sign in sign up
<<
Home , Polio vaccine

Evidence Report/Technology Assessment Number 215

Safety of Used for Routine in the United States Executive Summary

Background Evidence-based Practice Vaccines are considered one of the greatest Program achievements of the last century for their role in eradicating smallpox and The Agency for Healthcare Research and controlling , measles, rubella, and other Quality (AHRQ), through its Evidence- infectious diseases in the United States.1 based Practice Centers (EPCs), sponsors Despite their effectiveness in preventing and the development of evidence reports and eradicating disease, substantial gaps in technology assessments to assist public- uptake persist. rates for young and private-sector organizations in their children are high;2 however, vaccination rates efforts to improve the quality of health remain well below established Healthy People care in the United States. The reports 2020 targets for many vaccines recommended and assessments provide organizations for adolescents,3 adults,4 and pregnant with comprehensive, science-based women.5 information on common, costly In the United States, vaccine guidelines medical conditions and new health care are set by the Centers for Disease Control technologies. The EPCs systematically and Prevention’s Advisory Committee for review the relevant scientific literature Immunization Practices (ACIP). The number on topics assigned to them by AHRQ of routine recommended for and conduct additional analyses when children and adolescents, adults, and pregnant appropriate prior to developing their women has expanded considerably over the reports and assessments. past 10 years. For example, since 2005, the AHRQ expects that the EPC evidence routine adolescent has reports and technology assessments will grown to include the following vaccines at inform individual health plans, providers, ages 11 or 12 years: meningococcal conjugate and purchasers as well as the health care vaccine; tetanus, , and acellular system as a whole by providing important pertussis (Tdap); human papillomavirus information to help improve health care (HPV); and influenza (one dose annually). quality. Tables A–C display ACIP recommendations as The full report and this summary are of October 2011. These recommendations were available at www.ahrq.gov/research/ in effect when this review began. findings/evidence-based-reports/ ptsafetyuptp.html.

Evidence-Based Practice Table A. Vaccines routinely recommended for children and adolescents, 2011

Vaccine Age

DTaP (diphtheria, tetanus, and acellular pertussis) 2 months–6 years Hepatitis A 12 months and older Birth and older Hib ( type b) 6 weeks–59 months HPV (human papillomavirus) 9 years–21 years (male) 9 years–26 years (female) Influenza (inactivated) 6 months and older Influenza (live attenuated) 2 years and older IPV (inactivated ) 6 weeks and older MCV (meningococcal ) 2 years and older MMR (measles, , and rubella) 12 months and older MPSV (meningococcal polysaccharide vaccine) 2 years and older in specific circumstances PCV13 (pneumococcal conjugate vaccine) 6 weeks–18 years Pneumococcal polysaccharide vaccine 2 years and older in specific circumstances Rotavirus 6 weeks–8 months Tdap (tetanus, diphtheria, and acellular pertussis) 7 years and older Varicella 12 months and older

Table B. Vaccines routinely recommended for nonpregnant adults, 2011

Vaccine Recommendation

Hepatitis A All adults at increased risk for hepatitis A Hepatitis B All unvaccinated adults at risk for or requesting protection from hepatitis B infection HPV (human papillomavirus) Adults 26 years and younger Influenza (inactivated) All adults Influenza (live attenuated) All adults 49 years and younger Meningococcal conjugate vaccine (MCV4) and meningococcal Adults at risk of meningococcal disease (MCV4 or MPSV if polysaccharide vaccine (MPSV) younger than 55 years; MPSV if 55 years and older) MMR (measles, mumps, and rubella) All adults Pneumococcal polysaccharide vaccine Adults 64 years and younger with certain conditions and all adults 65 years and older Td (tetanus, diphtheria) All adults who are not immune through prior infection Tdap (tetanus, diphtheria, and acellular pertussis) All adults 19–64 years old; some adults 65 years and older Varicella All adults without evidence of varicella Zoster All adults 60 years and older aIn 2013, pregnant women were advised to receive Tdap during every to protect their newborns from pertussis.

