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Immunization Safety Review: Measles-Mumps-Rubella Vaccine and Autism

Immunization is widely regarded as one of the most effective and beneficial tools for protecting the public's health. In the United States, immunization programs have resulted in the eradication of smallpox, the elimination of polio, and the control and near-elimination of other once-common, often debilitating, and potentially life-threatening diseases, including measles, mumps, rubella, diphtheria, pertussis, tetanus, and Haemophilus influenzae type b.

Along with the benefits of widespread immunization, however, have come concerns about the safety of the vaccines. No vaccine is perfectly safe or effective, and vaccines may lead to serious adverse effects in some instances. Furthermore, if a serious illness is observed following vaccination, it is often unclear whether that sequence is coincidental or causal, and it can be difficult to determine the true nature of the relationship, if any, between the vaccination and the illness.

Ironically, the successes of vaccine coverage in the United States have made it more difficult for the public to weigh the benefits and risks of vaccines because the now controlled diseases and their often-serious complications, are no longer familiar. However, because vaccines are so widely used—and because state laws require that children be vaccinated before entering daycare and school, in part to protect others—it is essential that safety concerns be fully and carefully studied.

This report, the first of a series from the Immunization Safety Review Committee, presents an assessment of the evidence regarding a hypothesized causal association between the measles-mumps-rubella (MMR) vaccine and autism, the committee's conclusions and recommendations based on that assessment, and an assessment of the broader significance for society of the issues



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Page 13 Immunization Safety Review: Measles-Mumps-Rubella Vaccine and Autism Immunization is widely regarded as one of the most effective and beneficial tools for protecting the public's health. In the United States, immunization programs have resulted in the eradication of smallpox, the elimination of polio, and the control and near-elimination of other once-common, often debilitating, and potentially life-threatening diseases, including measles, mumps, rubella, diphtheria, pertussis, tetanus, and Haemophilus influenzae type b. Along with the benefits of widespread immunization, however, have come concerns about the safety of the vaccines. No vaccine is perfectly safe or effective, and vaccines may lead to serious adverse effects in some instances. Furthermore, if a serious illness is observed following vaccination, it is often unclear whether that sequence is coincidental or causal, and it can be difficult to determine the true nature of the relationship, if any, between the vaccination and the illness. Ironically, the successes of vaccine coverage in the United States have made it more difficult for the public to weigh the benefits and risks of vaccines because the now controlled diseases and their often-serious complications, are no longer familiar. However, because vaccines are so widely used—and because state laws require that children be vaccinated before entering daycare and school, in part to protect others—it is essential that safety concerns be fully and carefully studied. This report, the first of a series from the Immunization Safety Review Committee, presents an assessment of the evidence regarding a hypothesized causal association between the measles-mumps-rubella (MMR) vaccine and autism, the committee's conclusions and recommendations based on that assessment, and an assessment of the broader significance for society of the issues

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Page 14 surrounding the MMR-autism question. Since the late 1990s, this hypothesis has received increasing attention from scientific researchers, Congress, the media, parents, advocacy organizations, public health professionals, and vaccine manufacturers (60 Minutes, 2000; U.S. House Committee on Government Reform, 2000; Wakefield et al., 1998, 2000). ORIGINS OF THE IMMUNIZATION SAFETY REVIEW PROJECT The federal government has responded to concerns about the safety of vaccines through several mechanisms. In 1986, Congress passed the National Childhood Vaccine Injury Act (Public Law 99-660), followed by the Vaccine Compensation Amendments of 1987 (Public Law 100-203). This legislation mandated the establishment of a National Vaccine Injury Compensation Program to handle related claims, and of the Vaccine Adverse Event Reporting System (VAERS), which is a national passive surveillance system. The legislation also provided for the development of vaccine information statements for parents of children receiving immunizations. These activities are managed by three agencies of the U.S. Department of Health and Human Services (DHHS): the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), and the Health Resources and Services Administration (HRSA). The compensation program is jointly administered by HRSA and the Department of Justice. The legislation also called for the Institute of Medicine (IOM) to review evidence regarding possible adverse consequences of childhood immunizations. The three expert committees convened by IOM produced the reports Adverse Effects of Pertussis and Rubella Vaccines (IOM, 1991), Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality (IOM, 1994a), and DPT Vaccine and Chronic Nervous System Dysfunction: A New Analysis (IOM, 1994b). Following the completion of the third study, IOM was asked to organize the Vaccine Safety Forum to provide a framework for continued discussion of vaccine safety issues. Forum participants included representatives of government agencies, advocacy groups, and pharmaceutical companies, as well as parents, health care providers, academic researchers, and IOM staff. Forum discussions, on topics such as research strategies and risk communication, were documented in brief reports (IOM, 1996, 1997a,b) but were not intended to produce conclusions or recommendations. The final meeting of the Forum explored the early emerging data regarding the hypothesized relationship between MMR vaccine and autism. A list of research ideas from that open meeting can be found in Appendix D. In 1995 and 1997, in response to the findings and recommendations of Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality (IOM, 1994a), the Secretary of the DHHS updated the Vaccine Injury Table, a list of post-vaccination events that must be reported to DHHS and that

