Safety of Vaccines Used for Routine Immunization of US Children: a Systematic Review

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 systematic 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 researchers and confirmed by the Causality.4 That report evaluated the such as the Vaccine Injury Compensa- project leader. If a study reported se- scientific evidence for AEs potentially tion Program, Vaccine Adverse Event verity or if adequate information was

326 MAGLIONE et al Downloaded from www.aappublications.org/news by guest on September 28, 2021 REVIEW ARTICLE provided for our investigators to cate- It is important to note that the 2011 IOM children with preexisting conditions gorize severity, we used the Common report used different terminology to such as HIV, juvenile arthritis, or Terminology Criteria for Adverse Events classify the strength of evidence; evi- cancer, which left 67 studies. These classification system6 to characterize dence was classified as either “convinc- studies are in addition to those in- AEs. The definition of “serious” differs ingly supports,”“favors acceptance,” cluded in the 2011 IOM consensus by AE type; each category of AE (ie fever, “inadequate to accept or reject,” or report Adverse Effects of Vaccines: headache) is rated on a 5-point scale, “favors rejection” of a causal associa- Evidence and Causality,whichwere with 1 being very mild and 5 being tion. They also included mechanistic not abstracted. death due to the event. studies and individual case reports to We present the results for each vaccine assess the biological plausibility of AE The McHarm instrument7 was used to in alphabetical order. Results are evaluate the quality of the studies with and considered this in addition to any summarized in Table 1. statistical association. For each vaccine regard to their assessment of AEs. discussed in the IOM report, we started Studies that reported timing and se- DTaP with the IOM findings and modified them, verity and defined AEs using standard, if needed, on the basis of any additional The IOM studied diphtheria toxoid, precise definitions were rated higher evidence we identified. tetanus toxoid, and acellular pertussis- than those that did not. We assessed containing vaccines alone and in com- the overall strength of evidence by us- binationinbothchildrenandadults.The ing guidance suggested by AHRQ for its RESULTS IOM committee did not find evidence Effective Health Care Program8 as of As presented in Fig 1, 20 478 titles were that “favors acceptance” of causal 2013. (The guidance has since been identified through electronic literature relationships for any conditions. They fi modi ed slightly.) The method is based searches; review of product inserts; found the evidence “favors rejection” of on one developed by the Grading of review of Food and Drug Administra- a causal relationship between type 1 Recommendations Assessment Work- tion, Advisory Committee on Immuni- diabetes and vaccines containing 9 fi ing Group and classi es the evidence zation Practices, and other Web sites; diphtheria toxoid, tetanus toxoid, and – based on risk of bias, consistency, di- reference mining; and requests for acellular pertussis antigens.10 14 We rectness, precision, dose–response, Scientific Information Packets from found no additional studies in children plausible confounders that would de- drug manufacturers. Of those, 17 270 published after the IOM search date; crease the observed effect, strength of were excluded on review of abstract or our review of their assessment sup- association, and publication bias. Pos- title for reasons such as “not about ports their conclusions. sible ratings are as follows: a vaccine,”“vaccine not within the High = High confidence that the ev- scope of this project” (formulations Hib Vaccine idence reflects the true effect. Fur- never available in the United States, The IOM did not study the safety of Hib ther research is very unlikely to recommended only for travel), or be- vaccine. We identified 3 controlled trials change our confidence in the esti- cause they were animal studies. Upon of the Hib vaccine in children15–17; 1 was mate of effect. full text review of the remaining 3208 set in the United States, the other 2 in fi Moderate = Moderate confidence articles, 392 were identi ed as relevant Asia. Results of the US trial (N = 5190) that the evidence reflects the true background/theoretical materials and indicated that Hib vaccination was as- effect. Further research may change set aside as potential references for sociated with redness (odds ratio [OR] the Introduction; 2749 other articles 2.71, 95% confidence interval [CI] 1.57– our confidence in the estimate of were excluded. The most common 4.67) and swelling (OR 9.44, 95% CI effect and may change the estimate. reason for exclusion was lack of suit- 4.90–18.19) but not with hospital- fi Low = Low con dence that the ev- able study design (1549): individual izations. Vaccination was not associ- fl idence re ects the true effect. Fur- case reports, nonsystematic reviews, ated with high fever in either the US ther research is likely to change and studies using passive surveillance trial or a trial in the Philippines. A trial fi our con dence in the estimate of were excluded. Many publications in Vietnam15 found the vaccine was not effect and is likely to change the (458) discussed vaccines on the rec- associated with any serious AEs, in- estimate. ommended schedule but did not report cluding convulsion, diarrhea, fungal Insufficient = Evidence either is un- or assess AEs. Eighty-eight studies on infection, or gastroesophageal reflux available or does not permit a con- adults or adolescents were excluded disease. No other AEs were associated clusion. for this article, as were 11 studies of with the Hib vaccination.

