MMR-varicella vaccine is about twice as likely to cause febrile seizures in toddlers than separate, same-day MMR and varicella shots, but it’s otherwise just as safe, according to a review of adverse events in children 12-23 months old vaccinated between 2000 and 2012.

The investigators – all from institutions participating in the Centers for Disease Control and Prevention’s Vaccine Safety Datalink project – compared outcomes after 123,200 doses of the MMR-varicella (MMRV) combination vaccine and 584,987 doses of MMR and varicella (MMR+V) vaccines given on the same day (Pediatrics 2015 [doi:10.1542/peds.2014-1822 ]).There were no statistically significant difference in the main outcomes: anaphylaxis, immune thrombocytopenia purpura (ITP), ataxia, arthritis, meningitis/encephalitis, acute disseminated encephalomyelitis, and Kawasaki disease. “This study provides reassurance that most of these outcomes are extremely rare and unlikely after either vaccine,” said Dr. Nicola P. Klein of the Kaiser Permanente Vaccine Study Center in Oakland, Calif., and her associates.

For instance, they found 0.86 cases of meningitis/encephalitis per 100,000 doses of MMR+V, and 1.86 per 100,000 doses of MMRV within 3 weeks of vaccination. Similarly, there were 0.52 cases per 100,000 doses of arthritis/arthralgia for MMR+V, and 0.84 cases for MMRV. There were 2.93 Kawasaki cases per 100,000 doses of MMR+V, but no cases in the MMRV group. Such small differences “could be ruled out with 95% confidence,” the investigators said.

Two children had cases of anaphylaxis after MMRV shots, but neither “was confirmed as acute anaphylaxis after chart review; both diagnoses were related to a history of allergic reactions.” Even so, “continued monitoring for anaphylaxis after these vaccines is warranted,” they said. There were no cases of acute disseminated encephalomyelitis in either group.

With both vaccines, however, there were around 800 cases of fever per 100,000 doses within 7-10 days of the shots; there were also 52.37 febrile seizures per 100,000 doses of MMR+V, and 101.01 per 100,000 doses of MMRV (relative risk, 1.99 MMRV, compared with MMR+V).

The fever and seizure findings aren’t new; “measles-containing vaccines are” known to be associated with seizure, fever, and ITP, the investigators noted, and MMRV’s higher seizure risk has been reported before.

As expected, both immunization strategies increased the risk of ITP, which peaked 2-4 weeks after vaccination, but the absolute number of cases was small, about 5-10 per 100,000 doses. “To our knowledge, [this is] the first report that MMRV is associated with a similar increased risk of ITP during the same postvaccination risk intervals as MMR,” the investigators said.

MMRV and MMR+V both were associated with a small and surprising decrease in ataxia, but “this observation is more likely due to chance, outcome misclassification, or other unmeasured confounding,” they said.

Dr. Klein, Dr. Roger Baxter, and Allison Naleway, Ph.D., disclosed research funding from Merck, which manufactures the vaccines used in the study, and GlaxoSmithKline, among other industry ties. Dr. Edward A. Belongia reported research support from Medimmune. The remaining authors reported no relevant financial disclosures. The work was funded by the CDC.