26. Safety: demyelinating diseases, multiple sclerosis, acute disseminated encephalomyelitis.

Study ID and design	Population	Outcome definition	Exposure MMR/MMRV vaccine	Findings	Crude data	Estimate (95% CI)
cb‐Ahlgren 2009 Cohort study	Residents in the great Gothenburg area (Sweden) born between 1959 and 1990. The study area was the greater Gothenburg area on the Swedish west coast, with 731,592 residents on 31 December 2000.	Multiple sclerosis (probable or definite) and clinically isolated syndromes. Incidence of multiple sclerosis (4 Poser's criteria) and clinically isolated syndrome with onset between 10 and 39 years of age was assessed in birth cohorts immunised within 4 vaccination programmes. The Gothenburg multiple sclerosis register was established from the 1950s. All records are reviewed with the following MS‐related diagnoses, according to the International Classification of Diseases (ICD) 10, 9, and 8: G359; 340; 340.99 multiple sclerosis; G368; G378; G379; 341W; 341.09 demyelinating disorders in the central nervous system; G360; 341A; 341.01 neuromyelitis optica; G369; 341X acute disseminated encephalomyelitis; G373 acute transverse myelitis: H46; 377D; 367.02 optic neuritis; H48,1; 367.03 retrobulbar neuritis.	MMR vaccine: not described. Different vaccination programmes carried out from 1971 with different vaccines (single‐component measle, mumps and rubella vaccine so as with MMR vaccine) having as target population children of different ages. 5 population birth cohorts were selected from the total incidence material: (0) born 1959 to 1961: the pre‐vaccine era; (1) born 1962 to 1966: monovalent rubella vaccine; (2) born 1970 to 1973: only received later dose of the MMR vaccine; (3) born 1974 to 1978: monovalent measles; (4) July 1981 to June 1984: combined MMR vaccine.	Conclusion: there was no significant change in the age‐ and gender‐specific incidence of MS in any of the selected cohorts compared with the incidence in the preceding selected birth cohorts. There was thus no significant change in MS incidence related to the implementation of the rubella vaccination programme in the 12‐year‐old female cohort born in 1962 to 1966 compared with the unvaccinated cohort born in 1959 to 1961. The incidence did not significantly change with all preceding selected cohorts as baseline, neither in the MMR‐vaccinated 12‐year‐old cohort born in 1970 to 1973, nor in the cohort born in 1974 to 1978, half of which were measles vaccinated in the preschool age and the majority MMR vaccinated at 12, nor in the cohort born in July 1981 to June 1984, which were MMR vaccinated at both 18 months and 12 years of age. Restricting the analyses to probable and definite MS cases did not change the results.	Incidence per 100,000 person‐years (‐) (male female) versus (male female) (*) (1) (14.98; 6.97) versus (17.61; 4.28) (2) (15.28; 6.61) versus (13.17; 5.27) (3) (12.29; 3.85) versus (9.48; 4.62) (4) (4.96; 1.18) versus (3.78; 2.55) (*) including both the unvaccinated cohort 1959 to 1961 and the preceding vaccinated birth cohorts selected for this study, in the corresponding age groups	No data available for meta‐analysis
bb‐Ahlgren 2009 Case‐control study	Cases (n = 206): birth years 1959 to 1986, to be resident in the greater Gothenburg area (Sweden), MS onset from age of 10 years onwards, did attend the 6th school grade within study area, availability of CHSH records. Controls (n = 888): matched to cases for year of birth by random selection from the population register. Controls should have attended the 6th school grade within study area, and have available CHSH record.	Multiple sclerosis (probable or definite) and clinically isolated syndromes	MMR vaccine: not described MMR vaccination (vaccination with single‐component vaccines has also been considered). The second analysis was therefore restricted to the subgroup of the MMR vaccinations. The first analysis was restricted to the subgroup "MMR vaccination". 4 disjointed vaccination categories were defined: (0) no MMR vaccination; (1) early MMR vaccination only; (3) late MMR vaccination only; (4) both an early and a late MMR vaccination. Comparisons were made within the group of MMR vaccinations.	Conclusions: no significant association for vaccinated versus unvaccinated.	Cases = 206; controls = 888	OR (95% CI) 1.13 (0.62 to 2.05)
bb‐Chen 2018 Case‐control study	Case (n = 272): acute disseminated encephalomyelitis. Controls (n = 1096): for each ADEM case, 4 control individuals randomly selected from the same hospital with no history of ADEM were matched to the case according to year of birth (within 1 year), gender, and zip code (a surrogate measure for socioeconomic status) during the same period. The control participants were assigned the same index date as their matched case (symptom onset date). Controls were patients referred for headache (except trigeminal neuralgia), migraine, vascular, or other diseases which were thought not to modify the probability of vaccination. Patients with chronic severe neurological diseases or autoimmune diseases were excluded.	Acute disseminated encephalomyelitis: immune‐mediated central nervous system disorder, characterised by an acute encephalopathy with polyfocal neurological deficits. From the Hospital Information Systems first mention of International Classification of Diseases, Tenth Revision (ICD‐10), diagnostic codes (G04.001, G04.002, G04.051, G04.903, and G04.912) for ADEM from 1 January 2011 to 31 December 2015, for individuals of any age. Diagnoses were confirmed by neurologists from clinical data, such as clinical manifestations, computed tomography, electroencephalograph, cerebrospinal fluid, and magnetic resonance imaging examinations.	MMR vaccine: not described	Conclusions: findings from the present study do not demonstrate an association of vaccines with an increased risk of ADEM and its recurrence among either paediatric (< 18 years) or adult (≥ 18 years) individuals within the 180 days after vaccinations.	11/272 versus 36/1096	OR (95% CI) adjusted estimate 1.03 (0.68 to 3.75)

ADEM: acute disseminated encephalomyelitis
CI: confidence interval
CHSH: child health and school health records
CIS: clinically isolated syndromes
HMO: health maintenance organisation
incidence: cases/PT
MMR: measles, mumps, rubella vaccine
MMRV: measles, mumps, rubella, and varicella vaccine
MS: multiple sclerosis
OR: odds ratio
PT: person‐time
rr: rate ratio (relative incidence, incidence rate ratio)
RR: risk ratio (relative risk)
VSD: Vaccine Safety Datalink