PEDIATRICS Volume 134, Number 2, August 2014 327 Downloaded from www.aappublications.org/news by guest on September 28, 2021 FIGURE 1 Literature diagram.

Hepatitis A enrolled in 5 US health maintenance and purpura in children aged 7 to Hepatitis A vaccine was not covered by organizations.18 Purpura was not as- 17 years. the IOMreport onvaccinesafety.Wedid sociated with any of the vaccines in not identify any studies of children that children aged 2 to 6 years but was Hepatitis B assessed the association of hepatitis A associated with vaccination against Althoughnoepidemiologicstudieswere alonewithAEs.However,wedididentify hepatitis A in children aged 7 to 17 identified by the IOM, mechanistic evi- a recent analysis that investigated years (incidence rate ratio 23.14, 95% dence “favored acceptance” of a causal possible relationships among Hib, PCV, CI 3.59–149.30; findings related to relationship between the vaccine and MMR, DTaP, trivalent inactivated vac- other vaccines are reported in their anaphylaxis in yeast-sensitive individ- cine (TIV), hepatitis A, varicella, and respective sections). This study pro- uals. The 2011 IOM study found “in- meningococcal vaccines and immune vides evidence for a moderate asso- sufficient” evidence of an association thrombocytopenic purpura in children ciation between hepatitis A vaccine of hepatitis B vaccine with any short- or

328 MAGLIONE et al Downloaded from www.aappublications.org/news by guest on September 28, 2021 EITISVlm 3,Nme ,Ags 2014 August 2, Number 134, Volume PEDIATRICS TABLE 1 Results: Safety of Vaccines Used for Routine Immunization of Children Vaccine Conclusions and Strength of Evidence 2011 IOM Findings New Findings DTaP Moderate: no association Evidence “favors rejection” of a causal No additional studies met inclusion criteria. with type 1 diabetes relationship between vaccines containing diphtheria toxoid, tetanus toxoid, and acellular pertussis antigens and type 1 diabetes. Hepatitis A vaccine Moderate: purpura Not covered. In a large postlicensure study of .1.8 million vaccine recipients, purpura was associated with vaccination against hepatitis A in children aged 7–17 y. These results were based on 1 or 2

