You are leaving Medscape Education
Cancel Continue
Log in to save activities Your saved activities will show here so that you can easily access them whenever you're ready. Log in here CME & Education Log in to keep track of your credits.


MMRV Doubles Risk for Febrile Seizures 7 to 10 Days After Vaccination

  • Authors: News Author: Pauline Anderson
    CME Author: Charles P. Vega, MD
  • CME Released: 6/30/2010
  • Valid for credit through: 6/30/2011, 11:59 PM EST
Start Activity

Target Audience and Goal Statement

This article is intended for primary care clinicians and other specialists who care for young children.

The goal of this activity is to provide medical news to primary care clinicians and other healthcare professionals in order to enhance patient care.

Upon completion of this activity, participants will be able to:

  1. Identify adverse events previously associated with the measles-mumps-rubella-varicella vaccine.
  2. Compare the rate of seizures after administration of the measles-mumps-rubella-varicella vaccine and measles-mumps-rubella plus varicella vaccines.


As an organization accredited by the ACCME, Medscape, LLC requires everyone who is in a position to control the content of an education activity to disclose all relevant financial relationships with any commercial interest. The ACCME defines "relevant financial relationships" as financial relationships in any amount, occurring within the past 12 months, including financial relationships of a spouse or life partner, that could create a conflict of interest.

Medscape, LLC encourages Authors to identify investigational products or off-label uses of products regulated by the US Food and Drug Administration, at first mention and where appropriate in the content.


  • Pauline Anderson

    Pauline Anderson is a freelance writer for Medscape.


    Disclosure: Pauline Anderson has disclosed no relevant financial relationships.


  • Brande Nicole Martin

    CME Clinical Editor, Medscape, LLC


    Disclosure: Brande Nicole Martin has disclosed no relevant financial relationships.

CME Author(s)

  • Charles P. Vega, MD

    Associate Clinical Professor, Residency Program Director, Prime-LC, University of California-Irvine, Orange, California; Department of Family Medicine, University of California-Irvine, Orange, California


    Disclosure: Charles P. Vega, MD, has disclosed no relevant financial relationships.

CME Reviewer(s)

  • Sarah Fleischman

    CME Program Manager, Medscape, LLC


    Disclosure: Sarah Fleischman has disclosed no relevant financial relationships.

Accreditation Statements

    For Physicians

  • Medscape, LLC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

    Medscape, LLC designates this educational activity for a maximum of 0.25 AMA PRA Category 1 Credit(s)™ . Physicians should only claim credit commensurate with the extent of their participation in the activity. Medscape News CME has been reviewed and is acceptable for up to 300 Prescribed credits by the American Academy of Family Physicians. AAFP accreditation begins September 1, 2009. Term of approval is for 1 year from this date. Each issue is approved for .25 Prescribed credits. Credit may be claimed for 1 year from the date of this issue.

    Note: Total credit is subject to change based on topic selection and article length.

    Medscape, LLC staff have disclosed that they have no relevant financial relationships.

    AAFP Accreditation Questions

    Contact This Provider

For questions regarding the content of this activity, contact the accredited provider for this CME/CE activity noted above. For technical assistance, contact [email protected]

Instructions for Participation and Credit

There are no fees for participating in or receiving credit for this online educational activity. For information on applicability and acceptance of continuing education credit for this activity, please consult your professional licensing board.

This activity is designed to be completed within the time designated on the title page; physicians should claim only those credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the activity online during the valid credit period that is noted on the title page.

Follow these steps to earn CME/CE credit*:

  1. Read the target audience, learning objectives, and author disclosures.
  2. Study the educational content online or printed out.
  3. Online, choose the best answer to each test question. To receive a certificate, you must receive a passing score as designated at the top of the test. MedscapeCME encourages you to complete the Activity Evaluation to provide feedback for future programming.

You may now view or print the certificate from your CME/CE Tracker. You may print the certificate but you cannot alter it. Credits will be tallied in your CME/CE Tracker and archived for 6 years; at any point within this time period you can print out the tally as well as the certificates by accessing "Edit Your Profile" at the top of your Medscape homepage.

*The credit that you receive is based on your user profile.


MMRV Doubles Risk for Febrile Seizures 7 to 10 Days After Vaccination

Authors: News Author: Pauline Anderson CME Author: Charles P. Vega, MDFaculty and Disclosures

CME Released: 6/30/2010

Valid for credit through: 6/30/2011, 11:59 PM EST


June 30, 2010 — Infants aged 12 to 23 months have about double the risk of developing a febrile seizure for 7 to 10 days after being vaccinated with the measles-mumps-rubella-varicella (MMRV) combination vaccine compared with those receiving separate MMR and varicella vaccines, according to a new study.

