REVIEW ARTICLE Safety of Vaccines Used for Routine Immunization of US Children: A Systematic Review AUTHORS: Margaret A. Maglione, MPP,a Lopamudra Das, MPH,a Laura Raaen, MPH,a Alexandria Smith, MPH,a Ramya abstract a a Chari, PhD, Sydne Newberry, PhD, Roberta Shanman, BACKGROUND: Concerns about vaccine safety have led some parents MLS,a Tanja Perry, BHM,a Matthew Bidwell Goetz, MD,b and Courtney Gidengil, MD, MPHa,c to decline recommended vaccination of their children, leading to the resurgence of diseases. Reassurance of vaccine safety remains critical aRAND Corporation, Santa Monica, California; bVA Greater Los Angeles Healthcare System and David Geffen School of Medicine, for population health. This study systematically reviewed the literature University of California, Los Angeles, Los Angeles, California; and on the safety of routine vaccines recommended for children in the cBoston Children’s Hospital, Boston, Massachusetts United States. KEY WORDS evidence-based medicine, vaccine/immunization, infectious METHODS: Data sources included PubMed, Advisory Committee on Im- disease munization Practices statements, package inserts, existing reviews, ABBREVIATIONS manufacturer information packets, and the 2011 Institute of Medicine AEs—adverse events consensus report on vaccine safety. We augmented the Institute of Med- AHRQ—Agency for Healthcare Research and Quality icine report with more recent studies and increased the scope to in- CI—confidence interval DTaP—diphtheria, tetanus, and acellular pertussis clude more vaccines. Only studies that used active surveillance and had H1N1—Swine Flu a control mechanism were included. Formulations not used in the Hib—Haemophilus influenza type b United States were excluded. Adverse events and patient and vaccine ILI—influenza-like illness IOM—Institute of Medicine characteristics were abstracted. Adverse event collection and report- IPV—inactivated poliovirus ing was evaluated by using the McHarm scale. We were unable to pool IRR—incidence rate ratio results. Strength of evidence was rated as high, moderate, low, or in- — LAIV live attenuated vaccine sufficient. MMR—measles/mumps/rubella Oka VZV—Oka strain varicella zoster virus RESULTS: Of 20 478 titles identified, 67 were included. Strength of OR—odds ratio evidence was high for measles/mumps/rubella (MMR) vaccine and PCV—pneumococcal conjugate vaccine PRISM—Post-Licensure Rapid Immunization Safety Monitoring febrile seizures; the varicella vaccine was associated with complications Td—tetanus-diphtheria in immunodeficient individuals. There is strong evidence that MMR TIV—trivalent inactivated vaccine vaccine is not associated with autism. There is moderate evidence VSD—Vaccine Safety Datalink that rotavirus vaccines are associated with intussusception. Limitations Ms Maglione conceptualized and designed the study, oversaw of the study include that the majority of studies did not investigate or the abstraction of data, interpreted the results, and drafted the manuscript; Ms Das abstracted data, interpreted results, and identify risk factors for AEs; and the severity of AEs was inconsistently revised the manuscript; Ms Raaen abstracted data, interpreted reported. results, and revised the manuscript; Ms Smith designed data collection instruments, analyzed data, and revised the CONCLUSIONS: We found evidence that some vaccines are associated manuscript; Dr Chari abstracted data, interpreted results, and with serious AEs; however, these events are extremely rare and must revised the manuscript; Dr Newberry revised the manuscript for be weighed against the protective benefits that vaccines provide. important content and approved the final manuscript as – submitted; Ms Shanman developed the literature search Pediatrics 2014;134:325 337 strategy, conducted electronic literature searches, and acquired data; Ms Perry acquired data and designed screening and data abstraction forms; Dr Goetz contributed to the conceptualization and design of the study, interpreted results, and critically reviewed and revised the manuscript; Dr Gidengil participated in study design, interpreted the results, drafted part of the manuscript, and critically reviewed the manuscript, and all authors approved the final manuscript as submitted. (Continued on last page) PEDIATRICS Volume 134, Number 2, August 2014 325 Downloaded from www.aappublications.org/news by guest on September 28, 2021 Vaccines are considered one of the associated with varicella, influenza, hep- Reporting System, and the Food and greatest public health achievements of atitis A, hepatitis B, human papilloma- Drug Administration’s Mini-Sentinel the 20th century for their role in virus, MMR, meningococcal, tetanus, Program. A Technical Expert Panel eradicating smallpox and controlling diphtheria, and