A Population-Based Study of Measles, Mumps, and Rubella Vaccination and AutismNovember 7, 2002
Authors:Kreesten Meldgaard Madsen, M.D., Anders Hviid, M.Sc.
Mogens Vestergaard, M.D., Diana Schendel, Ph.D.
Jan Wohlfahrt, M.Sc., Poul Thorsen, M.D.
Jørn Olsen, M.D., and Mads Melbye, M.D.
Background:It has been suggested that the measles, mumps, and rubella (MMR) vaccine causes autism.
1-4 The widespread use of the MMR vaccine has reportedly coincided with an increase in the incidence of autism in California,
5 and there are case reports of children in whom signs of both developmental regression and gastrointestinal symptoms developed shortly after MMR vaccination.
1 Measles virus has been found in the terminal ileum in children with developmental disorders and gastrointestinal symptoms but not in developmentally normal children with gastrointestinal symptoms.
6 The measles virus used in the MMR vaccine is a live attenuated virus that normally causes no symptoms or only very mild ones. However, wild-type measles can infect the central nervous system and even cause postinfectious encephalomyelitis, probably as a result of an immune-mediated response to myelin proteins.
7-9Studies designed to evaluate the suggested link between MMR vaccination and autism do not support an association, but the evidence is weak and based on case-series, cross-sectional, and ecologic studies. No studies have had sufficient statistical power to detect an association, and none had a population-based cohort design.
10-16 The World Health Organization and other organizations have requested further investigation of the hypothetical association between the MMR vaccine and autism.
2,17-20 We evaluated the hypothesis in a cohort study that included all children born in Denmark in 1991 through 1998.
Study:We designed a retrospective follow-up study of all children born in Denmark during the period from January 1, 1991, to December 31, 1998. The cohort was established on the basis of data obtained from the Danish Civil Registration System and five other national registries.
All live-born children and new residents in Denmark are assigned a unique personal identification number (a civil-registry number), which is stored in the Danish Civil Registration System together with information on vital status, emigration, disappearance, address, and family members (mother, father, and siblings).
21 The registry is updated once a week, and all changes in the stored information are reported to the registry according to established legal procedures. The civil-registry number is used as the link to information at the individual level in all other national registries. This system provides completely accurate linkage of information between registries at the individual level.
We determined MMR-vaccination status on the basis of vaccination data reported to the National Board of Health by general practitioners, who administer all MMR vaccinations in Denmark. The general practitioners are reimbursed by the state on the basis of these reports. We retrieved information on vaccinations from 1991 through 1999. The MMR vaccine was introduced in Denmark in 1987, and the single-antigen measles vaccine has not been used. The MMR vaccine used in Denmark during the study period was identical to that used in the United States and contained the following vaccine strains: Moraten (measles), Jeryl Lynn (mumps), and Wistar RA 27/3 (rubella).
The national vaccination program recommends that children be vaccinated at 15 months of age and again at 12 years. No change was made in the program during the study period. We obtained information on MMR vaccination at 15 months of age, since only this exposure is relevant to the end point under study. Since the vaccination data are transferred to the National Board of Health once a week, we chose Wednesday as the day of vaccination. When the vaccination information was recorded with the child's own civil-registry number, the information was directly linked with other registries. Before 1996, in most cases the vaccination information and the age of the child were recorded with the civil-registry number of the accompanying adult; we used information from the Danish Civil Registration System to identify the link from the accompanying adult to the child. Thus, 98.5 percent of the children were identified with the use of the child's civil-registry number or the civil-registry number of the mother or father and the age of the child at vaccination. The remaining 1.5 percent of children were identified on the basis of additional information from the Danish Civil Registration System on other relatives and information on the address at the time of vaccination.
Information about diagnoses of autism was obtained from the Danish Psychiatric Central Register, which contains information on all diagnoses received by patients in psychiatric hospitals, psychiatric departments, and outpatient clinics in Denmark.
22 In our cohort, 93.1 percent of the children were treated only as outpatients, and 6.9 percent were at some point treated as inpatients in a psychiatric department. All diagnoses were based on the International Classification of Diseases, 10th Revision (ICD-10), which is similar to the 4th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) with regard to autism.
23-26 In Denmark, children are referred to specialists in child psychiatry by general practitioners, schools, and psychologists if autism is suspected. Only specialists in child psychiatry diagnose autism and assign a diagnostic code, and all diagnoses are recorded in the Danish Psychiatric Central Register. We identified all children given a diagnosis of autistic disorder (ICD-10 code F84.0 and DSM-IV code 299.00) or another autistic-spectrum disorder (ICD-10 codes F84.1 through F84.9 and DSM-IV codes 299.10 and 299.80). When a child was given diagnoses of both autistic disorder and one or more other autistic-spectrum disorders, we classified the diagnosis as autistic disorder. Autism is associated with the inherited genetic conditions tuberous sclerosis, Angelman's syndrome, and the fragile X syndrome and with congenital rubella. To maximize the homogeneity of the study population, data for children with these conditions were censored when the diagnosis was made. We obtained information on these conditions from the National Hospital Registry.
