Measles-Mumps-Rubella Vaccination and Asthma-like Disease in Early Childhood

Anders Hviid; Mads Melbye

Disclosures

Am J Epidemiol. 2008;168(11):1277-1283. 

In This Article

Materials and Methods

Since April 1968, vital records on all people living in Denmark have been kept and updated daily in the Danish Civil Registration System.[10] Each individual is indexed by a unique personal identification number that is also used in other national registries. From the Civil Registration System, we obtained a cohort of all children born in Denmark from January 1, 1991, through December 31, 2003. Using the unique personal identification number, we were able to individually link information on MMR vaccination, hospitalizations with asthma diagnoses, use of anti-asthma medication (only available for children born since 1995), and potential confounders and effect modifiers to the children in the cohort.

MMR Vaccination

MMR vaccination was introduced in the Danish childhood vaccination program in 1987. The MMR vaccine used in Denmark contains live attenuated Moraten measles virus, Jeryl Lynn mumps virus, and Wistar RA 27/3 rubella virus and is administered at 15 months and 12 years of age. Dates of vaccination were obtained from the National Board of Health. In Denmark, only general practitioners administer routine childhood vaccines, and the practitioners are reimbursed when reporting these vaccinations to the National Board of Health. The National Board of Health has kept a register of these reports since 1990.

Hospitalization with Asthma Diagnoses

Information on inpatient hospitalization with asthma diagnoses during the period from January 1, 1992, to December 31, 2004, was obtained from the Danish National Hospital Register.[11] From 1990 to 1993, the International Classification of Diseases, Eighth Revision (ICD-8), was used, and from 1994 to 2001, the International Classification of Diseases, Tenth Revision (ICD-10), was used. We included the following categories of asthma diagnoses in our study: code 493.xx (ICD-8) and codes J45.x and J46.x (ICD-10). Severe asthma (status asthmaticus; ICD-8 code 493.01 and ICD-10 code J46.9) was further considered as a separate outcome.[12]

Anti-asthma Medication

Information on use of anti-asthma medication during the period from January 1, 1996, to December 31, 2004, was obtained from the Danish Prescription Drug Database. This registry includes detailed individual-level information on all prescriptions filled at Danish pharmacies, as well as aggregated data on hospital medication use; these are the only 2 places where prescription medication can be legally obtained in Denmark. To ensure that people are subsidized according to the total amount of money spent on prescribed medication, as dictated by Danish law, the Danish Prescription Drug Database has been built as an interactive system, where the information keyed in at the local pharmacy is immediately forwarded to a central registry at the Danish Medicines Agency. Here the patient's records are compiled for the previous year, and information is instantly returned to the pharmacy with the calculated reduction in price which should be given to the person. Therefore, the registry is considered to be of very high quality, with coverage that is virtually complete for all medication prescribed in Denmark. Information on individual-level prescriptions includes the date on which the prescription was filled and the anatomic-therapeutic-chemical (ATC) code. For analytical purposes, we considered the date of filling the prescription to be the date of use. The classes of anti-asthma medication used in this study and their ATC codes were: glucocorticoid inhalants (ATC code R03BA), short-acting β2-agonist inhalants (ATC codes R03AC02, R03AC03, and R03AC04), long-acting β2-agonist inhalants (ACT codes R03AC12 and R03AC13), systemic β2-agonists (ACT code R03CC), and other types of anti-asthma medication (all other ATC codes under R03).

Statistical Analysis

Children in the cohort contributed person-time to follow-up from 1 year of age until death, disappearance/emigration, age 5 years, or December 31, 2004, whichever occurred first. Recurrence of outcome events was allowed—that is, neither asthma hospitalization nor use of anti-asthma medication terminated follow-up. To reduce unnecessary computational complexity, we counted only the first 20 events for each individual. The resulting incidence rates for asthma hospitalizations and use of anti-asthma medication were analyzed with Poisson regression (log-linear regression on the incidences using the logarithm to the follow-up time as offset), producing estimates of incidence rate ratios (hereafter called rate ratios) according to MMR vaccination status.[13] MMR vaccination status was considered a time-varying variable—that is, individual children could contribute person-time as both unvaccinated and vaccinated individuals. We estimated the possible effect of MMR vaccination on asthma through 1) rate ratios comparing vaccinated children with unvaccinated children, 2) rate ratios comparing vaccinated children with unvaccinated children in subgroups defined by factors such as gender or birth weight, and 3) rate ratios comparing vaccinated children with unvaccinated children according to age at vaccination (<15, 15-18, 19-22, 23-26, or ≥27 months).

Possible Confounding and Effect-modifying Factors

We adjusted MMR rate ratios for age and calendar period. Further information on possible confounding factors that were also adjusted for and possible MMR vaccination effect modifiers—child's sex, child's place of birth, child's birth weight, mother's country of birth, mother's age at birth of child, birth order, and infant vaccine compliance—was obtained from the Civil Registration System, the Danish Medical Birth Registry,[14] and the National Hospital Register. For asthma hospitalization, we further included adjustment for infant hospitalization propensity. For study of anti-asthma medication, we further included information on both mother's and father's income in the year preceding the year of birth.

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