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Page 15 are covered by the National Vaccine Injury Compensation Program. Also in 1995, the National Vaccine Advisory Committee (NVAC) of the National Vaccine Program Office of DHHS added a Vaccine Safety Subcommittee to its efforts. In 1999, this subcommittee expanded its scope and was renamed the Vaccine Safety and Communication Subcommittee. Concern over cases of vaccine-associated paralytic poliomyelitis prompted another CDC committee—the Advisory Committee on Immunization Practices—to recommend in 1997 that the immunization schedule be changed to replace oral poliovirus vaccine with inactivated poliovirus vaccine (CDC, 2000e). But since the mid-1990s, a number of additional challenges to the safety of vaccinations have gained attention in various settings. During 1999–2000, the Committee on Government Reform of the U.S. House of Representatives held seven hearings on vaccine-safety issues. The media have covered these issues on news programs such as 60 Minutes, 20/20, and Nightline, and the Internet is playing an increasingly important communications role. Also, many consumer and professional organizations have sponsored conferences and scientific symposia to address vaccine safety. Given these growing concerns, CDC and the National Institutes of Health (NIH) recognized the need for an independent, expert group to address vaccine safety in a timely and objective manner. In 1999, as a result of IOM's previous work and its access to independent scientific experts, CDC and NIH began a year of discussions with IOM to develop the Immunization Safety Review project to address vaccine-safety issues both existing and emerging. THE CHARGE TO THE COMMITTEE The Immunization Safety Review Committee is responsible for examining a broad variety of vaccine-safety concerns. Committee members have expertise in pediatrics, neurology, immunology, internal medicine, infectious diseases, genetics, epidemiology, biostatistics, risk perception and communication, decision analysis, public health, nursing, and ethics. To preclude any real or perceived conflicts of interest, candidate members were subject to strict selection criteria that excluded anyone who had financial ties to vaccine manufacturers or their parent companies, previous service on major vaccine advisory committees, and prior expert testimony or publications on issues of vaccine safety. While all committee members share a belief in the benefits of vaccines, none of them has a vested interest in the vaccine-safety issues that will come before the group. Additional discussion of the committee composition can be found in the Foreword, written by Dr. Kenneth Shine, President of the IOM. The committee is charged with examining three vaccine-safety hypotheses each year during the 3-year study period (2001–2003). The Interagency Vaccine Group, comprising officials from the National Vaccine Program Office at DHHS, the National Immunization Program and the National Center for Infectious Diseases at the CDC, the National Institute for Allergy and Infectious Dis-

