LA, Grether, JK, Hoogstrate, J, Selvin, S. The changing prevalence of autism in
California. J Autism Dev Disord 2002; 32:207.
22.
Fombonne, E. The prevalence of autism. JAMA 2003; 289:87.
23.
Wing, L, Potter, D. The epidemiology of autistic spectrum disorders: is the prevalence
rising?. Ment Retard Dev Disabil Res Rev 2002; 8:151.
24.
Fombonne, E. Epidemiological surveys of autism and other pervasive developmental
disorders: an update. J Autism Dev Disord 2003; 33:365.
25.
Shattuck, PT. The contribution of diagnostic substitution to the growing administrative
prevalence of autism in US special education. Pediatrics 2006; 117:1028.
26.
Uhlmann, V, Martin, CM, Sheils, O, et al. Potential viral pathogenic mechanism for new
variant inflammatory bowel disease. Mol Pathol 2002; 55:84.
27.
Fombonne, E, Chakrabarti, S. No evidence for a new variant of measles-mumps-rubellainduced autism. Pediatrics 2001; 108:E58.
28.
Stratton, K, Wilson, CB, McCormick, MC (Eds). Immunization Safety Review: MeaslesMumps-Rubella Vaccine and Autism. National Academy Press, Washington, DC 2001.
29.
Offit, PA. Vaccines and autism. Immunization Action Coalition, www.immunize.org.
(www.immunize.org/catg.d/p2065.htm) (Accessed on January 18, 2006).
30.
Horton, R. The lessons of MMR. Lancet 2004; 363:747.
31.
Murch,SH, Anthony, A, Casson, DH, et al. Retraction of an interpretation. Lancet 2004;
363:750.
32.
Offit, PA, Coffin, SE. Communicating science to the public: MMR vaccine and autism.
Vaccine 2003; 22:1.
33.
Taylor, B, Miller, E, Lingam, R, et al. Measles, mumps, and rubella vaccination and bowel
problems or developmental regression in children with autism: population study. BMJ
2002; 324:393.
34.
Evans, AS. Causation and disease: a chronological journey. The Thomas Parran Lecture.
1978. Am J Epidemiol 1995; 142:1126.
35.
Immunization Safety Review: Vaccines and Autism. A report of the Institute of
Medicine. The National Academy Press, Washington, DC 2004.
36.
Kawashima, H, Mori, T, Kashiwagi, Y, et al. Detection and sequencing of measles virus
from peripheral mononuclear cells from patients with inflammatory bowel disease and
autism. Dig Dis Sci 2000; 45:723.
37.
Fernell, E, Fagerberg, UL, Hellstrom, PM. No evidence for a clear link between active
intestinal inflammation and autism based on analyses of faecal calprotectin and rectal
nitric oxide. Acta Paediatr 2007; 96:1076.
38.
Bitnun, A, Shannon, P, Durward, A, et al. Measles inclusion-body encephalitis caused by
the vaccine strain of measles virus. Clin Infect Dis 1999; 29:855.
39.
McQuaid, S, Cosby, SL, Koffi, K, et al. Distribution of measles virus in the central
nervous system of HIV-seropositive children. Acta Neuropathol (Berl) 1998; 96:637.
40.
Martin, CM, Uhlmann, V, Killalea, A, et al. Detection of measles virus in children with
ileo-colonic lymphoid nodular hyperplasia, enterocolitis and developmental disorder. Mol
Psychiatry 2002; 7 Suppl 2:S47.
41.
Afzal, MA, Ozoemena, LC, O'Hare, A, et al. Absence of detectable measles virus genome
sequence in blood of autistic children who have had their MMR vaccination during the
routine childhood immunization schedule of UK. J Med Virol 2006; 78:623.
42.
D'Souza, Y, Fombonne, E, Ward, BJ. No evidence of persisting measles virus in
peripheral blood mononuclear cells from children with autism spectrum disorder.
Pediatrics 2006; 118:1664.
43.
Katz, SL. Has the measles-mumps-rubella vaccine been fully exonerated?. Pediatrics
2006; 118:1744.
44.