Downloaded from cases per vaccine type/age group. According to the authors, most cases were mild and acute. Hepatitis B vaccine Insufficient: food allergy Although no epidemiologic studies were Hepatitis B vaccine in the first 6 mo of life was associated with identified by the IOM, mechanistic evidence elevated total immunoglobulin E in a postlicensure study of “favored acceptance” of a causal relationship children with a family history of food allergy but not with between the vaccine and anaphylaxis in clinical allergy. yeast-sensitive individuals. www.aappublications.org/news Moderate: no association with MS A 2002 IOM report “favors rejection” of a causal relationship with MS onset or exacerbation. Hib vaccine Moderate: no association with Not covered. No serious AEs were associated in 3 high-quality clinical trials. serious AEs in short term IPV Insufficient: food allergy Not covered. One postlicensure study reported association between polio vaccine in newborns and sensitivity to food allergens. Influenza vaccines (live Moderate: mild gastrointestinal Evidence was “inadequate to accept or We identified 1 trial of seasonal influenza vaccine (including attenuated and inactivated) disorders, febrile seizures reject” a causal relationship with any a strain of H1N1) and 1 cohort comparison study of 2009 AEs investigated. monovalentH1N1vaccinepublishedafter theIOMsearchdates; the studies found no evidence of an association of the vaccines byguest on September28, 2021 with any AEs. Low: Influenza-like symptoms Both seasonal influenza vaccines and monovalent H1N1 vaccine (administered only in 2009 season) were associated with mild gastrointestinal disorders, such as vomiting and diarrhea, in children in the short term in 2 large postlicensure studies. One of these studies found that younger vaccinated children (aged 5–8 y) were more likely to experience these symptoms than older vaccinated children (aged 9–17 y). (Children aged ,5y were not included in that study). Both live and inactivated seasonal influenza vaccines were associated with influenza-like symptoms in children in the short term in 1 new study. A large US postlicensure study of children aged ,5 y found TIV associated with febrile seizures. Risk was increased if PCV13 was administered concomitantly. MMR High: no association with autism Evidence “convincingly supports” Five new postmarketing studies were identified. Vaccination was

spectrum disorders causal relationships anaphylaxis in associatedwiththrombocytopenicpurpuraintheshorttermin ARTICLE REVIEW allergic children and febrile seizures. 3; it was not studied in the other 2. In 1 study, MMR vaccination was associated with increased emergency department visits within 2 wk; this is indirect support of the IOM’s ﬁndings that MMR vaccine is associated with febrile seizures. 329 330 TABLE 1 Continued Vaccine Conclusions and Strength of Evidence 2011 IOM Findings New Findings ALOEe al et MAGLIONE High: anaphylaxis in children with Evidence “favors acceptance” of a causal A new case-control study found MMR vaccine was unrelated to allergies, febrile seizures relationship between MMR and autism. transient arthralgia Moderate: transient arthralgia Evidence “favors rejection” of a causal relationship between MMR and autism. Moderate: thrombocytopenic purpura Meningococcal Moderate: anaphylaxis in Evidence “convincingly supports” a causal Two new trials of quadrivalent meningococcal conjugate vaccines vaccines (MCV4, MPSV) children with allergies relationship with anaphylaxis allergic children. found no association with any AEs assessed.

Downloaded from PCV13 Moderate: febrile seizures Not covered. The US VSD found an association with febrile seizures. Estimated rate for 16-mo-old patients is 13.7 cases per 100 000 doses for PCV13 without concomitant TIV and 44.9 per 100 000 doses for concomitant TIV and PCV13. Rotavirus vaccines: Moderate: Intussusception Not covered. In 31 clinical trials, there was no association between eitherof the RotaTeq and Rotarix current vaccines (RotaTeq and Rotarix) and any serious AEs, www.aappublications.org/news including intussusception, in the long or short term. A high-quality Australian epidemiologic study found RotaTeq associated with intussusception 1–21 d after the ﬁrst of 3 required doses in infants 1–3 mo of age. Two case–control studies conducted in Latin America found an association of Rotarix with intussusception in children after the ﬁrst of 2 required doses. Although 1 US epidemiologic study found no association, a recent analysis of the US PRISM program found both RotaTeq and Rotarix associated with intussusception in the short term. Estimated rate was 1.1–1.5 cases per 100 000

