lation or susceptible subgroups of interest) who do not substantially differ from those vaccinated on any known, important confounders (e.g., age and exposure to other vaccinations or other agents or factors known to cause the adverse event). None of these preconditions is fully met for the adverse events reviewed in this report.

The committee also notes here that large epidemiologic studies that report no cases of the adverse event of interest in vaccinated study participants, if included in our analyses, raise particular concerns. If at least some cases of the adverse event occurred in a study’s unvaccinated comparison population, an upper limit of the 95% confidence interval (CI) for the study’s relative risk or absolute risk difference could be estimated, but one would be unable to rule out a possibly increased risk unless the vaccine was significantly protective against that particular adverse effect. Also, including such studies may have exacerbated problems with detection biases unless precautions were taken to ensure equal surveillance for the adverse event in the unvaccinated and vaccinated populations being compared.

Discussion of the adverse events where the committee concluded that there is evidence to support causation illustrates more fully the challenge of specifying rates, although for some estimates can be provided.

MMR vaccine: The committee concluded that the evidence favors acceptance of a causal relationship between measles, mumps, and rubella (MMR) vaccine and febrile seizures. Approximately 4 percent of children will experience a febrile seizure by 5 years of age (Marin et al., 2010). Fever may occur following MMR vaccination, and some children who have fever following MMR may have a febrile seizure. It is important to note that simple febrile seizures are benign and have no permanent sequelae. For example, children with simple febrile seizures have no greater chance of getting epilepsy or experiencing long-term brain damage than children who do not have febrile seizures.

Three of the studies the committee examined provided both a number of children vaccinated with MMR (the denominator) and the number of febrile seizures considered to be attributable to MMR (Farrington et al., 1995; Griffin et al., 1991; Vestergaard et al., 2004). Children who receive the MMR vaccine are at risk for febrile seizures 8–14 days after vaccination (Marin et al., 2010). About one additional febrile seizure occurs during the 30 days after vaccination among every 3,000–4,000 children who receive MMR vaccine, compared with children who are not vaccinated (Marin et al., 2010). Using the number of febrile seizures attributed to MMR vaccine, and dividing by the number of children in the cohort, each of the other studies provides a similar rate, between one in 1,000 and one in 4,000 doses.

Varicella vaccine: The varicella vaccine accounted for five of the affirmative causality conclusions. All were caused by infection of persons with



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