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Age at First MMR Vaccination and Autism

This study examines the possible association between age at first MMR vaccination and autism, comparing vaccination histories between autism subgroups and controls. It discusses previous studies supporting and opposing the association and highlights limitations in previous investigations.

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Age at First MMR Vaccination and Autism

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  1. Age at First MMR Vaccination and Autism

  2. Vaccines and Autism • Two main arguments in support of association • Prevalence of autism has been increasing at the same time that childhood vaccination coverage has increased • Temporal associations in which autistic characteristics become apparent shortly (weeks to months) after vaccination

  3. Studies Reporting Possible Association Between Vaccines and Autism • Wakefield: • 12 cases with Inflammatory Bowel Disease and Autism • 9 of 12 cases had reports of MMR contributed to onset of symptoms • No evidence of measles virus in IBD • Review of UK expert Medical Research Council: No association

  4. Studies Reporting Possible Association Between Vaccines and Autism Serologic evidence: Zecca: Increased measles antibody in children with autism Singh: Children with autism and brain autoantibodies (MBP) had higher measles IgG titers than children with autism with no brain antibodies Gupta: Increased rubella antibody titers in mothers of some patients with autism

  5. Recent Studies Not Supporting Association Between MMR Vaccine and Autism • Taylor: • Population-based: 498 known autism cases in one region • Link with immunization registry • No association found • Gillberg: • No difference in autism prevalence for children born before or after introduction of MMR vaccinations (1982) • Fombonne: • Utilized two large databases, 9000 clinical records and a second survey of autism in school aged children. • No cases that had co-occurrence of ulcerative colitis or Crohn’s disease.

  6. Recent Studies Not Supporting Association Between MMR Vaccine and Autism • Working Party of UK’s Medicines Control Agency: Reviewed all cases of autism and GI disease, GI disease only and autism only Information available did not support an association between vaccines and autism • Peltola et al: Examined 1.8 million individuals with ~ 3 million MMR vaccine doses from 1982-1996. Of the 173 potentially adverse events claimed to be causally associated with MMR, 45% had evidence suggesting other causes (i.e., infectious agents, viruses). No cases of autism were associated with MMR vaccination

  7. Recent Studies Not Supporting Association Between MMR Vaccine and Autism • Kaye et al: Examined children 12 years or younger for the UK diagnosed with autism between 1988-1999. While there was significant increased rates in autism, no temporal association was found between MMR vaccination prevalence rates and risk for autism. • Dales et al: Retrospective analyses of children from kindergartens born in 1980-1994 (600-1900 children each year) and of autism cases from California Department of Developmental Services. Results showed no correlation between the trend in MMR vaccine coverage and the occurrence of autism.

  8. Limitations of Previous Investigations • Incomplete ascertainment • Small sample sizes • Lack of standard case definitions • Lack individual-specific vaccine histories

  9. Statement from the Institute of Medicine, 2001 • Rejects causal relationship at the population level between MMR vaccine and ASD • Committee based this conclusion on: consistent body of evidence showing no association, original case series of children with ASD is uninformative with respect to causality, biologic models linking MMR with ASD are fragmentary, and there are no animal models linking MMR vaccine and ASD • Strongly encouraged additional studies to examine possible associations between MMR and subgroups of autistic children

  10. CDC Autism and MMR Vaccine History:Case-Control Study Main Objective • To evaluate the association between autism and age of receipt of the MMR vaccine Secondary objectives • To compare MMR vaccination histories between certain autism subgroups and controls

  11. Study Methods • The Metropolitan Atlanta Developmental Disabilities Surveillance Program (MADDSP) • Active, ongoing (since 1991) • Population-based: 3-10 year old children in five counties of Metropolitan Atlanta • Multiple source ascertainment of select DDs including: mental retardation,cerebral palsy, hearing impairment and vision impairment, and autism (from 1996)

  12. MADDSP Autism Surveillance Approach • Identifypotential cases at multiple educational and clinical sources • Schools: pyschoeducational assessments, special education files • Clinical sources: ASD as discharge diagnosis, billing code, or referral reason • Screen source files for autism indicators (“triggers”) • Abstract source files with autism “triggers” • Expert review of abstracted data to determine case status: • Autism Case • Suspected Case • Not a case

  13. Study methods: Autism Case Definition • A child 3-10 years old during the study year • Whose parent (s) or legal guardian(s) resided in the five-county metropolitan Atlanta area during the study year • And who displayed behaviors (as described by a qualified professional) consistent with the DSM-IV criteria for autistic disorder, PDD-NOS (including atypical autism), or Asperger’s disorder on evaluations conducted through the end of the year.