byguest on September28, 2021 doses of RotaTeq and 5.1 cases per 100 000 doses of Rotarix. Varicella vaccine High: anaphylaxis; disseminated Oka Evidence “convincingly supports” In a large postlicensure study of .1.8 million vaccine recipients, VZV without other organ involvement; causal relationships between varicella purpura was associated with vaccination against varicella in disseminated Oka VZV with subsequent virus vaccine and the following: children aged 11–17. These results were based on 1 or 2 cases infection resulting in pneumonia, disseminated Oka VZV without other per vaccine type/age group. According to the authors most meningitis, or hepatitis in individuals organ involvement; disseminated cases were mild and acute. with demonstrated immunodeficiencies; Oka VZV with subsequent infection vaccine strain viral reactivation without resulting in pneumonia, meningitis, or other organ involvement; vaccine strain hepatitis in individuals with demonstrated viral reactivation with subsequent immunodeficiencies; vaccine strain viral infection resulting in meningitis reactivation without other organ or encephalitis. involvement; vaccine strain viral reactivation with subsequent infection resulting in meningitis or encephalitis; and anaphylaxis. Moderate: purpura Miscellaneous High: no association of childhood Not applicable. Four large epidemiologic studies conducted analyses to assess leukemia with MMR, DTaP, Td, Hib, which,ifany, ofthe followingvaccinesmightbeassociated with hepatitis B, and polio vaccines childhood leukemia: MMR, DTaP, Td, Hib, hepatitis B, and polio vaccine. No association was found for any vaccine. EPC, Evidence-based Practice Center; MS, multiple sclerosis; MCV, meningococcal conjugate vaccine; MPSV, meningococcal polysaccharide vaccine; PCV, pneumococcal conjugate vaccine; VZV, varicella-zoster virus. REVIEW ARTICLE long-term AEs in children. A 2002 IOM wheezing and lower respiratory syn- vaccinated children (aged 9–17 years). review on hepatitis B vaccine and drome associated with DTaP, IPV, Hib, (Children ,5 years of age were not demyelinating neurologic disorders varicella, PCV7, MMR, or TIV vaccina- included in that study). Finally, an Ital- concluded that the evidence “favors tion. In sum, the strength of evidence is ian study31 of children hospitalized for rejection” of a causal relationship insufficient to determine an associa- influenza-like illness (ILI) found those with incident multiple sclerosis or tion between polio vaccine in new- vaccinated with seasonal vaccine (OR multiple sclerosis relapse.19 We iden- borns and sensitivity to food allergens. 2.1, 95% CI 1.1–4.1) were significantly tified 1 study published after the IOM more likely to show symptoms of ILI 2011 search: Gallagher and Goodman Influenza Vaccines than unvaccinated children, whereas (2010)20 conducted a secondary anal- Influenza vaccine is administered in 2 those vaccinated for H1N1 were not at ysis of National Health Interview Survey forms: live attenuated vaccine (LAIV), higher risk (OR 1.3, 95% CI 0.6–3.1). data on 7074 boys born before 1999. administered intranasally, and TIV, ad- Strength of evidence is moderate for Vaccination status and health out- ministered intramuscularly. The IOM mild gastrointestinal events and fe- comes were reported by parents. found no evidence that “convincingly brile seizures and low for ILI. Results were significant for the risk of supports” causal relationships in the autism in children who received their pediatric population for any AEs. We MMR first dose of hepatitis B vaccine during identified 1 trial of seasonal influenza The IOM committee found that mecha- the first month of life (OR 3.00, 95% CI vaccine (which included a strain of nistic evidence “convincingly supports” 1.11–8.13), compared with those who H1N1 [swine flu])23 and 1 cohort com- causal relationships between MMR and received the vaccination after the parison study of 2009 monovalent H1N1 measles inclusion body encephalitis in first month of life or not at all. Signifi- vaccine24 published after the IOM immunocompromised children and cant protective factors included non- search dates; the studies found no ev- anaphylaxis in allergic patients. They Hispanic white ethnicity (OR 0.36, idence of an association of the vaccines also found epidemiologic evidence that 95% CI 0.15–0.88) and belonging to a with AEs. “convincingly supports” a causal re- household with 2 parents (OR 0.30, 95% Six observational studies also met our lationship between MMR vaccine and – – CI 0.12 0.75). It is unclear why the inclusion criteria.25–30 A 2011 UK study febrile seizures.32 38 The IOM committee “fi ” authors selected rst month of life as of 2336 children25 found no association found the evidence “favors acceptance” the only vaccination time period stud- between flu vaccines and febrile seizures; of a causal relationship between MMR ied, without presenting analyses for however, a recent study using the and transient arthralgia in the pediatric “ 39–45 other time periods or comparing ever US Vaccine Safety Datalink (VSD)26 population. They found the evidence ” “ ” vaccinated with never vaccinated. found an association of flu vaccine with “favors rejection” of a causal relation- Because of high risk of bias and low febrile seizures, which increased with ship between MMR and autism.46–50 In fi quality, this study presents insuf cient concomitant administration of pneu- addition, a causal relationship between evidence that hepatitis B vaccine is mococcal vaccine (PCV13). In the the Urabe strain of mumps and aseptic associated with autism. highest risk age group (16 months), meningitis has been shown; there is estimated rate was 12.5 per 100 000 no evidence to link Jeryl Lynn strain, IPV: Inactivated Polio Virus doses for TIV without concomitant commonly used in the United States, to The IOM did not study IPV vaccine. Our PCV13, 13.7 per 100 000 doses for this AE. search identified a case–control study PCV13 without concomitant TIV, and We identified 5 postlicensure studies of of .2000 children with atopic derma- 44.9 per 100 000 doses for concomitant childhood MMR vaccination published titis and a family history of allergy in 12 TIV and PCV13. In large, high-quality after the IOM searches. In a case– Western countries,21 which found that postlicensure studies, both LAIV and control study of 189 young adults with newborns immunized against polio TIV were associated with mild gastro- autism spectrum disorder and 224 had higher odds (OR 2.60, 95% CI 1.08– intestinal disorders,27,28 such as short- controls, Uno et al51 found that child- 6.25) of sensitivity to food allergens. term vomiting and diarrhea in children. hood receipt of MMR vaccine was not This relationship did not hold for those Strength of evidence is moderate associated with an increased rate of immunized against polio later in life. A for these AEs. One of these studies new-onset autism (OR 1.10, 95% CI self-controlled case series of pre- found that younger vaccinated children 0.64–1.90). In 3 studies,18,52,53 MMR mature infants born in the United (aged 5–8 years) were more likely to vaccination was associated with throm- States22 found no increased risk of experience these symptoms than older bocytopenic purpura in children in the