We performed an extensive record review for 40 children with autistic disorder (13 percent of all the children with autistic disorder) to validate the diagnosis of autism. A consultant in child psychiatry with expertise in autism examined the medical records. Thirty-seven of the children (92 percent) met the operational criteria for autistic disorder according to a systematic coding scheme developed by the Centers for Disease Control and Prevention for surveillance of autism and used in a prevalence study in Brick Township, New Jersey.
27 The three children who did not meet the criteria for autistic disorder were all classified as having other autistic-spectrum disorders. For two of the children, the diagnosis of autistic disorder was questionable because of profound intellectual impairment. For the third child, we did not have information about the onset of symptoms before the age of three years, which is a prerequisite for the diagnosis of autistic disorder.
We obtained information on birth weight and gestational age from the Danish Medical Birth Registry and the National Hospital Registry.
28,29 Information on potential confounders, including socioeconomic status (as indicated by the employment status of the head of the household) and mother's education was obtained from Statistics Denmark from the time when the child was 15 months of age.
Statistical brown townysis:Follow-up for the diagnosis of autistic disorder or another autistic-spectrum disorder began for all children on the day they reached one year of age and continued until the diagnosis of autism or an associated condition (the fragile X syndrome, Angelman's syndrome, tuberous sclerosis, or congenital rubella), emigration, death, or the end of follow-up, on December 31, 1999, whichever occurred first. The incidence-rate ratios for autistic disorder and other autistic-spectrum disorders in the group of vaccinated children, as compared with the unvaccinated group, were examined in a log-linear Poisson regression model with the use of PROC GENMOD (SAS, version 6.12).
30 We treated vaccination as a time-dependent covariate. The children were assigned to the nonvaccinated group until they received the MMR vaccine. From that date, they were followed in the vaccinated group. In additional brown townyses, the MMR-vaccinated children were grouped according to their age at the time of vaccination, the interval since vaccination, and the calendar period when vaccination was performed.
In reporting the results, we refer to the incidence-rate ratios as relative risks. For all risk estimates, we considered possible confounding by age (1, 2, 3, 4, 5, 6, 7, or 8 to 9 years), love, calendar period (1992 to 1993, 1994, 1995, 1996, 1997, 1998, or 1999; for other autistic-spectrum disorders, the years 1992, 1993, and 1994 were grouped together), socioeconomic status (six groups), mother's education (five groups), gestational age (≤36, 37 to 41, or ≥42 weeks), and birth weight (≤2499, 2500 to 2999, 3000 to 3499, 3500 to 3999, or ≥4000 g).
Results:A total of 537,303 children were included in the cohort and followed for a total of 2,129,864 person-years. Follow-up of 5811 children was stopped before December 31, 1999, because of a diagnosis of autistic disorder (in 316 children), other autistic-spectrum disorders (in 422), tuberous sclerosis (in 35), congenital rubella (in 2), or the fragile X or Angelman's syndrome (in 8), and because of death or emigration in the cases of 5028 children, whose data were censored. For children who received MMR vaccine, there were 1,647,504 person-years of follow-up, and for children who did not receive the vaccine, there were 482,360 person-years of follow-up.
Table 1Characteristics of the 537,303 Children in the Danish Cohort.
shows the distribution of the MMR cohort according to vaccination status, love, birth weight, gestational age, socioeconomic status, mother's education, and age when autism was diagnosed. The mean age at diagnosis was four years and three months for autistic disorder and five years and three months for other autistic-spectrum disorders. The mean age at the time of the MMR vaccination was 17 months, and 98.5 percent of the vaccinated children were vaccinated before 3 years of age. The proportion of children who were vaccinated was the same among boys and girls (82.0 percent).
Table 2Adjusted Relative Risk of Autistic Disorder and of Other Autistic-Spectrum Disorders in Vaccinated and Unvaccinated Children.
shows the association between variables related to MMR vaccination and the risk of autism. We calculated the relative risk with adjustment for age, calendar period, love, birth weight, gestational age, mother's education, and socioeconomic status. Overall, there was no increase in the risk of autistic disorder or other autistic-spectrum disorders among vaccinated children as compared with unvaccinated children (adjusted relative risk of autistic disorder, 0.92; 95 percent confidence interval, 0.68 to 1.24; adjusted relative risk of other autistic-spectrum disorders, 0.83; 95 percent confidence interval, 0.65 to 1.07). Furthermore, we found no association between the development of autistic disorder and the age at vaccination (P=0.23), the interval since vaccination (P=0.42), or the calendar period at the time of vaccination (P=0.06).
Adjustment for potential confounders with the exception of age resulted in similar estimates of risk. Changing the start of follow-up for autistic disorder and other autistic-spectrum disorders to the date of birth or 16 months of age had little effect on the estimates (data not shown). Furthermore, including children with the fragile X syndrome, tuberous sclerosis, congenital rubella, or Angelman's syndrome in the brown townysis did not change the estimates (data not shown).
Citation:Citationmarkdown can be found here:
http://www.nejm.org/doi/full/10.1056/NEJMoa021134#t=citedbytl;dr:Vaccine your damn kids.