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Page 16 eases at the NIH, the Department of Defense, the FDA, the National Vaccine Injury Compensation Program at HRSA, the Health Care Financing Administration, and the Agency for International Development, selects the hypotheses to be examined by the committee. For each hypothesis examined, the committee will hold an open scientific meeting followed directly by a 1- to 2-day closed meeting for committee deliberations and formulation of conclusions and recommendations. The committee's findings will be released to the public in a brief consensus report 60-90 days after its meeting. For each hypothesis to be examined, the committee has been asked to assess both its scientific plausibility and the significance of the issue in a broader societal context. The plausibility assessment has two components: (1) an examination of the causal relationship between the vaccine and the adverse event and (2) an examination of any pathogenic mechanism(s) in support of the hypothesis. The significance assessment addresses such considerations as the nature of the health risks associated with the vaccine-preventable disease and that of the adverse event in question. Other considerations may include the perceived intensity of public or professional concern or the feasibility of additional research to help resolve scientific uncertainty regarding causal associations. The findings of the plausibility and significance assessments provide the basis for the committee's recommendations on public health response, immunization-policy review, current and future research, and effective communication strategies for the specific immunization-safety questions. Although the committee has been asked to make recommendations related to immunization policy, there are clear limits on this element of the charge. For example, it would exceed the authority of this committee to recommend a change in the licensure, scheduling, or administration of a vaccine. If the committee concluded that the scientific evidence or other important factors justified such action, it could recommend convening the appropriate advisory group(s) to examine the question. THE STUDY PROCESS The committee held an initial organizational meeting in January 2001. CDC and NIH presented the committee's charge at the meeting, and the committee conducted a general review of immunization-safety concerns and determined its methodology for assessing causality. This approach would be used for the hypotheses to be considered at subsequent meetings (see Appendix A). To evaluate the hypothesis on MMR vaccine and autism, the committee then collected information from several sources. An extensive review was performed of the published, peer-reviewed scientific and medical literature pertinent to the hypothesis. A background paper reviewing the epidemiological studies of MMR vaccine and autism was commissioned and made available on the project's website to inform the committee and to generate discussion among committee members and other interested parties. Critiques of the paper were reviewed during the committee's deliberations. (The committee emphasizes that

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Page 17 this background paper does not represent the views of the committee, only those of the authors.) At an open scientific meeting in March 2001 ( Appendix B), academic researchers, NIH scientists and other federal officials, and representatives of vaccine safety advocacy groups gave presentations and offered comments. The formal presentations reviewed the current state of knowledge of the etiology and epidemiology of autism and current research efforts. The committee also heard presentations from researchers currently investigating the MMR vaccine-autism hypothesis. Unpublished data shared with the committee through presentations and personal communications helped inform the committee's conclusions and recommendations. A working group of the committee conferred with parents of autistic children, as well as vaccine-safety advocates and educators, to discuss their concerns regarding the MMR vaccine, autism, and the hypothesized association between the two. THE FRAMEWORK FOR ASSESSING CAUSALITY The Immunization Safety Review Committee has adopted the framework for assessing causality developed by the committees previously convened by the IOM (1991, 1994a) to address questions of vaccine safety. Reviews begin from a position of neutrality regarding the specific vaccine-safety hypothesis under question. That is, there is no presumption that a specific vaccine does or does not cause the adverse event in question. The weight of the available evidence determines whether it is possible to shift that position toward causality (“the evidence favors acceptance of a causal relationship”) or away from causality (“the evidence favors rejection of a causal relationship”). The committee does not conclude that the evidence favors rejecting causality merely if the evidence toward causality is inadequate. Rather, the committee requires epidemiological evidence showing no association before concluding that the evidence favors rejection of a causal relationship. Furthermore, while biological plausibility must be demonstrated in order to establish a causal relationship, demonstrated biological plausibility in the absence of adequate epidemiological evidence is not sufficient. Standard approaches are used for evaluating evidence. Controlled epidemiological studies published in peer-reviewed journals always carry the most weight. Uncontrolled observational studies are important but generally are considered less definitive than controlled studies. Case reports and case series are reviewed, although they are generally inadequate to establish causality. Despite the limitations of case reports, the causality argument for at least one adverse event (the relationship between vaccines containing tetanus-toxoid and Guillain-Barré syndrome) was strengthened most by a single, well-documented case report on recurrence of the adverse event following re-administration of the vaccine, referred to as a “rechallenge” (IOM, 1994a).