PEDIATRICS Volume 134, Number 2, August 2014 331 Downloaded from www.aappublications.org/news by guest on September 28, 2021 short term after vaccination. Strength of the same visit was associated with in- Dose 2 of Rotarix. The RotaTeq analysis evidence is moderate because findings creased risk. For example, in the high- had higher statistical power because were consistent and ORs similar in 3 est risk group, which was 16-month-old that vaccine was administered to European countries, Canada, and the children, the estimated rate was 13.7 orders of magnitude more children United States. Finally, 1 Canadian study per 100 000 doses for PCV13 without than Rotarix. Estimated rate of in- found MMR vaccination was associated concomitant TIV and 44.9 per 100 000 tussusception was 1.1 to 1.5 cases per with increased emergency department doses for concomitant TIV and PCV13. 100 000 doses of RotaTeq and 5.1 cases visits within 2 weeks. This finding is Risk difference estimates varied by age per 100 000 doses of Rotarix. consistent with the IOM’s findings that due to the varying baseline risk for In addition, 2 case–control studies MMR vaccine is associated with febrile seizures in young children. Thus the conducted in Latin America found an seizures. strength of evidence for an association association with intussusception in between PCV13 and febrile seizures is children after the first of 2 required Meningococcal moderate, and the risk is particularly doses of Rotarix. One study estimated high when coadministered with in- The IOM found the evidence “convinc- Rotarix increased risk by 3.7 additional fluenza vaccine. ingly supports” a causal relationship cases per 100 000 person years in with anaphylaxis in children who may Mexico.87 The other Latin American be allergic to ingredients. The IOM Rotavirus Vaccines: RotaTeq and study estimated risk as 1 case per conclusion does not differentiate be- Rotarix 51 000 vaccinations in Mexico and 1 case per 68 000 vaccinations in Brazil.88 In tween meningococcal conjugate or TheIOMreportdidnotaddressvaccines sum, there is moderate strength evi- meningococcal polysaccharide vac- against rotavirus. Thirty-one trials of dence that vaccination against rotavi- cines. We found 2 studies of quadriva- rotavirus vaccine56–85 met our inclusion rus is associated with intussusception, lent meningococcal conjugate vaccine criteria. Participants in the accepted but the occurrence is extremely rare, in children54,55 published after the IOM studies received 2 or 3 oral-administered and risk factors have not been in- report. A trial in Saudi Arabia found no doses of Rotarix (18 studies) or RotaTeq vestigated. statistical association with grade 2 or 3 (13 studies). Neither Rotarix nor RotaTeq fever, malaise, myalgia, or headache in was associated with increased risk of the short term.54 A trial in the United AEs other than cough, runny nose, or Varicella States and South America55 found irritability. The IOM committee found evidence vaccination was not associated with We identified 5 postlicensure studies “convincingly supports” causal rela- severe change in eating habits, severe on intussusception risk86–90; an earlier tionships in children between varicella irritability, severe persistent crying, brand of rotavirus vaccine (Rotashield) virus vaccine and the following: dis- severe sleepiness, or urticaria in the was withdrawn from the market in seminated Oka strain varicella zoster year after vaccination. 1999 due to concerns about risk for virus (Oka VZV) without other organ Thus, the strength of evidence is mod- this condition. A high-quality epidemi- involvement; disseminated Oka VZV erate that meningococcal vaccine may ologic study (N = 296 023) conducted in with subsequent infection resulting in cause anaphylaxis in children who are Australia86 found RotaTeq associated pneumonia,91 meningitis, or hepatitis allergic to ingredients. Strength of ev- with intussusception in children 1 to 21 in individuals with demonstrated immu- idence is insufficient to determine an days after the first of 3 required doses nodeficiencies; vaccine strain viral association with less serious events but found no association with Rotarix. reactivation without other organ in- such as headache, irritability, and ur- Two postlicensure studies were re- volvement; vaccine strain viral reac- ticaria. cently conducted in the United States. tivation with subsequent infection Shui et al89 analyzed VSD data on resulting in meningitis or encephali- PCV13 786 725 doses of RotaTeq and found tis92; and anaphylaxis.91 The IOM did not study the safety of no association with intussusception at We identified 1 study that investigated PCV13. As noted earlier, the VSD26 an- any time after vaccination. However, possible relationships among Hib, PCV, alyzed data on .200 000 US children a recent analysis of data from the US MMR,DTaP,TIV,hepatitisA,varicella,and aged ,5 years and found that vaccine Post-Licensure Rapid Immunization meningococcal vaccines and immune against pneumonia (PCV13) was asso- Safety Monitoring (PRISM) program90 thrombocytopenic purpura in chil- ciated with febrile seizures; importantly, found that intussusception risk was dren enrolled in 5 US health mainte- administration of influenza vaccine at increased after Dose 1 of RotaTeq and nance organizations.18 Purpura was not