Despite this increase, physicians and parents should understand that the overall risk for febrile seizures from either the MMR or MMRV vaccine is low, stressed lead study author Nicola P. Klein, MD, PhD, codirector of the Kaiser Permanente Vaccine Study Center in Oakland, California.

"The risk is less than 1 per 1000 doses, but the risk is twice as much for febrile seizures for MMRV when you compare it with MMR and varicella," Dr. Klein said. "The MMRV will cause 1 additional febrile seizure for every 2300 doses of MMRV given instead of the separate vaccine.”

The study appears in the July 2010 issue of Pediatrics and was published online June 28.

Double the Data

For the study, researchers used electronic health records from the Vaccine Safety Datalink (VSD), a collaborative effort between the Centers for Disease Control and Prevention Immunization Safety Office and 8 managed care organizations across the country. The analysis included data on 459,000 children who had been vaccinated — 83,000 with the MMRV vaccine and 376,000 with the MMR plus varicella vaccines — from 2000 to 2008.

The MMRV vaccine was licensed by the US Food and Drug Administration (FDA) in 2005. Shortly after that, the VSD began actively monitoring the safety of new vaccines, including the MMRV vaccine, explained Dr. Klein. Preliminary studies showed a roughly 2-fold increased rate of seizures with this combination vaccine compared with the separate vaccines — information that was reported to the Advisory Committee on Immunization Practices in February 2008.

Since then, they've doubled the available data on the MMRV vaccine, said Dr. Klein. "Also, when we originally reported in 2008, we just looked at the 7 to 10 days after vaccination; since then, we've looked at the entire 42 days after vaccination and found that the febrile seizure risk is confined to just the 7- to 10-day window."

According to background information in the study, the VSD creates aggregated dynamic data sets that are updated weekly and contain vaccine information and outcomes. MMRV rapid cycle analysis surveillance monitored children 12 to 23 months old for 6 outcomes. In addition to seizures, outcomes of interest included thrombocytopenia, encephalitis or meningitis, ataxia, allergic reactions, and arthritis.

The researchers compared the cumulative number of seizures observed with the number expected on the basis of the historical VSD seizure rates from 2000 to 2006 after MMR vaccine was administered with or without varicella. They examined postvaccination outpatient fever visits for fever or febrile illness at 7 participating VSD sites from January 2000 to October 2008.

Seizures were defined according to the International Classification of Diseases, Ninth Revision. To assess whether postvaccination seizures were febrile seizures, researchers conducted medical record reviews. When available, they also captured data on previous seizure history, family history of seizures, and whether the seizure resulted in hospitalization.

For the primary analysis, as well as for 3 supplementary analyses, researchers adjusted for age group, site, calendar year, and respiratory virus season.

Seizure Peak

The study found that seizure incidence peaked during the period days 7 to 10 after vaccination with all measles-containing vaccines. Primary analysis revealed significantly higher seizure risk after MMRV vaccination than after MMR plus varicella vaccination during this time (relative risk, 1.98; 95% confidence interval [CI], 1.43 – 2.73).

"What we found in our study is that when you take combination vaccine — measles, mumps, rubella, and varicella — in the combination vaccine, there's a doubling of the risk for febrile seizures when you compare them with children who received separate MMR and varicella vaccines," said Dr. Klein.

MMRV vaccination was associated with an estimated 4.3 additional seizures per 10,000 doses (95% CI, 2.6 – 5.6) during the 7 to 10 days after vaccination. This translates into about 1 additional febrile seizure for every 2300 MMRV doses administered to 12- to 23-month-olds instead of separately administered same-day MMR plus varicella vaccination.

Medical record reviews verified 94% of electronically identified seizures as acute seizures, with 87% being febrile seizures. Using case-centered analyses strengthened the results because they addressed confounding caused by coding or diagnostic practices, data error, patient demographics, or care-seeking behavior, said the study authors.

The study results "show that both MMRV and MMR vaccines, but not varicella vaccine alone, are associated with increased outpatient fever visits and seizures 7 to 10 days after vaccination, with MMRV vaccine increasing fever and seizure twice as much as the MMR plus varicella vaccines," said the study authors. "MMRV vaccine doubles an already elevated risk for febrile seizures."

Dr. Klein pointed out that febrile seizures are common but usually harmless in children. "Up to 5% of children 6 months to 5 years of age can have a febrile seizure, and they are almost always due to colds or other infections. These seizures are a benign condition and they self-resolve. They don't have any long-term side effects; they don't, for example, lead to seizures and they don't lead to epilepsy."

However, they can be alarming. "The seizures can be very frightening for parents," said Dr. Klein. "Typically, it's a full-body convulsion and so parents do bring [the] child to the emergency department."