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Page 18 Unpublished or non-peer-reviewed data presented to the committee are often reviewed. Such findings could be used in support of a body of published literature with similar findings, but only in extraordinary circumstances could an unpublished study refute a body of published literature. If, however, the committee felt that the unpublished data were well described, were obtained using sound methodology, and presented very clear results, the committee could consider, with sufficient caveats in the discussion, how those data fit with the entire body of published literature. Five categories are used to summarize the direction and strength of the evidence for causality (see Table 1). The wording of the causality categories used in the 1991 IOM report was revised in the 1994 report because the IOM had found that some people misinterpreted the 1991 language. The changes in wording are shown in Table 1 . The types and strength of evidence required to determine a specific level of causal association were the same for the two reports. The Immunization Safety Review Committee is using the wording adopted in 1994. UNDER REVIEW: THE MMR–AUTISM HYPOTHESIS The Immunization Safety Review Committee examined the hypothesized causal relation between MMR vaccination and autism. Autism is a complex and severe developmental disorder characterized by impairments of social interaction, impairments in verbal and nonverbal communication, and restricted or repetitive and stereotyped patterns of behaviors and interests (APA, 1994; Filipek et al., 1999). Over time, research has identified subtle differences in the onset and progression of autistic symptoms. The term “autistic spectrum disorders” (ASD), synonymous with “pervasive developmental disorders” (PDD), refers to a continuum of related cognitive and neurobehavioral disorders that reflects the heterogeneity of these symptoms. ASD includes autistic disorder, childhood disintegrative disorder, Asperger's syndrome, Rett's syndrome, and pervasive developmental disorder not otherwise specified (PDD-NOS or atypical autism). While the primary deficits are similar for all of these disorders, patients vary in the severity of their symptoms and level of cognitive impairment. Although Rett's syndrome is included in the diagnostic category of ASD, it is considered by many to be a distinct neurologic disorder and this diagnosis is not included in most research which has evaluated the association of the MMR vaccine with autism. In this report, the terms “autism,” “autistic,” and “autistic spectrum disorders” are used interchangeably to refer to this broader group of pervasive developmental disorders. The term “autistic disorder” refers to a more narrow diagnosis defined by criteria in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) (APA, 1994).

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Page 19 TABLE 1 Summary Categories and Levels of Evidence Regarding Causality Category IOM, 1991 IOM, 1994a Level of Evidence 1 No evidence bearing on a causal relation No evidence bearing on a causal relation No case reports or epidemiological studies identified. 2 Evidence insufficient to indicate a causal relation The evidence is inadequate to accept or reject a causal relation One or more case reports or epidemiological studies were located, but the evidence for the causal relation neither outweighs nor is outweighed by the evidence against a causal relation. 3 Evidence does not indicate a causal relation The evidence favors rejection of a causal relation Only evidence from epidemiological studies can be used as a basis for possible rejection of a causal relation. Requires a rigorously performed epidemiologica study (or meta-analysis) of adequate size that did detect a significant association between the vaccine and the adverse event. 4 Evidence is consistent with a causal relation The evidence favors acceptance of a causal relation The balance of evidence from one or more case reports or epidemiological studies provides evidence for a causal relation that outweighs the evidence agains 5 Evidence indicates a causal relation The evidence establishes a causal relation Epidemiological studies and/or case reports provide unequivocal evidence for a causal relation. Most cases of ASD appear to result from prenatal or early postnatal insults (Bristol et al., 1996). Although it is clear that a vaccine given in the second year of life, as MMR is, could not cause the cases of autism originating in the prenatal or early postnatal period, the emergence of more pronounced symptoms at the time of vaccination may leave the temporal relationship with vaccine exposure uncertain. Moreover, because in some cases autistic symptoms emerge after