Hornig, M, Briese, T, Buie, T, et al. Lack of association between measles virus vaccine
and autism with enteropathy: a case-control study. PLoS ONE 2008; 3:e3140.
45.
Cass, H, Gringras, P, March, J, et al. Absence of urinary opioid peptides in children with
autism. Arch Dis Child 2008; 93:745.
46.
Nagamitsu, S, Matsuishi, T, Kisa, T, et al. CSF beta-endorphin levels in patients with
infantile autism. J Autism Dev Disord 1997; 27:155.
47.
Gillberg, C, Terenius, L, Lonnerholm, G. Endorphin activity in childhood psychosis.
Spinal fluid levels in 24 cases. Arch Gen Psychiatry 1985; 42:780.
48.
Gillberg, C, Terenius, L, Hagberg, B, et al. CSF beta-endorphins in childhood
neuropsychiatric disorders. Brain Dev 1990; 12:88.
49.
Feldman, HM, Kolmen, BK, Gonzaga, AM. Naltrexone and communication skills in young
children with autism. J Am Acad Child Adolesc Psychiatry 1999; 38:587.
50.
Willemsen-Swinkels, SH, Buitelaar, JK, van Engeland, H. The effects of chronic
naltrexone treatment in young autistic children: a double-blind placebo-controlled
crossover study. Biol Psychiatry 1996; 39:1023.
51.
Willemsen-Swinkels, SH, Buitelaar, JK, Weijnen, FG, van Engeland, H. Placebocontrolled acute dosage naltrexone study in young autistic children. Psychiatry Res
1995; 58:203.
52.
Baird, G, Pickles, A, Simonoff, E, et al. Measles vaccination and antibody response in
autism spectrum disorders. Arch Dis Child 2008; 93:832.
53.
Schonberger, LB, Bregman, DJ, Sullivan-Bolyai, JZ, et al. Guillain-Barre syndrome
following vaccination in the National Influenza Immunization Program, United States,
1976--1977. Am J Epidemiol 1979; 110:105.
54.
Murphy, TV, Gargiullo, PM, Massoudi, MS, et al. Intussusception among infants given an
oral rotavirus vaccine. N Engl J Med 2001; 344:564.
55.
Miller, E, Waight P, Farrington, CP, et al. Idiopathic thrombocytopenic purpura and MMR
vaccine. Arch Dis Child 2001; 84:227.
56.
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.
57.
DeStefano, F, Bhasin, TK, Thompson, WW, et al. Age at first measles-mumps-rubella
vaccination in children with autism and school-matched control subjects: a
population-based study in metropolitan Atlanta. Pediatrics 2004; 113:259.
58.
Makela, A, Nuorti, JP, Peltola, H. Neurologic disorders after measles-mumps-rubella
vaccination. Pediatrics 2002; 110:957.
59.
Patja, A, Davidkin, I, Kurki, T, et al. Serious adverse events after measles-mumpsrubella vaccination during a fourteen-year prospective follow-up. Pediatr Infect Dis J
2000; 19:1127.
60.
Peltola, H, Patja, A, Leinikki, P, et al. No evidence for measles, mumps, and rubella
vaccine-associated inflammatory bowel disease or autism in a 14-year prospective
study. Lancet 1998; 351:1327.
61.
Smeeth, L, Cook, C, Fombonne, E, et al. MMR vaccination and pervasive developmental
disorders: a case-control study. Lancet 2004; 364:963.
62.
Fombonne, E, Zakarian, R, Bennett, A, et al. Pervasive developmental disorders in
Montreal, Quebec, Canada: prevalence and links with immunizations. Pediatrics 2006;
118:e139.
63.
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.
64.
Wilson, K, Mills, E, Ross, C, et al. 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.
65.
Farrington, CP, Miller, E, Taylor, B. MMR and autism: further evidence against a causal
association. Vaccine 2001; 19:3632.
66.
DeStefano, F, Mullooly, JP, Okoro, CA, et al. Childhood vaccinations, vaccination timing,
and risk of type 1 diabetes mellitus. Pediatrics 2001; 108:E112.
67.
Infections and vaccinations as risk factors for childhood type I (insulin-dependent)
diabetes mellitus: a multicentre case-control investigation. EURODIAB Substudy 2
Study Group. Diabetologia 2000; 43:47.