  14. Methods: Types of Data Collected for MADDSP • Demographic • Child and maternal identifying information • Date of birth, race, gender • Educational • Special education eligibility category • Psychometric test results (intelligence, developmental, adaptive, autism-specific) • Medical/Clinical • Physical findings • Associated medical conditions, family history, lab/genetic test results • Other developmental disabilities • Behavioral • Verbatim abstraction of behavioral features

  15. Methods: Expert Review Process • Case status determined by systematic review of abstracted information by autism experts • Behavioral coding scheme developed based on DSM-IV criteria for Autistic Disorder and PDD-NOS • Abstracted evaluations from all sources for a child were compiled and behaviors scored individually • Criteria were summarized to arrive at case status • Questionable cases were re-reviewed • 20% reliability sample – 96% agreement

  16. Study of Autism and MMR Vaccine: Study design and population • Case-control study design • Cases: 624 children with ASD • Identified through MADDSP Autism Surveillance in 1996 • Born from 1986-1993 • With valid MMR vaccination dates on the immunization form in the school record • Controls: 1,824 children without known DD • 3:1 control to case ratio • Selected from regular education programs • Matched to case-children based on age, sex, and school of attendance at the time of abstraction* * Certain exceptions had to be made for some control children

  17. Study of Autism and MMR Vaccine: Flow Chart of Sample Selection MADDSP Confirmed Autism Cases (N = 987) Cases With Immunization records (N = 660) Cases with available controls (N = 647) Matched Controls (N = 1,891) Cases with valid MMR vaccination dates (N = 624) Matched Controls with valid MMR vaccination dates (N = 1,824)

  18. Study of Autism and MMR Vaccine History: Data Collection Vaccination History: Collected from the standard State of Georgia Immunization Form • Vaccine information consists of vaccines required by school law for entry into the school (i.e., MMR, DTP, OPV, IPV, HepB (1992)). • Other information included location of vaccine administration, name of physician, and administration of vaccines not required by school (i.e., Hib) or additional doses of vaccines that are required. • Vaccine exemption data are alsocollected when available.

  19. Study of Autism and MMR Vaccine History: Data Collection • Child’s School Record and Birth Certificate • Demographic and other information that was collected included child’s birth state, birth certificate number, sex, race, date of birth, parent’s names, adoption status • Cases and controls born in Georgia were linked to State Birth Certificate Files to collect information on key variables (mother’s education and age, birth weight, gestational age, etc.) • MADDSP • Presence of other DDs, co-existing medical conditions, and IQ functioning • MACDP • Information on major congenital malformations

  20. Study of Autism and MMRVaccine History: Exposure Variables • Three specific age cut-offs were chosen: • 18 months: indicator of “on-time” vaccination and also median age for the occurrence of regression • 24 months: the upper age limit at which onset of regression or parental concern usually occurs • 36 months: the age by which autistic characteristics must have developed according to DSM-IV criteria for autism

  21. Study of Autism and MMR Vaccine History: Classification of Autism Subgroups • Subgroups based on demographic factors • Gender • Age at ascertainment • Subgroups based on clinical presentation • Children without a pre-existing condition < 1 year of age No birth defect, diagnosed disability, indication of developmental delay, or neonatal event that is related to onset of autistic behaviors by 1 year of age • Children identified with regression or plateau • Children with and without mental retardation

  22. Study of Autism and MMR Vaccine History: Classification of Autism Subgroups • Subgroups based on factors related to case selection • Children with records abstracted at school sources only • Children with records abstracted from multiple sources and/or clinical sources • Children with and without a previous ASD diagnosis

  23. Study of Autism and MMR Vaccine Study: Potential Confounding Variables • Age at ascertainment (1996) • Child’s sex • Child’s race • Maternal age • Maternal education • Birth weight • Multiplicity • Parity

  24. Study of Autism and MMR Vaccine History: Analytic Approach • Conditional logistic regression analysis stratified by matched case-control sets • Confounding variables included as covariates that had an odds ratio p-value of < .20 when evaluated individually for association with autism case definition • Odds ratios were adjusted for confounding variables in assessing association between age at vaccination and autism

  25. Results: Comparison between case-children included in MMR studyand case-children not included in the study • Significant findings • Case-children included in the study were more likely to be identified at a school source only (AOR=1.6; 95% CI= 1.1,2.5). • Case-children NOT included in the study were less likely to be from mothers of lower education (AOR=0.4; 95% CI=0.2,0.8).

  26. Results: Age of 1st MMR Vaccination by Case Status For Total Sample

  27. CDC Autism and MMR Vaccine History: Case-Control Study Strengths: • Population-based sample of children with autism available from MADDSP • Immunization records of children available from existing records • Case:control study design provides information on children without autism from the same population • Information 700+ children with autism and 1600+ control children

  28. CDC Autism and MMR Vaccine History: Case-Control Study Limitations: • Record-based review of autism: Difficult to pinpoint earliest onset of disorder for a number of children • Information on other possible contributing factors not always available

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