332 MAGLIONE et al Downloaded from www.aappublications.org/news by guest on September 28, 2021 REVIEW ARTICLE associated with any of the vaccines DISCUSSION Our findings are based on only the most in children aged 2 to 6 years but was This study updated the evidence pre- rigorous study designs to assess po- associated with vaccination against sented in the 2011 IOM report and ex- tential statistical associations; how- varicella in children aged 11 to 17 panded the scope of that study by ever,thesedesignshavelimitationsthat years (incidence rate ratio R 12.14, 95% including additional vaccines such as must be considered. Controlled trials – fi fi CI 1.10 133.96; ndings related to other those against Hib, hepatitis A, PCV13, often have insuf cient sample size to vaccines are reported in their re- rotavirus, and IPV. Findings related to identify rare AEs and do not have ex- spective sections). This study provides these vaccines indicate that the Hib tended follow-up to identify long-term evidence for a moderate association vaccine is associated with local dis- sequelae. In addition, trials may pur- between varicella vaccine and purpura comfort such as redness and swelling posely exclude subjects who could be in children aged 11 to 17 years. butisnotassociatedwithseriousAEsor more susceptible to AEs. For this rea- hospitalization. Strength of evidence is son, any comprehensive review of Studies Controlling for Multiple moderate for the following associa- vaccine safety must include post- Vaccinations During Childhood tions:HepatitisAvaccineandpurpurain licensure studies, but these also have Four high-quality epidemiologic studies children aged 7 to 17 years, PCV13 and limitations. Large epidemiologic stud- investigated the potential relationship febrile seizures with an escalation of ies sometimes include any available between vaccinations and onset of risk when coadministered with TIV, and formulation of vaccines against a par- childhood leukemia. Groves and col- rotavirus vaccine and intussusception. ticular disease and may not stratify leagues93 included 439 US children None of the vaccines studied here were results by dosage or formulation. For with lymphoblastic leukemia in a associated with childhood-onset leu- example, the relationship between the case–control analysis to investigate kemia. “seasonal influenza vaccine” and an AE any possible relationship with oral Our findings support the following IOM could be studied over several years of or injected polio vaccine, diphtheria- results: vaccine against hepatitis B is data without considering the changes tetanus pertussis vaccine, MMR, Hib, not associated with any long- or short- in formulation over the seasons or or hepatitis B vaccine. Controls were termAEs;theMMRvaccineisassociated differentiating between live or inactive selected using random-digit dialing, with febrile seizures; MMR vaccine is vaccine. In addition, people who avoid which resulted in controls of higher not associated with autism. In addition, vaccinations (whether purposely or socioeconomic status then the 439 our study found moderate evidence not) may differ from those who receive cases. None of the vaccines were as- linking both LAIV and TIV forms of the vaccinations in terms of race, gender, sociated with leukemia. The relation- influenza vaccines with mild gastroin- age, socioeconomic status, and preex- ship between vaccination and leukemia testinal events; TIV was associated with isting medical conditions, and these was also assessed in a case–control febrile seizures. We also found mod- differences may be associated with study of children in Northern California.94 erate (but consistent) strength evi- health outcomes. Observational stud- Cases were matched on date of birth, dence of an association between the ies may attempt to control for such gender, and race/ethnicity. Analysis also MMR vaccine and thrombocytopenic potential confounders by using controlled for maternal education and purpura in children;there was asimilar matched cohorts or multivariate re- family income. None of the vaccines association between the varicella vac- gression analysis; still, some factors investigated (DPT, polio vaccine, MMR, cine and thrombocytopenic purpura in such as environmental exposures Hib, hepatitis B vaccine) were associ- children aged 11 to 17 years. may be unmeasured or challenging to ated with increased risk of leukemia. Literature search procedures for this adequately control for. Similarly, the Cross-Canada Child- review were extensive; however, some The self-controlled case series was hood Leukemia Study95 found no as- unpublished trial results may not have developed specifically to assess the sociation between vaccines against been identified. An independent Scien- safety of vaccines; this method eli- mumps, measles, rubella, diphtheria, tific Resource Center under contract minates confounding by all time- tetanus, pertussis, polio, or hepatitis B with AHRQ requested Scientific In- independent variables by using and leukemia. Finally, a large case– formation Packets from the vaccine casesastheirowncontrolsandpre- control study of children born in manufacturers. (The research team defined “time windows” before and Texas96 found that several vaccines was prohibited from contacting man- after vaccination. This design has may have a protective effect against ufacturers directly.) Only 2 companies been used to study purpura, febrile acute lymphoblastic leukemia. responded. seizures, intussusception, and autism