pertussis vaccines. We reviewed the draft list of AEs and polio, measles, rubella, and other in- report the IOM findings regarding suggested additional AEs of interest. fectious diseases in the United States.1 children and update those findings by We included studies that used active Despite their effectiveness in prevent- identifying and evaluating studies surveillance and had a control mech- ing and eradicating disease, routine published after the IOM searches. We anism; eligible designs were controlled childhood vaccine uptake remains sub- also identify studies and evaluate evi- trials, cohorts comparing a vaccinated optimal. Parent refusal of vaccines has dence on pneumococcal, rotavirus, with nonvaccinated group, case–control contributed to outbreaks of vaccine- Hib, and inactivated poliovirus (IPV) studies, self-controlled case series, preventable diseases such as measles2 vaccines because these are recom- and observational studies that used and pertussis.3 In addition, although mended for children aged 6 years and regression to control for confounders fi multiple large studies have con rmed younger. and test multiple relationships simul- the lack of association between measles/ The following databases were searched: taneously (multivariate risk factor mumps/rubella (MMR) and autism, pa- DARE (Database of Abstracts of Reviews analyses). Common sources of data rental worries about the safety of vac- of Effects), the Cochrane Database of included medical records, health in- cines persist. Systematic Reviews, CENTRAL, PubMed, surance claims, and government reg- The Agency for Healthcare Research Embase, CINAHL (Cumulative Index to istries. and Quality (AHRQ) requested an evi- Nursing and Allied Health), TOXLINE To maintain applicability to the current dence report on the safety of vaccines (Toxicology Literature Online), and US context, we excluded studies of recommended for routine immuniza- TOXFILE. The IOM report, Advisory vaccine formulations never used or no tion of adults (including pregnant Committee on Immunization Practices longer available in the United States; women), children, and adolescents to statements, vaccine package inserts, examples include whole cell pertussis fi be used by the Of ce of the Assistant and review articles were mined for vaccine, oral polio vaccine, and pneu- Secretary of Health to identify the gaps studies. Using the IOM keyword search mococcal conjugate vaccine (PCV)7 in evidence. This article addresses the strategy, we updated their searches to vaccine. The recent IOM report, The safety of vaccines recommended for identify more recently published Childhood Immunization Schedule and routine usein children aged6years and studies. The following structure was Safety: Stakeholder Concerns, Scien- younger: DTaP (diphtheria, tetanus, and used: “vaccine term” AND “health term,” tific Evidence, and Future Studies,5 acellular pertussis), hepatitis A, hepa- where vaccine terms include the tech- makes recommendations for future re- titis B, Haemophilus influenza type b nical vaccine name, general descrip- search on childhood vaccine schedules (Hib), influenza (live attenuated and tions of the vaccine of interest (eg, and cumulative effect, so the current inactivated), meningococcal (conjugate rotavirus AND vaccine), or manufac- project focused on specific vaccines, or polysaccharide), MMR, pneumococ- turer names; health terms include a list rather than any cumulative effect. cal (conjugate or polysaccharide), ro- of AEs potentially associated with the tavirus, and varicella. It represents the Two researchers experienced in sys- vaccine. We also added more general AE results of a comprehensive and sys- tematic review methodology inde- keywords to the list of health terms tematic review of scientificevidence, pendently reviewed the titles and “ ” “ ”“ ” describes statistical associations be- such as safe or safety, side effect abstracts identified. The union of their “ ” tween vaccines and adverse events or harm. We searched from a year selections was retrieved. These re- (AEs), and reports on any risk factors before the publication of the IOM report searchers independently reviewed the identified. through August 2013. Using this ap- full text of study reports and met to proach, we developed new search reach consensus regarding exclusion/ strategies for the vaccines not originally inclusion. Disputes were settled by METHODS included in the IOM report and searched the lead investigators and team physi- In 2011, the Institute of Medicine (IOM) each database from its inception cian experts. Patient and study char- published a consensus report titled Ad- through August 2013. AE terms were acteristics were abstracted by single verse Effects of Vaccines: Evidence and based on AEs reported in systems