ReviewRisk of febrile seizure after measles–mumps–rubella–varicella vaccine: A systematic review and meta-analysis
Introduction
Combination measles–mumps–rubella–varicella (MMRV) vaccine was originally designed as an alternative to separate measles–mumps–rubella (MMR) and varicella (V) vaccines, based on similar vaccination schedules and good concomitant safety profiles [1], [2], [3]. Two MMRV vaccines have been available since mid-2000s with different formulations: ProQuad (Merck&Co., Inc, West Point, PA) and Priorix-Tetra (GlaxoSmithKline Biologicals, Rixensart, Belgium). Both were developed based on the existing MMR and varicella vaccines [4], [5].
Pre-licensure clinical trials have demonstrated that MMRV vaccines are generally well tolerated and have comparable immunogenicity and overall safety profiles to MMR or MMR + V vaccines in healthy children, except higher fever rate following the administration of MMRV vaccine [6], [7], [8], [9]. Fever can precipitate febrile seizure in susceptible children aged between 6 months and 5 years, especially in the range of 12–23 months [10], [11].
Febrile seizure is the most common neurologic adverse event following immunization with measles-containing vaccines [12]. Given the evidence for an increase in risk of febrile seizure associated with the use of combination vaccine, the Advisory Committee on Immunization Practices has no longer expressed a preference for use of MMRV vaccine over MMR + V vaccines [13]. And since then, febrile seizure following MMRV vaccine has been investigated intensively. Although febrile seizures are common and not associated with long-term neurologic sequelae or developmental delay, they often frighten parents, which may precipitate acute care visits and undermine confidence in immunization programs [14], [15]. For this reason, the incidence and timing of vaccine related febrile seizure have to be carefully studied [16].
Up to date, a number of studies focused on the incidence of febrile seizure following MMRV vaccine have been published. However, the risks of febrile seizure following different measles-containing vaccines have not been directly compared, or discrepant among studies. To achieve a comprehensive evidence-based suggestion for the fair use of MMRV vaccine, we conducted a systematic review and meta-analysis of clinical trials and post-marketing observational safety surveillance studies to evaluate the risk of febrile seizure after MMRV vaccine in children.
Section snippets
Eligibility criteria
Eligible study designs were randomized controlled trials (RCTs), quasi-RCTs, controlled clinical trials, uncontrolled clinical trials, cohort studies, case control studies or cross-sectional studies, involving MMRV, MMR, MMR + V vaccines and other pediatric vaccines co-administered with MMRV vaccine. The population of interest were children aged 0–6 years, irrespective of sex and ethnic origin. The numbers or incidence of febrile seizure or vaccine related febrile seizure had been reported.
Literature search
We
Description of studies included
The searches identified 532 potentially relevant studies and clinical trial records. Most ineligible studies were excluded on the basis of information in the title or abstract. The selection process is shown in Fig. 1.
We included 31 clinical trials (30 RCTs) in the review (Table 1) [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50]. Twenty-three clinical trials [28], [29], [30], [31], [32], [33],
Discussion
This systematic review synthesized evidences about the risk of febrile seizure after MMRV vaccine in 39 studies involving more than 3,240,000 children. We used systematic strategy and broad search terms in multiple databases and related websites to identify as many published and unpublished studies as possible. We also used rigorous methods to extract and appraise the data. Considering different comparison groups and corresponding clinical significance, hierarchical analyses of four comparisons
Conclusion
Clinical studies did not find any difference in the incidence of febrile seizure or vaccine related febrile seizure between MMRV vaccine recipients and MMR + V, MMR, MMRV + others vaccine recipients after any doses, in the risk windows of 0–28/42/56 days and 7–10 days. However, an approximately 2-fold increase in risk for seizure or febrile seizure during 7–10 days or 5–12 days after MMRV vaccination among children aged 10–24 months was demonstrated in several post-marketing surveillance studies.
Conflicts of interest
None.
Funding
The authors have not accepted any financial support for this work.
Author contributions
All authors: analysis and interpretation of data, and preparation of manuscript. Qing Chen and Shu-Juan Ma: Conception and design.
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2022, The LancetCitation Excerpt :A 2012 Cochrane review of the safety of measles–mumps–rubella vaccine found no significant association between measles–mumps–rubella vaccination and autism, asthma, leukaemia, hay fever, type 1 diabetes, gait disturbance, Crohn's disease, demyelinating diseases, or secondary bacterial or viral infections,83 but did report an association with febrile seizures among children, and potentially with thrombocytopenic purpura. The risk of febrile seizures is higher among children younger than 2 years in the second week following receipt of the measles–mumps–rubella–varicella vaccine compared to the measles–mumps–rubella vaccine.84 Approximately 25–34 additional febrile seizures for every 100 000 vaccinations are attributable to the measles–mumps–rubella vaccine.85
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2019, Medical HypothesesCitation Excerpt :Subsequently, hyperthermia and loss of energy would be caused by overstimulation of immune system. Invasive hyperthermia could be led to complicated febrile seizure that frequently reported after vaccination [15–20]. From the other point of view, we speculated that by increasing in the concentration of antibodies in bloodstream, an in vivo prozone phenomenon could be happened.
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2019, The Lancet Infectious DiseasesProtection against varicella with two doses of combined measles-mumps-rubella-varicella vaccine or one dose of monovalent varicella vaccine: 10-year follow-up of a phase 3 multicentre, observer-blind, randomised, controlled trial
2019, The Lancet Infectious DiseasesCitation Excerpt :A two-dose live varicella vaccine schedule was recommended by the USA's Advisory Committee on Immunization Practices in 2007, for the active immunisation of children aged 9 months or older, which further decreased the incidence of varicella.5 Vaccination schedules could include a monovalent live attenuated varicella vaccine (V), or a combination measles-mumps-rubella-varicella vaccine (MMRV).5–7 Previous studies have shown comparable antibody responses after dose two, whether this was administered 6–12 weeks or 3–6 years after dose one.8
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2018, VaccineCitation Excerpt :An increased risk of non-febrile seizures was not observed in vaccinated, compared to non-vaccinated, children [40]. A recent meta-analysis of 39 studies, which involved approximately 40,000 children between 10- to 24-months-of-age, found an ∼2-fold increase in the risk of seizure or febrile seizure following MMRV vaccination [43]. Vaccination with MMRV vaccine, instead of separate MMR and VZV vaccines, resulted in one additional febrile seizure for every 2300 doses administered.