2 Table C. Vaccines routinely recommended for pregnant women, 2011

Vaccine Recommendation

Hepatitis B Recommended in some circumstances Influenza (inactivated) All pregnant women Td (tetanus, diphtheria) If indicated Tdap (tetanus, diphtheria, and acellular pertussis) All pregnant women at the first trimester if indicateda

As the number of recommended immunizations has b. What AEs are reported in clinical studies (Phases I– expanded across the population, so too have concerns about IV) and in observational studies containing a control/ the safety of vaccines. Perhaps the most highly publicized comparison group? safety concern of the last two decades was the proposed c. What AEs are associated with these vaccines? link between autism and the measles, mumps, and rubella (MMR) vaccine, first reported in 1998 in The Lancet by 1. For each AE associated with a particular vaccine, Dr. Andrew Wakefield.6 In 2010, The Lancet fully retracted what is the average severity (grade 1/mild; grade 2/ the 1998 report,7 noting that elements of the research had moderate; grades 3 and 4/severe)? been deliberately falsified. Although multiple large studies 2. For AEs without statistically significant associations have confirmed the lack of association between MMR with a particular vaccine, what is the level of and autism, parental worries about the safety of vaccines certainty?a persist. Other parental concerns about childhood vaccines include potential links to multiple sclerosis, sudden infant 3. For each AE associated with a particular vaccine, death syndrome, asthma, and diabetes.8 Thus, vaccine what are the risk factors for the AE (including age, safety is high on the Nation’s public health agenda. sex, race/ethnicity, genotype, underlying medical condition, whether a vaccine is administered Objectives individually or in a combination vaccine product, schedule of vaccine administration, adjuvants, and The Agency for Healthcare Research and Quality medications administered concomitantly)? (AHRQ) requested an evidence report on the safety of KQ 2. What is the evidence that vaccines included in the vaccines recommended for routine immunization of adults immunization schedules recommended for U.S. children (including pregnant women), children, and adolescents as and adolescents in 201110 are safe in the short term of October 2011. This report, which represents the results (within 30 to 42 days following immunization) or long term of a comprehensive and systematic review of scientific (>42 days after immunization)? evidence, describes potential associations between vaccines and adverse events (AEs) and will be used by the Office of a. What AEs are collected in clinical studies (Phases I– the Assistant Secretary for Health (OASH) to identify the IV) and in observational studies containing a control/ gaps in evidence. The report was guided by the following comparison group? Key Questions (KQs): b. What AEs are reported in clinical studies (Phases I– KQ 1. What is the evidence that vaccines included in IV) and in observational studies containing a control/ the 2011 immunization schedule recommended for U.S. comparison group? 9 adults are safe in the short term (within 30 to 42 days c. What AEs are associated with these vaccines? following immunization) or long term (>42 days after immunization)? 1. For each AE associated with a particular vaccine, what is the average severity (grade 1/mild; grade 2/ a. What adverse events are collected in clinical studies moderate; grades 3 and 4/severe)? (Phases I–IV) and in observational studies containing a control/comparison group?

aLevel of certainty was operationalized as the 95-percent confidence interval surrounding the risk or odds estimate—i.e., the statistical significance

