Elsevier

Vaccine

Volume 33, Issue 31, 17 July 2015, Pages 3636-3649
Vaccine

Review
Risk of febrile seizure after measles–mumps–rubella–varicella vaccine: A systematic review and meta-analysis

https://doi.org/10.1016/j.vaccine.2015.06.009Get rights and content

Highlights

  • We use systematic strategy and broad search terms in multiple databases and websites.

  • We use rigorous methods to extract and appraise the data.

  • Both clinical trials and post-marketing observations are included to analyze.

  • MMRV vaccine increases potential risk of febrile seizure during second observed week.

  • We provide evidence-based knowledge of febrile seizure risk after MMRV vaccine.

Abstract

Background

Considering the febrile seizure rate, there is no longer a clear preference for use of measles–mumps–rubella–varicella (MMRV) vaccine over separate measles–mumps–rubella (MMR) and varicella (V) vaccine. This work was undertaken to assess the risk of febrile seizure after MMRV vaccine in children.

Methods

We searched PubMed, Embase, BIOSIS Previews, Scopus, Web of Science, Cochrane Library and other databases through 12 December 2014. Meta-analysis was conducted using R version 3.1.2 and Stata version 12.0.

Results

A total of thirty-nine studies were included. Thirty-one published or unpublished clinical trials involving about 40,000 subjects did not show significant differences in incidence of febrile seizure or vaccine related febrile seizure between MMRV and MMR with or without varicella vaccine after any doses, in the risk windows of 0–28, 0–42 or 0–56 days and 7–10 days. In addition, these studies showed that the receipt of concomitant use of MMRV and other pediatric vaccines was not a significant predictor of febrile seizure. Eight post-marketing observations involving more than 3,200,000 subjects were included. No evidence suggested elevated risk of febrile seizure associated with MMRV vaccine among children aged 4–6 years old during 7–10 days or 0–42 days after vaccination. However, an approximately 2-fold increase in risk of seizure or febrile seizure during 7–10 days or 5–12 days after MMRV vaccination was found among children aged 10–24 months, although the highest incidence of seizure was still lower than 2.95‰.

Conclusions

First MMRV vaccine dose in children aged 10–24 months was associated with an elevated risk of seizure or febrile seizure. Further post-marketing restudies based on more rigorous study design are needed to confirm the findings.

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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