PEDIATRICS Volume 134, Number 2, August 2014 333 Downloaded from www.aappublications.org/news by guest on September 28, 2021 in children. However, the assumption however, these events were extremely stratified by formulation and brand of of no temporal shifts in this model is rare: absolute risk is low. For example, vaccine whenever possible. difficult to justify in very young chil- strength of evidence is moderate for dren because any patient character- association of vaccines against rotavi- ACKNOWLEDGMENTS istics that change with time will not rus with intussusception. Although 1 The authors thank Aneesa Motala, BA, be adequately controlled for. large US epidemiologic study found for compiling the many peer review Importantly, some AE signals that no association, a recent analysis of comments and formatting the final re- warrant future research may not have the US PRISM program90 found both port. We thank Susanne Hempel, PhD, been identified by this project. Passive RotaTeq and Rotarix associated with for her advice on study design, Paul surveillance systems such as the US intussusception in the short term. Esti- Shekelle, MD, PhD, for his advice and re- Vaccine Adverse Event Reporting Sys- mated rates were 1.1 to 1.5 cases per viewofthedraftandfinalversionsofthe tem97 are crucial in identifying signals 100 000 doses of RotaTeq and 5.1 cases evidence report, Kim Wittenberg, MA, regarding AEs post licensure, but they per 100 000 doses of Rotarix. for serving as the AHRQ Task Order Of- are not designed to assess a statistical Few studies were powered to detect ficer and Steve Bende, PhD, for repre- association, so they were excluded as patient characteristics associated with senting the Office of the Assistant sources of data. increased risk of rare AEs. Advanced Secretary for Health. We thank the following individuals for serving on the CONCLUSIONS health information technology systems that contain both vaccination and Technical Expert Panel for the project: Our findings may allay some patient, health outcome records may be used to Meghan Baker, MD ScD; Richard Beigi, caregiver, and health care provider conduct such investigations. In the MD, MSc; Kathryn Edwards, MD; Kristen concerns. Strength of evidence is high United States, the VSD contains data Feemster, MD, MSPH; Bruce Fireman, that MMR vaccine is not associated with from such systems at 9 large managed MA; David Martin, MD; and Claudia the onset of autism in children; this care organizations. In addition, the Vellozzi, MD, MPH. Finally, we would like conclusion supports findings of all PRISM program also conducts active to thank the following Peer Reviewers: previous reviews on the topic. There is surveillance using electronic health Janet D. Cragan, MD, MPH; Francesca also high-strength evidence that MMR, care databases from managed care Cunningham, Pharm D; Frank Destefano, DTaP, Td, Hib, and hepatitis B vaccines organizations. Nations with single- MD, MPH; and Laura Elizabeth Riley, MD. are not associated with childhood leu- payer health care systems often have Please note that service as a Peer kemia. electronic registries that allow large Reviewer or Expert Panel member Evidence was found for an association epidemiologic studies of entire pop- does not imply endorsement of the of several serious AEs with vaccines; ulations. Future analyses should be study findings.