68.
Heijbel, H, Chen, RT, Dahlquist, G. Cumulative incidence of childhood-onset IDDM is
unaffected by pertussis immunization. Diabetes Care 1997; 20:173.
69.
Karvonen, M, Cepaitis, Z, Tuomilehto, J. Association between type 1 diabetes and
Haemophilus influenzae type b vaccination: birth cohort study. BMJ 1999; 318:1169.
70.
Hviid, A, Stellfeld, M, Wohlfarht, J. Childhood vaccination and type 1 diabetes. N Engl J
Med 2004; 350:1398.
71.
Graves, PM, Barriga, KJ, Norris, JM, et al. Lack of association between early childhood
immunizations and beta-cell autoimmunity. Diabetes Care 1999; 22:1694.
72.
Blom, L, Nystrom, L, Dahlquist, G. The Swedish childhood diabetes study. Vaccinations
and infections as risk determinants for diabetes in childhood. Diabetologia 1991;
34:176.
73.
Hyoty, H, Hiltunen, M, Reunanen, A, et al. Decline of mumps antibodies in type 1
(insulin-dependent) diabetic children and a plateau in the rising incidence of type 1
diabetes after introduction of the mumps-measles-rubella vaccine in Finland. Childhood
Diabetes in Finland Study Group. Diabetologia 1993; 36:1303.
74.
Levitsky, LL. Childhood immunizations and chronic illness. N Engl J Med 2004;
350:1380.
75.
Progress toward elimination of Haemophilus influenzae type b invasive disease among
infants and children--United States, 1998-2000. MMWR Morb Mortal Wkly Rep 2002;
51:234.
76.
Progress toward eliminating Haemophilus influenzae type b disease among infants and
children-United States, 1987-1997. MMWR Morb Mortal Wkly Rep 1998; 47:993.
77.
Smith, MJ, Ellenberg, SS, Bell, LM, Rubin, DM. Media coverage of the measles-mumpsrubella vaccine and autism controversy and its relationship to MMR immunization rates
in the United States. Pediatrics 2008; 121:e836.
78.
The measles epidemic. The problems, barriers, and recommendations. The National
Vaccine Advisory Committee. JAMA 1991; 266:1547.
79.
Feikin, DR, Lezotte, DC, Hamman, RF, et al. Individual and community risks of measles
and pertussis associated with personal exemptions to immunization. JAMA 2000;
284:3145.
80.
White, CC, Koplan, JP, Orenstein, WA. Benefits, risks and costs of immunization for
measles, mumps and rubella. Am J Public Health 1985; 75:739.
81.
Gangarosa, EJ, Galazka, AM, Wolfe, CR, et al. Impact of anti-vaccine movements on
pertussis control: the untold story. Lancet 1998; 351:356.
82.
Friederichs, V, Cameron, JC, Robertson, C. Impact of adverse publicity on MMR vaccine
uptake: a population based analysis of vaccine uptake records for one million children,
born 1987-2004. Arch Dis Child 2006; 91:465.
83.
Johnson, RT, Griffin, DE, Hirsch, RL, et al. Measles encephalomyelitis: clinical and
immunologic studies. N Engl J Med 1984; 310:137.
84.
Weibel, RE, Caserta, V, Benor, DE, Evans, G. Acute encephalopathy followed by
permanent brain injury or death associated with further attenuated measles vaccines: a
review of claims submitted to the National Vaccine Injury Compensation Program.
Pediatrics 1998; 101:383.
85.
Roos, RP, Graves, MC, Wollmann, RL, et al. Immunologic and virologic studies of
measles inclusion body encephalitis in an immunosuppressed host: the relationship to
subacute sclerosing panencephalitis. Neurology 1981; 31:1263.
86.
Brooks, GF, Butel, JS, Morse, SA. Paramyxoviruses and rubella virus. In: Jawetz,
Melnick, & Adelberg's Medical Microbiology, 21st ed, Butler, JP, Ransom, J, Ryan, E
(Eds), Appleton & Lange, Stamford, CT 1998. p.50.
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