3 2. For AEs without statistically significant associations condition, whether the vaccine is administered with a particular vaccine, what is the level of individually or in a combination vaccine product, the certainty?a schedule of vaccine administration, adjuvants, and 3. For each AE associated with a particular vaccine, medications administered concomitantly)? what are the risk factors for the AE (including age, Methods sex, race/ethnicity, genotype, underlying medical condition, whether a vaccine is administered In 2011, the Institute of Medicine (IOM) published a individually or in a combination vaccine product, consensus report titled “Adverse Effects of Vaccines: schedule of vaccine administration, adjuvants, and Evidence and Causality.”12 That report evaluated the medications administered concomitantly)? scientific evidence for event-vaccine relationships and KQ 3. What is the evidence that vaccines recommended for covered the following vaccines on the 2011 recommended pregnant women11 are safe both for the woman and for her immunization schedules: varicella, influenza, hepatitis fetus/infant? A, hepatitis B, HPV, MMR, meningococcal, tetanus, diphtheria, and pertussis. We report the IOM findings a. What AEs are collected in clinical studies (Phases I– and update them by identifying and evaluating studies IV) and in observational studies containing a control/ published after the IOM searches. We also searched comparison group? for studies of pneumococcal, rotavirus, Haemophilus b. What AEs are reported in clinical studies (Phases I– influenzae type b, inactivated , and zoster IV) and in observational studies containing a control/ vaccines; these were not included in the IOM report. comparison group? We searched electronic databases such as Medline® for c. What AEs are associated with these vaccines in women? relevant studies; complete search terms are provided in Appendix A . Databases were searched 1. For each AE associated with a particular vaccine, of the full report from inception through August 2013 for the vaccines not what is the average severity (grade 1/mild; grade 2/ covered by the IOM report; for the other vaccines, the moderate; grades 3 and 4/severe)? searches dated from a year before the IOM search. We also 2. For AEs without statistically significant associations reviewed ACIP statements, package inserts, and Scientific with a particular vaccine, what is the level of Information Packets requested from vaccine manufacturers certainty?a by an AHRQ-funded Scientific Resource Center. Finally, 3. For each AE associated with a particular vaccine, we scanned review articles for relevant references. what are the risk factors for the AE (including age, The following study designs were included: sex, race/ethnicity, genotype, underlying medical condition, whether the vaccine is administered • Controlled . Human subjects are assigned individually or in a combination vaccine product, the prospectively, usually through randomization, to receive schedule of vaccine administration, adjuvants, and an intervention (in this case, a vaccine) or an alternative medications administered concomitantly)? intervention (another vaccine) or placebo. Clinical trials are used to determine safety and efficacy.13 d. What AEs are associated with these vaccines in the fetus/infant? • Cohort study. Cohort studies follow two or more similar groups that differ with respect to whether they 1. For each AE associated with a particular vaccine, received a vaccine (the “exposure”) to determine how/ what is the average severity (grade 1/mild; grade 2/ whether the vaccination affects rates of one or more moderate; grades 3 and 4/severe)? AEs (the “outcome”).13,14 2. For AEs without statistically significant ssociationsa • Case-control study. Case-control studies compare with a particular vaccine, what is the level of people who have a disease or adverse event (“cases”) certainty? a with people who do not have the disease or event 3. For each AE associated with a particular vaccine, (“controls”) and look back retrospectively to compare what are the risk factors for the AE (including age, exposure to vaccine in each group to determine the sex, race/ethnicity, genotype, underlying medical relationship between the vaccine and the disease/ event.13,14 aLevel of certainty was operationalized as the 95-percent confidence interval surrounding the risk or odds estimate—i.e., the statistical significance

