Age at First Measles-Mumps-Rubella Vaccination in Children with Autism and School-matched Controls: A Population-Based Study in Metropolitan Atlanta F. De. Stefano, MD, MPH 2, T. Karapurkar, MPH 3, W. W. Thompson, Ph. D 2, M. Yeargin-Allsopp, MD 1, C. Boyle, Ph. D 1 1 National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention 2 National Immunization Program, Centers for Disease Control and Prevention 3 Battelle Centers for Public Health Research and Evaluation Background • Recent estimates of autism prevalence are as high as 2 -6 per 1, 000. • There is growing concern over the apparent rise in prevalence of autism. • The causes are largely unknown • Evidence for strong genetic component • Environmental factors, such as vaccines, have been implicated Measles-Mumps-Rubella (MMR) Vaccine 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 more apparent around the time of MMR vaccination. Institute of Medicine (IOM) Statement, 2001 • IOM reviewed MMR-autism hypothesis and rejected causal association based on findings of previous epidemiologic investigations. • Encouraged additional studies to evaluate the possibility that subgroups of children might be at increased risk of autism from MMR vaccination Study Purpose Study purpose: To compare ages at first MMR vaccination between children with autism and children without autism in the total population and in select subgroups, including children with regression in development Study Design and Population • Case-control study design • Cases: 624 children with ASD • Identified through MADDSP Autism Surveillance in 1996 • Controls: 1, 824 children selected from schools • 3: 1 controls: cases matched on age, gender, and school of attendance Metropolitan Atlanta Developmental Disabilities Surveillance Program (MADDSP) • Population based program begun in 1991: 3 -10 year old children in the 5 counties of Metropolitan Atlanta MADDSP Study Areas • Multiple source ascertainment of select developmental disabilities MADDSP Autism Surveillance Case definition based on DSM IV criteria: • Autistic Disorders: 299. 10 • Atypical Autism (PDD-NOS & Asperger’s Syndrome): 299. 80 Case status: • Established by a team of expert reviewers Classification of Autism Subgroups Subgroup 1: Children without any indication of developmental delay or pre-existing condition (PEC) prior to age 12 months Subgroup 2: Children with any indication of loss of age-appropriate developmental skills (regression) or appropriate skills that failed to progress Subgroup 3: Children with and without coexisting mental retardation (MR) Data Collection Georgia Standard Immunization Form • Vaccinations required by law for entry into early intervention and school programs - MMR, DTP, OPV/IPV, Hepatitis B (in 1992) • Vaccine exemption Child’s Birth Certificate data were also collected if available. • Child’s sex, child’s birth date, mother’s race, multiple gestation, birth weight, and maternal age and education MADDSP • Other developmental disabilities, and co-existing medical conditions Analytic Approach Compared distribution of ages at first MMR vaccination by case status • Overall distributions of age at vaccination • By three age cut-offs: • < 18 months of age – an indicator of ‘on time’ vaccination • < 24 months of age – the age by which atypical development has become apparent • < 36 months of age – the age requirement to meet DSM-IV criteria for autism Conditional Logistic Regression Models • Likelihood ratio test for examining overall distributions of ages at first MMR vaccination • Odds ratios (ORs) calculated for the association between autism and age at MMR vaccination dichotomized according to three age cut-offs (18 mo, 24 mo & 36 mo). • Total sample- unadjusted analyses • Birth certificate sample – ORs adjusted for birth certificate factors (birth weight, multiple gestation, maternal age and education) Results: Age at First MMR Vaccination by Case Status for Total Sample • Most case (70. 5 %) and control (67. 5%) children were vaccinated between 12 -17 months. • Distributions not significantly different (p=0. 22) Results: Age at First MMR Vaccination and Autism by Demographic Factors Case Subgroup All Cases Males Cases (N) 624 500 < 18 mo OR (95% CI) 1. 12 (0. 91 -1. 38) 1. 22 (0. 97 -1. 54) < 24 mo OR (95% CI) 1. 21 (0. 93 -1. 57) 1. 29 (0. 96 -1. 73) < 36 mo OR (95% CI) 1. 49 (1. 04 -2. 14) 1. 67 (1. 10 -2. 53) Females 3 -5 yrs 6 -10 yrs 124 214 410 0. 83 (0. 52 -1. 30) 1. 08 (0. 73 -1. 60) 1. 14 (0. 90 -1. 46) 0. 96 (0. 55 -1. 68) 1. 66 (0. 95 -2. 92) 1. 10 (0. 82 -1. 49) 1. 06 (0. 51 -2. 20) 2. 34 (0. 99 -5. 54) 1. 33 (0. 89 -1. 98 • In birth certificate subsample (N=311), most OR’s were lower and all CI’s included 1. 0. (data not shown) • More case (93. 4 %) than control children (90. 6) were vaccinated before 36 months. - Association strongest among 3 -5 year old children in both total and birth certificate samples. Results: Age at First MMR Vaccination and Autism, by Clinical Subgroups Case Subgroup < 18 mo OR (95% CI) No PEC or delay < 1 year (N=390) 1. 07 (0. 83 -1. 39) < 24 mo < 36 mo OR(95% CI) OR (95% CI) 1. 14 (0. 82 -1. 59) 1. 51 (0. 96 -2. 37) Regression or Plateau (N=80) 1. 37 (0. 78 -2. 41) 1. 30 (0. 64 -2. 66) 1. 45 (0. 54 -3. 93) With MR (N=376) 1. 06 (0. 82 -1. 38) 1. 09(0. 79 -1. 51) 1. 21(0. 79 -1. 84) Without MR (N=248) 1. 23(0. 87 -1. 73) 1. 46(0. 93 -2. 30) 2. 45(1. 20 -5. 00) • In birth certificate subsample (N=311), ORs were lower or similar to those in total sample and all CI’s included 1. 0 (data not shown). Summary • Similar proportion of case and control children vaccinated around recommended age for MMR vaccination (< 18 months) and before the age at which atypical development becomes apparent (24 months). • No significant associations found for either age cut-offs < 18 or < 24 months among all cases and in case subgroups • Vaccination < 36 months more common in case children than control children, , particularly in 3 -5 year old age group - Possibly reflecting immunization requirements of early intervention programs.
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