1. Age at First Measles-Mumps-Rubella Vaccination in Children with Autism and School-Matched Control Subjects William W. Thompson, PhD Presented at the Institute of Medicine Meeting February 9th, 2004

2. CDC Collaborators National Immunization Program
Frank DeStefano, MD, MPH
National Center for Birth Defects and Developmental Disabilities
Tanya Karapurkar, MPH
Marshalyn Yeargin-Allsopp, MD
Coleen Boyle, PhD

3. Background
Observations which may suggest a potential association between MMR vaccination and autism
Prevalence of autism has increased at same time that coverage for MMR vaccinations has increased among young children
Timing of initial recognition of autism symptoms occurs about the same time as recommended age for first MMR vaccination
Wakefield et al (1998)

4. Background Institute of Medicine Review (2001)
IOM rejected causal relationship at the population level between MMR vaccination and Autism Spectrum Disorder (ASD)
Consistent body of evidence showing no association
Fragmentary biologic models linking MMR with ASD
No animal models linking MMR vaccine and ASD
Original case series was uninformative regarding causality
IOM strongly encouraged additional studies to examine possible associations between MMR vaccination and ASD subgroups

5. Study Objectives Primary Objective Secondary Objective
Evaluate association between ASD and age of receipt of MMR vaccine
Secondary Objective
Compare MMR vaccination histories among ASD subgroups and matched controls
Objective was defined after data collection was completed for study
Developed in response to IOM (2001) report

6. Methods - Study Population
Metropolitan Atlanta Developmental Disabilities Surveillance Program (MADDSP)
Population based surveillance program started in 1991
Population area included approximately 300,000 children aged 3-10 years in the five county Metropolitan Atlanta area

7. Methods - Study Population
MADDSP Cont.
Multiple source ascertainment of several developmental disabilities
Mental retardation
Cerebral palsy
Hearing loss
Visual impairment
ASD was added to list of conditions in 1996

8. Methods Study Design Case-Control Study Design
Cases: 624 children with ASD
Controls: 1,824 children without known DDs
The exceptions made for the selection of control children are regarding cases that were : 1) in psychoeducational program 2) case-children who were older than there grade-level classmates (we don’t get into this in the paper-it is too confusing)

9. Methods Selection of Cases
Cases: 624 children with ASD
Identified children through MADDSP who had evaluations available through 1996
Born between 1986 and 1993
Abstraction of records by trained abstractors
DSM-IV criteria used to classify children
ASD classification determined by ASD experts
Inclusion in study sample required one of following:
Valid MMR vaccination date from school immunization form
DTP vaccination by age 2 from school immunization form
Immunization exemption form
The exceptions made for the selection of control children are regarding cases that were : 1) in psychoeducational program 2) case-children who were older than there grade-level classmates (we don’t get into this in the paper-it is too confusing)

10. Methods Defining ASD Subgroups
Pre-existing conditions < 1 Year of Age
Any known birth defect
Other co-occurring developmental disabilities
Major perinatal or postnatal insult that could have contributed to developmental delay
CNS Infections
Traumatic Brain Injuries

11. Methods Defining ASD Subgroups
Developmental Delay < 1 Year of Age
Lack of speech at appropriate ages
Cooing
Babbling
Socially unresponsive in 1st year of life
Cuddling
Appropriate eye contact
Responding to parents voices

12. Methods Defining ASD Subgroups
Regression and/or Plateau
Children with an indication of loss of age appropriate developmental skills (regression)
Children with appropriate skills that failed to progress (plateau)

13. Methods Summary of ASD Subgroups
Clinical Characteristics N
Percent
Mental retardation (MADDSP case def)
378
61%
Pre-existing condition
235
38%
Regression/Plateau 80
13%
ASD subgroups were not mutually exclusive
MR definition was IQ < 70

14. Methods Selection of Matched Controls
Controls: 1,824 children without known DD
Controls selected at 3:1 ratio
Controls selected from regular education programs
Matched based on age, sex, and school of attendance at the time of abstraction *
Inclusion in study sample required one of following:
Valid MMR vaccination date from school immunization form
DTP vaccination by age 2 from school immunization form
Immunization exemption form
The exceptions made for the selection of control children are regarding cases that were : 1) in psychoeducational program 2) case-children who were older than there grade-level classmates (we don’t get into this in the paper-it is too confusing)
* Controls for case children in special education schools were selected from the
public school the case child would attend as a regular education student

15. Methods GA State Birth Certificate Sample
Matched cases and controls to GA State Birth Certificates to assess effects of potential confounders
Maternal Age
Maternal Education
Child Birth Weight
Multiplicity (Singleton versus other)
Parity (1st born versus other)
Results in similar follow-up time for both cases and controls

16. Methods Demographic Subgroups
Demographic Matching Factors
Age
Gender
Birth Certificate Data
Race
Birth Weight
Maternal Age
Maternal Education

17. Methods Specific Hypotheses
Assessed whether variation in age at first MMR vaccination was different for cases and controls
Also assessed 3 specific age cut-offs:
< 18 months - evaluation of whether vaccination by the recommended age
< 24 months – evaluation of whether vaccination by the time of first parental concern regarding atypical development
< 36 months – evaluation of whether vaccination prior to timeframe required by DSM-IV for symptom onset for autism