4 • Self-controlled case series (SCCS). Only cases The McHarm instrument19 was used to evaluate the quality (individuals who experienced the AE) are included in of the studies with regard to assessment of adverse events. the analysis. Each individual serves as his or her own Studies that reported timing and severity and that defined control. The analysis inherently controls for covariates AEs using standard precise definitions were rated higher that remain stable within a person during the study than those that did not. (Many studies provided data on a period—for example, race and sex. SCCSs compare list of AEs but did not address severity.) Epidemiological outcome event rates during times when a person is studies that used medical records to ascertain vaccination exposed (postvaccination) with those during times and health outcomes were rated higher than those that when the same person is unexposed (prevaccination) to relied on patient or parent report. 13,15 calculate the relative incidence of AEs. We assessed the overall strength of evidence using • Other designs. We included all active surveillance guidance suggested by AHRQ for its Effective Health Care studies that used regression to control for confounders Program.20 This method is based on one developed by and test multiple relationships simultaneously. We the GRADE (Grading of Recommendations Assessment, refer to these as multivariate risk factor analyses. Data Development and Evaluation) Working Group21 and sources may include medical records, health insurance classifies the evidence according to the following criteria: 13 claims, and government registries. • High. High confidence that the evidence reflects the Studies that use passive surveillance, such as the U.S. true effect. Further research is very unlikely to change Reporting System,16 are crucial in our confidence in the estimate of effect. identifying signals regarding AEs postlicensure. However, • Moderate. Moderate confidence that the evidence because by definition they do not consider the rate of such reflects the true effect. Further research may change our events in nonvaccinated populations, they are not designed confidence in the estimate of effect and may change the to assess a statistical association between a vaccine and estimate. an adverse event, so such studies were excluded from this project. We also excluded studies of vaccine formulations • Low. Low confidence that the evidence reflects the never used or no longer available in the United States. true effect. Further research is likely to change our Examples include whole-cell , oral polio confidence in the estimate of effect and is likely to vaccine, and PCV7 . The recent IOM change the estimate. report “The Childhood Immunization Schedule and Safety: • Insufficient. Evidence either is unavailable or does not Stakeholder Concerns, Scientific Evidence, and Future permit a conclusion. Studies”17 makes recommendations for future research on childhood vaccination schedules and cumulative effect, so The evidence grade is based on four primary (required) this report focuses on assessing the association between domains and four optional domains. The required domains AEs and specific vaccines rather than the cumulative effect are risk of bias, consistency, directness, and precision, of vaccines. as described in the Methods section of the full report. The additional domains are dose response, plausible Two researchers independently reviewed the titles and confounders that would decrease the observed effect, abstracts identified. The union of their selections was strength of association, and publication bias. retrieved. Two researchers also independently reviewed the full text of study reports and met to reach consensus It is important to note that the 2011 IOM report used regarding exclusion/inclusion. Disputes were settled by the different terminology; evidence was classified as either lead investigators and team physician experts. Patient and “convincingly supports,” “favors acceptance,” “inadequate study characteristics were abstracted by single researchers to accept or reject,” or “favors rejection” of a causal and confirmed by the principal investigator. association. The IOM included mechanistic studies and individual case reports to assess the biological plausibility If a study reported severity or if adequate information was of AEs and considered this information in addition to provided for our investigators to categorize severity, we any statistical association. For each vaccine discussed in used the Common Terminology Criteria for Adverse Events the IOM report, we started with the IOM findings and classification system18 to characterize AEs. The definition modified them, if needed, based on any additional evidence of “serious” differs by AE type; each category of AE (e.g., identified. If the IOM found that evidence “convincingly fever, headache) is rated on a scale of 1 to 5, with 1 being supports” an association, we rated the strength of evidence very mild and 5 being death due to the event. as “high” unless additional evidence was identified. Similarly, if the IOM found evidence “favors acceptance”

5 we started with by rating as “moderate” strength of were excluded. The most common reason for exclusion evidence and evidence rated as “inadequate to accept or was lack of suitable study design (1,549): individual case reject” was considered “insufficient” in our grading system. reports, nonsystematic reviews, and studies using passive If new evidence was identified for vaccines evaluated by surveillance were excluded. Many publications (458) the IOM, ratings could be adjusted up or down according discussed vaccines on the recommended schedule but did to our assessment of the new studies. If the IOM found not report or assess AEs. that evidence “favors rejection” of a causal relationship, Studies using formulations never available or discontinued we chose between moderate and high based on our review in the United States were excluded at full-text review (e.g., of the IOM evidence plus any studies published after their , vaccines with the squalene adjuvant ASO3, search. and BCG vaccine against tuberculosis). Determining Results whether the potency or formulation was the one approved for clinical use in the United States was often difficult; As presented in Figure A, a total of 20,478 titles were the process involved comparing the potency, dosage, and identified through electronic literature searches; review of ingredients listed on product materials and in Food and product inserts; review of Food and Drug Administration, Drug Administration filings with the information reported ACIP, and other Web sites; reference mining; and in the study. requests for Scientific Information Packets from drug Based on full-text screening, 166 studies were accepted manufacturers. Of those, 17,270 were excluded upon for abstraction. These include 86 controlled trials or cohort review of abstract or title, mostly due to lack of data on studies directly comparing a group that received a vaccine safety of vaccines. Other reasons for exclusion included use with an unvaccinated group. (Five of the 86 studies also of vaccines not within the scope of this project (e.g., not reported a multivariate analysis.) We also abstracted 80 formulations available in the United States, recommended case-control studies, SCCSs, or multivariate risk factor only for travel), publication in languages other than analyses that met our inclusion criteria. These studies are English, and study not conducted on humans. Five reports in addition to those included in the 2011 IOM consensus could not be obtained; based on their titles, we do not think report “Adverse Effects of Vaccines: Evidence and this affected the project. Causality,” which were not abstracted. Based on abstract screening, 3,210 articles were selected for full-text review. Of those, 392 were identified as relevant background/theoretical materials and set aside as potential references. A total of 2,650 other articles