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Page 20 a period of apparently normal development (i.e., regression), usually in the second year of life, the possibility is left open that MMR vaccination may provoke the onset of the disorder. The MMR vaccine, which consists of three separate, attenuated viruses directed against three different diseases, has been hypothesized many times over the years to cause neurologic disorders, especially encephalitis or encephalopathy. Biologic plausibility is demonstrated for this association, because natural or wild-type measles clearly infects the central nervous system (CNS) and can lead to clinical neurologic events. In addition, rubella virus is known to produce CNS–related birth defects. Although neurologic effects are biologically plausible, the totality of biological, clinical, and epidemiological data led previous IOM committees to conclude that the evidence is inadequate to accept or reject a causal relationship between MMR vaccine and encephalopathy, subacute sclerosing panencephalitis (SSPE), or residual seizure disorder. The specific question of MMR and ASD was not addressed in the 1991 or 1994 IOM reports. Current attention to the possible relationship between MMR and ASD stems primarily from a case series reported in 1998 (Wakefield et al., 1998). The authors investigated 12 children, consecutively referred to a London gastroenterology clinic, who exhibited regression in development (loss of previously acquired developmental milestones) and gastrointestinal symptoms. For eight of these children, according to retrospective accounts by their parents or physicians, the onset of their behavioral problems was associated with MMR vaccination. While the authors acknowledge that the study did not prove an association between MMR and the conditions seen in these children, the report generated considerable interest and concern about a possible link between MMR vaccination and ASD, and regressive autism in particular. Subsequent epidemiological studies have investigated the possible relationships among the MMR vaccine, ASD, and bowel disease. Some studies have focused on ASD with no specific relation to bowel disease; other studies have focused on the bowel disease with no particular relationship to ASD. There are also more general concerns in the United States and the United Kingdom that the introduction and wide-scale use of the MMR vaccine coincides with an apparent increase in the incidence of autism. A report by the California Department of Developmental Services (1999) showed a significant increase between 1987 and 1998 in its caseload of children with autism, and this report is often cited as supporting an increase in ASD occurrence, although these reported increases occurred well after the licensure and introduction of MMR in the United States in 1971. The evidence from other studies of trends in ASD prevalence and incidence is unclear. While several recent reviews have found an increase in autism prevalence rates, these observed increases may reflect such factors as reporting bias, changes in diagnostic criteria for ASD, and better detection of cases (Fombonne, 1999, 2001a; Gillberg and Wing, 1999). Given these broader concerns and uncertainties about ASD, parents of autistic children who spoke to members of the IOM committee urged consideration of biologic mechanisms other than those involving bowel disorders.

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Page 21 The possible association between MMR vaccine and autism has been the focus of high-level scientific research and review, both in the United Kingdom and the United States. British health authorities have issued statements that the evidence shows MMR vaccine does not cause autism and MMR vaccine should be administered in its trivalent form (U.K. DOH, 2001a). The World Health Organization (WHO) has likewise issued a statement in support of the trivalent vaccine (WHO, 2001). In the United States, the American Academy of Pediatrics (AAP), at the request of CDC, convened a workshop in June 2000 to explore the data on this relationship. The report, due to be released in May 2001, was embargoed and therefore not available to this committee for review. However, a letter from the vice-president of AAP to the AAP membership states that “The bottom line is that a considerable body of evidence does not support a causal relationship between MMR vaccine and autism or inflammatory bowel disease. No data exist to suggest that separate administration of measles-mumps-rubella vaccines would offer any potential benefit over the MMR vaccine currently used in the United States” (Cooper, 2001). PLAUSIBILITY ASSESSMENT The Immunization Safety Review Committee undertook to answer the following question: What is the causal relationship between the MMR vaccine and ASD? The sources of evidence considered by the committee in its plausibility assessment include biological plausibility, reports of individual cases or series of cases, and epidemiological studies. Epidemiological studies assess health-related exposures or outcomes in a defined sample of subjects and making inferences about the values of those characteristics or the associations among them in the population from which the study sample originates. Epidemiological studies can either be uncontrolled (descriptive) or controlled (analytic), observational (survey) or experimental (clinical trial). Controlled and experimental studies are given more weight in causality assessments because of their more rigorous study designs. It is important to emphasize that the focus is on the hypothesized relationship between MMR vaccine and ASD, not the presence or absence of bowel disease in children with ASD. The committee recognizes the contribution to clinical medicine of the presentation of bowel disease in a subset of children with ASD, but the possible presence and role of measles vaccine-strain virus in the bowel of these children is not central to assessing the relationship between MMR vaccine and ASD. It does, however, suggest a potential biologic mechanism to link MMR vaccine and ASD, which is discussed below in the review of biologic plausibility. Further research on this subject might have more bearing on the possible role of measles-related virus in the etiology of bowel disease than on its role in the etiology of ASD.

