in quantity and of limited usefulness because of its focus on a preservative no longer used in the United States.

Seizures, Febrile Seizures, and Epilepsy

Fifty-eight papers of studies of the association among immunizations, immunization schedule, or vaccines and seizures, epilepsy, or febrile seizure were identified via an Ovid MEDLINE search. This list was then reduced to 14 papers. After an initial review, four of the papers were believed to focus on some aspect of the immunization schedule and were selected for a more in-depth review.

A study from Denmark by Sun and colleagues (2012) determined the risk of cumulative doses of combined DTaP-inactivated poliovirus vaccine (IPV)-Hib on the development of both febrile seizures and the later development of epilepsy as well as the risk of these adverse events after pneumococcal vaccine was added to the combined DTaP-IPV-Hib. This was a self-controlled case series study based on children with febrile seizures during follow-up of the cohort. In Denmark, DTaP-IPV was introduced in 1997, Hib was added in September 2002, and pneumococcal vaccine was added in October 2007. Data were collected from January 1, 2003, to December 31, 2008, and the immunization schedule that was evaluated included vaccine administration at 3, 5, and 12 months of age. The analysis did not include the 5-year booster immunization. Compared with a reference cohort of children who were not within 0 to 7 days of receiving an immunization, the increased risk of febrile seizure on the day of immunization only (but not between days 0 and 7 after immunization) was minimal after the first or second dose of combined DTaP-IPV-Hib vaccine but not after the third dose. The overall incidence of febrile seizures in these cohorts was small. The vaccinated group had a lower risk of developing epilepsy in the first 15 months of life than the reference cohort of children did, whereas the risk of epilepsy later in life was unchanged. The estimates did not change when pneumococcal vaccine was added to the vaccination program. It is not clear why the immunized children had a decreased risk of epilepsy. This may have been due to unmeasured confounding factors, as the investigators did not address whether children with a high risk of developing febrile seizures or epilepsy (such as children with preexisting neurological disorders) were less likely to have been vaccinated.

A VSD surveillance study by Klein et al. (2010) evaluated the risk of development of febrile seizures after children received the combined measles, mumps, rubella, and varicella (MMRV) vaccine, MMR plus the varicella vaccine, MMR alone, or the varicella vaccine alone. The investigators compared the incidence of evaluations for seizures in the emergency department or hospital and for fever in the clinic that occurred in patients at between 12

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