18. Methods Analytic Approach
We used conditional logistic regression analysis stratified by matched case-control sets
Analyses with Total Sample
Unadjusted analyses
Subjects did not require a GA State birth certificate
Analyses with GA State Birth Certificate Sample
Unadjusted analyses (not reported in manuscript)
Adjusted analyses for confounding with data available from the birth certificate

19. Descriptive Data

20. Descriptive Data Age Distribution of Cases and Controls

21. Descriptive Data Sex Distribution of Cases and Controls

22. Descriptive Data Maternal Age from Birth Certificate

23. Descriptive Data Maternal Education from Birth Certificate

24. Descriptive Data Birth Weight from Birth Certificate

25. Descriptive Data Parity

26. Results

27. Age at 1st MMR Vaccination For Total Sample

28. Demographic Case Subgroup Analyses For Total Sample
< 18
Months
< 24
< 36
All Cases
1.12 ( )
1.21 ( )
1.49 ( )
Boys
1.22 ( )
1.29 ( )
1.67 ( )
Girls
0.83 ( )
0.96 ( )
1.06 ( )
Aged 3-5 Yrs
1.08 ( )
1.66 ( )
2.34 ( )
Aged 6-10 Yrs
1.14 ( )
1.10 ( )
1.33 ( )

29. Demographic Case Subgroup Analyses For GA Birth Certificate Sample
< 18
Months
< 24
< 36
All Cases
0.93 ( )
0.99 ( )
1.23 ( )
Boys
0.94 ( )
1.01 ( )
1.64 ( )
Girls
0.79 ( )
0.84 ( )
0.24 ( )
Aged 3-5 Yrs
0.77 ( )
1.67 ( )
2.63 ( )
Aged 6-10 Yrs
0.98 ( )
0.87 ( )
1.09 ( )

30. Clinical Case Subgroup Analyses For Total Sample
< 18
Months
< 24
< 36
No pre-exist
1.07 ( )
1.44 ( )
1.51 ( )
Regression
1.37 ( )
1.30 ( )
1.45 ( )
With MR
1.06 ( )
1.09 ( )
1.21 ( )
Without MR
1.23 ( )
1.46 ( )
2.45 ( )

31. Clinical Case Subgroup Analyses For Birth Certificate Sample
< 18
Months
< 24
< 36
No pre-exist
1.05 ( )
1.02 ( )
1.82 ( )
Regression
0.83 ( )
0.41 ( )
0.69 ( )
With MR
1.13 ( )
0.96 ( )
0.82 ( )
Without MR
0.68 ( )
1.02 ( )
3.55 ( )

32. Other Demographic Subgroup Analyses For Birth Certificate Sample
Category
< 18
Mos
< 24
< 36
Race
White/Other
Black
0.87
0.83
0.77
0.98
0.89
1.68
Maternal Age
< 35 Yrs
35+ Yrs
0.90
0.53
0.91
0.59
1.23
2.64
Maternal Ed
< 16 Yrs
16+ Yrs
0.94
0.60
0.61
1.18
2.76
Birth Weight
< 2500 g
> 2500 g
0.50
0.48
0.93
1.41
1.26

33. Summary of Study Findings
The overall distribution of ages at MMR vaccination among children with autism was similar to that of controls
No significant associations were found between vaccination at < 18 or < 24 months and autism or any autism subgroups.
No increased risk of autism associated with vaccination by recommended age (18 months)
No association with vaccination by 24 months of age when developmental change is noted in most children

34. Summary of Study Findings
Cases more likely than controls to be vaccinated < 36 months of age.
Born Between 1991 and 1993
Boys
Without MR
Children of Older Mothers
Children of Better Educated Mothers

35. Summary of Study Findings
Cases more likely than controls to be vaccinated < 36 months of age.
Case-children more likely to be in contact with health care system, thus, more likely to have “early” vaccinations
Case-children more likely be vaccinated as requirement for entry into early intervention special education programs
Disabilities Education Act (1991)

36. Study Strengths Large population-based sample of children
Clinical information reviewed by autism experts
Linkage with GA State birth certificates
Most children received first MMR vaccination prior to publicity regarding possible association between MMR and autism
Evaluation of ASD subgroups

37. Study Limitations Very small unexposed group
Most children receive the MMR vaccine by 36 months
MMR immunization records not available on all cases
Other immunization vaccinations were not recorded reliably
Incomplete information available for determining age of onset for ASD
Information on potential confounders only available for GA State birth certificate sample
Study was not initially designed to assess ASD subgroups

38. Study Conclusions
Similar distribution of ages at MMR vaccination among cases and controls
Similar proportions of cases and controls vaccinated according to ACIP schedule (i.e., < 18 months)
Similar proportions of cases and controls vaccinated by typical age of onset for autism (i.e. < 24 months)
“Late” vaccination less common among cases compared to matched controls (i.e. < 36 months)

39. The End

40. Methods Total Sample Selection
Immunization
Record
Abstraction
Birth
Cohorts
Case Abstraction
1986
1993
1996
1999
2001

41. Methods GA State Birth Certificate Selection
Immunization
Record
Abstraction
Birth
Cohort
Born in GA
Case Abstraction
1986
1993
1996
1999
2001

42. Age at 1st MMR Vaccination by Availability of GA Birth Certificate
Case Status
GA State
Birth Certificates
No GA State
Cases
19.0 months
Controls
19.1 months
22.2 months