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Page 22 Clinical Description of Autistic Spectrum Disorders Autism was first described by Kanner in 1943, and a serious effort by Rutter and others to define the disorder more precisely came in the 1970s (Volkmar and Lord, 1998). Efforts to develop clear definitions for each of the autistic spectrum disorders have culminated in a convergence of the diagnostic criteria in DSM-IV (APA, 1994) and the latest version of the WHO's International Classification of Diseases, ICD-10 (Filipek et al., 1999; WHO, 1993). Widespread acceptance of these diagnostic criteria is expected to produce more consistent identification and categorization of cases, which will be more conducive to research and comparative studies. Kanner initially described “infantile autism” as exhibition of poor social and communication skills but not necessarily cognitive impairment. He described these impairments as being evident at birth or shortly thereafter and not associated with any medical conditions. Early research on autism was hampered by confusion resulting from the placement of autism in a continuum of psychotic disorders related to schizophrenia. Autism was also erroneously associated with high parental achievement, parental psychopathology, and dysfunctional parent-child interactions and care. In fact, autism occurs in families of all socioeconomic levels and ethnic backgrounds. Autism has been found to be associated with various organic abnormalities such as structural abnormalities in the brain, seizure disorders and EEG abnormalities, and mental retardation (Volkmar and Lord, 1998). Autopsy studies of a small number of brains of individuals who had autism have shown neuroanatomic abnormalities, including decreased cell size, increased cell density, and stunting of dendritic branching bilaterally in the limbic system (Bauman and Kemper, 1997; Kemper and Bauman, 1998). The limbic system is important for learning, memory, emotion, and behavior. A decrease in Purkinje cell density and, to a lesser extent, granule cell density in the cerebellum has also been described (Bauman, 1999; Bauman and Kemper, 1997). The cerebellum is linked to control of emotion, motivation, learning, memory, and the processing and integration of sensory and motor information. The pattern of neural abnormalities in the limbic system and the lack of reactive gliosis or other evidence of an inflammatory or infectious event in the autopsied brains suggest that the etiologic insult occurred in early embryonic development (Kemper, 2001). Furthermore, the existence of Purkinje cell lesions with the preservation of related olivary neurons as described in the brains of autistic patients is consistent with a prenatal insult because cerebellar lesions after birth generally lead to regression of the olivary neurons (Bauman and Kemper, 1997). Autism is believed to be the most genetic of all psychiatric disorders (Rutter et al., 1997). It is generally thought that the genetic mechanism is a complex interaction among multiple genes. However, interactions of other factors, including infectious, neurologic, metabolic, immunologic, and environmental insults, may also play an important role in the onset of autism. (Bristol-Power, 2001). An increased risk of autism in siblings of a child with autism and a high