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(Continued from first page) The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality or the US Department of Health and Human Services. www.pediatrics.org/cgi/doi/10.1542/peds.2014-1079 doi:10.1542/peds.2014-1079 Accepted for publication May 7, 2014 Address correspondence to Margaret A. Maglione, MPP, RAND Corporation, 1776 Main St Mailstop 4W, Santa Monica, CA 90407. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2014 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: Supported under Contract No. HHSA290200710062I from the Agency for Healthcare Research and Quality, US Department of Health and Human Services. POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose. COMPANION PAPER: A companion to this article can be found on page 377, and online at www.pediatrics.org/cgi/doi/10.1542/peds.2014-1494.

PEDIATRICS Volume 134, Number 2, August 2014 337 Downloaded from www.aappublications.org/news by guest on September 28, 2021 Safety of Vaccines Used for Routine Immunization of US Children: A Systematic Review Margaret A. Maglione, Lopamudra Das, Laura Raaen, Alexandria Smith, Ramya Chari, Sydne Newberry, Roberta Shanman, Tanja Perry, Matthew Bidwell Goetz and Courtney Gidengil Pediatrics 2014;134;325 DOI: 10.1542/peds.2014-1079 originally published online July 1, 2014;

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Downloaded from www.aappublications.org/news by guest on September 28, 2021 Safety of Vaccines Used for Routine Immunization of US Children: A Systematic Review Margaret A. Maglione, Lopamudra Das, Laura Raaen, Alexandria Smith, Ramya Chari, Sydne Newberry, Roberta Shanman, Tanja Perry, Matthew Bidwell Goetz and Courtney Gidengil Pediatrics 2014;134;325 DOI: 10.1542/peds.2014-1079 originally published online July 1, 2014;

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