Pediatric Academy Statement

Asked to comment on the research, John Bradley, MD, a member of the American Academy of Pediatrics (AAP) Committee on Infectious Disease, director of the Division of Infectious Diseases at Rady Children's Hospital, and associate clinical professor of pediatrics, University of California at San Diego, said the AAP supports both vaccines equally.

However, the increased risk for febrile seizures with the MMRV vaccine should be shared with parents. "You should then let them make the decision. If you can't communicate with them because of a language barrier or other reason, you should give the vaccines separately to minimize risks of adverse events."

Dr. Bradley agreed that some parents would still opt for the combined vaccine. "Some prefer the convenience of just coming to the doctor and getting 1 vaccine rather than 2 shots for their kids, but we want them to have that option."

He added that when the MMRV vaccine was first approved by the FDA, "we knew that there was a little bit of extra fever but at that time the repercussion of that extra fever, meaning febrile seizures, was not yet defined."

The AAP is preparing a statement on this issue, which should be released in a month, if not before, said Dr. Bradley.

Dr. Bradley reiterated that febrile seizures are usually "very brief" and benign. "They're not known to produce any neurological injury. If the seizures were horrible and children ended up with injury, we would not be recommending this vaccine."

However, they could be a burden on the healthcare system. The AAP is carrying out an analysis of the extra costs associated with visits to general practitioners and neurologists and trips to the emergency department because of vaccine-related febrile seizures, said Dr. Bradley.

It is not clear exactly why there is increased fever with the combination vaccine. It could be because this vaccine needs extra varicella virus to produce the same immune response as the separate vaccines, said Dr. Bradley.

This study was supported by the VSD contract with America's Health Insurance Plans, funded by the Centers for Disease Control and Prevention. Dr. Klein and Roger Baxter, MD, have reported research support from Merck & Co, Novartis, GlaxoSmithKline, Wyeth, and Sanofi-Pasteur; the other study authors have disclosed no relevant financial relationships.

Pediatrics. Published online June 28, 2010.

Clinical Context

The MMRV vaccine was licensed by the FDA in 2005. The combination of the MMR and varicella vaccines affords the promise of similar immune protection against important infections with a reduction in the number of injections, which young children need to endure. However, prelicensure studies of the MMRV revealed that it promoted higher rates of fever and measles-like rash in the 1 to 2 weeks after vaccination vs separate MMR and varicella vaccines.

There has also been evidence that the combined MMRV vaccine may promote a higher risk for seizures vs the separate MMR and varicella vaccines. The current study analyzes data from the VSD to address this issue.

Study Highlights

  • Researchers focused on data from the VSD from 2000 through 2008. In particular, they focused on 6 outcomes during the 42 days after vaccination of children between the ages of 12 and 23 months. Seizure events were confirmed with diagnosis codes from the emergency department or hospital.
  • Researchers examined medical records to determine whether the seizure was related to fever.
  • The main study outcome was the risk for seizures after the MMRV vaccine vs that associated with vaccination with MMR and varicella as separate injections.
  • The main study population included 83,107 children who received MMRV between 2006 and 2008, and 376,354 children who received MMR plus varicella between 2000 and 2008.
  • The seizure incidence was most prominent between days 7 to 10 after vaccination. Varicella vaccination alone was not associated with a postvaccination spike in the incidence of seizures.
  • MMRV vaccine was associated with higher rates of outpatient visits for fever between days 7 to 10 after vaccination vs separate vaccinations for MMR and varicella.
  • 491 cases of seizure were identified, 87% of which were classified as febrile seizures.
  • During days 7 to 10 after vaccination, application of the MMRV vaccine was associated with a nearly 2-fold increase in the risk for seizures vs the MMR plus varicella vaccines.
  • MMRV vaccine was not associated with a higher rate of seizures during any other postvaccination period studied.
  • The odds ratio for chart-confirmed febrile seizure associated with MMRV vaccine vs MMR plus varicella vaccine was slightly higher (2.17).
  • The rate of a positive family history of seizures was similar in comparing the MMRV vaccine vs MMR plus varicella vaccine groups.
  • Children with febrile seizures after administration of the MMR plus varicella vaccine were more likely to be hospitalized vs children with febrile seizures after the MMRV vaccine.
  • Overall, MMRV was associated with an additional 4.3 additional seizures per 10,000 doses during the 7 to 10 days after vaccination. This translated into 1 additional seizure per 2300 doses of MMRV vs MMR plus varicella vaccine.

Clinical Implications

  • Prelicensure studies found that the MMRV vaccine promoted higher rates of fever and measles-like rash in the 1 to 2 weeks after vaccination vs separate MMR and varicella vaccines.
  • The current study finds that MMRV vaccine is associated with a higher risk for seizures on postvaccination days 7 to 10 vs MMR plus varicella as separate vaccinations.

CME Test

  • Print