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Page 23 concordance rate in monozygotic twins have been found (Bailey et al., 1995; Trottier et al., 1999). In a recent study, Bailey and colleagues (1995) reevaluated the subjects of an original British twin study and also evaluated a new sample of twins. Consistent with previous studies, the study revealed a significant difference in the concordance rate of monozygotic (identical) versus dizygotic (fraternal) twins, 60% and 0%, respectively. Autism has been associated with a variety of clearly inherited (genetic) medical conditions including fragile X syndrome, tuberous sclerosis, Rett's syndrome, and phenylketonuria (Trottier et al., 1999). Furthermore, aberrations of almost all chromosomes, including the X and Y (sex-linked) chromosomes, have been described in some children diagnosed with autism (Gillberg, 1998). The frequency of the association of known medical conditions with autism has been a point of much debate, but the rate of concurrence is thought to be approximately 10% (Rutter et al., 1994). Clinical descriptions of autism suggest several different types of presentations, including early onset and regression. In the early-onset cases, developmental abnormalities appear within the first year or few months of life, and may be apparent as early as birth. Most cases of autism appear to be early onset (Bristol et al., 1996); however, the diagnosis is characteristically not made until the second year of life, when symptoms become more prominent. In a second course suggested by the minority of cases, apparently normal development is followed by regression, or the sudden or insidious loss of previously established developmental milestones, which may exhibit a fluctuating pattern (Rapin, 1997; Tuchman et al., 1991). There is no scientifically established definition of regressive autism, and data are not available regarding the fundamental differences in course or other features between early onset and regressive autism. The distinction is drawn by the reported time-course of developmental abnormalities. Differentiation between these two courses of autism may be confounded by delayed parental recognition of developmental problems that were actually present much earlier in childhood (Mars et al., 1998; Rogers and DiLalla, 1990; Tuchman and Rapin, 1997). Furthermore, it is possible that the regressive form does not represent actual regression of development but rather a failure to progress (Volkmar, 2001). It is an important possibility that regressive autism is a manifestation of a later insult that exacerbates an earlier insult, such as those outlined above. There are conflicting views regarding the frequency and timing of regression, and these are the subject of current research efforts aimed at producing a better understanding of this course of autism. Below, the specific diagnoses classified under ASD or PDD are briefly described. Autistic disorder occurs more often in boys than girls and is thought to have multiple etiologies that are not well described. Genetic factors are known to have a very strong influence in the etiology (Rutter et al., 1997). The standard criteria used for diagnosis, as described in DSM-IV/ICD-10 (see Table 2), include qualitative impairments of social interaction, such as lack of emotional reciprocity and failure to develop peer relationships; qualitative impairment in spoken or behavioral communication; and restrictive, repetitive and stereotyped

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Page 60 done on risk communication, including a better understanding of trade-off issues and of the complexity of developing and explaining quantitative risk-benefit estimates. In the meantime, the committee urges CDC, FDA, NIH, AAP, and similar organizations to take to heart the serious concerns and earnest offers from the concerned public to help with information exchange and communication strategies. Finally, the committee did not have time to address responsibly the appropriateness of alternative immunization schedules or practices, which might be requested in a clinical setting. This has been discussed by others, especially recently with regard to MMR vaccine, and is of great interest and concern to many. Because the committee believes these to be issues that will emerge in many of its subsequent meetings, it will hold specific comments, conclusions, and recommendations for the future. The committee does pledge to address these matters over the next 3 years and will develop a mechanism for further input into its work in this area. SUMMARY The Immunization Safety Review committee concludes that the evidence favors rejection of a causal relationship at the population level between MMR vaccine and ASD. However, this conclusion does not exclude the possibility that MMR vaccine could contribute to ASD in a small number of children. Because of the limitations of the evidence, the significant public concern surrounding the issue, the risk of disease outbreaks if immunization rates fall, and the seriousness of ASD, the committee recommends that continued attention be given to this issue. This committee has provided targeted research and communication recommendations. However, the committee does not recommend a policy review at this time of the licensure of MMR vaccine or of the current schedule and recommendations regarding administration of MMR vaccine. REFERENCES 60 Minutes. The MMR Vaccine. November 12, 2000. Afzal MA, Armitage E, Begley J, Bentley ML, Minor PD, Ghosh S, Ferguson A. 1998. Absence of detectable measles virus genome sequence in inflammatory bowel disease tissues and peripheral blood lymphocytes. J Med Virol 55(3): 243–249. Afzal MA, Armitage E, Ghosh S, Williams LC, Minor PD. 2000a. Further evidence of the absence of measles virus genome sequence in full thickness intestinal specimens from patients with Crohn's disease. J Med Virol 62(3): 377–382. Afzal MA, Minor PD, Schild GC. 2000b. Clinical safety issues of measles, mumps and rubella vaccines. Bull World Health Organ 78(2): 199–204. Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY. 1999. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nature Genet 23(2): 185–188. Andre FE, Peetermans J. 1986. Effect of simultaneous administration of live measles vaccine on the “take rate” of live mumps vaccine. Dev Biol Stand 65(6): 101–107.

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