6 Figure A. Study/literature flow diagram

IOM = Institute of Medicine aFive studies also contributed multivariate risk factor analyses.

7 Table D displays a summary of our results. The second Importantly, the vast majority of studies did not report column displays the strength of evidence regarding potential risk factors for AEs that were statistically statistical association of vaccines with AEs. Where associated with vaccination. Similarly, the severity of AEs we identified no additional studies on a vaccine, our was inconsistently reported, as was information that would conclusions are based entirely upon the 2011 IOM report. make independent severity determination possible. It is important to recognize that the strength of evidence refers to the chances the vaccine is truly associated with a particular AE, rather than the rate of that AE or severity. Strength of evidence may be high for an AE that is extremely rare, very mild, or without long-term consequences. Further details on the scientific evidence behind the findings are available in the full report and its appendixes.

8 Additional Findings From EPC Findings From Additional We identified 2 additional trials in adults. No AEs identified 2 additional trials in adults. No We associated with vaccine. were identified 1 additional postlicensure study; there We AEs or with any no association of the vaccine was onset of medical conditions. No additional studies met our inclusion criteria. ” a ” inadequate favors favors ” a causal ion” of a causal relationship IOM Findings ” a causal relationship: inadequate to accept or reject favors reject favors inadequate to accept or reject ” of a causal relationship between the ” of a causal relationship between convincingly supports convincingly Evidence “ and vaccine the tetanus relationship between anaphylaxis. Evidence is “ AEs the committee causal relationships with any acute disseminated with investigating: tasked was MS, GBS, myelitis, transverse encephalomyelitis, polyneuropathy, chronic inflammatory demyelinating and autoimmune hepatitis. anaphylaxis, palsy, Bells’ identified studies were Although no epidemiological “ mechanistic evidence on anaphylaxis, acceptance individuals. in yeast-sensitive and anaphylaxis vaccine AEs in adults studies of the following Epidemiological “ had evidence causal relationship: optic neuritis, first demyelinating of vasculitis, GBS, SLE, onset or exacerbation event, of nodosa, and onset or exacerbation polyarteritis rheumatoid arthritis. and on Hep B vaccine A 2002 IOM review disorders concluded that neurological demyelinating “ the evidence with incident MS or relapse. AEs in studies of the following No epidemiological is also “ found and evidence adults were to accept or reject ADEM, transverse encephalitis, encephalopathy, optica, chronic inflammatory neuromyelitis myelitis, brachial neuritis, polyneuropathy, demyelinating erythema of psoriatic nodosum, onset or exacerbation arthritis, and arthritis, of reactive onset or exacerbation fibromyalgia.

: Acute : Optic neuritis, : No association : Anaphylaxis in : Anaphylaxis Strength of Evidence Strength EPC Conclusions and High Insufficient disseminated transverse encephalomyelitis, MS, GBS, chronic myelitis, inflammatory demyelinating palsy, Bells’ polyneuropathy, and autoimmune anaphylaxis, hepatitis Insufficient GBS, event, first demyelinating of SLE, onset or exacerbation nodosa, polyarteritis vasculitis, of and onset or exacerbation rheumatoid arthritis Moderate with MS onset or exacerbation Moderate to yeast patients allergic Table D. Summary: safety of vaccines used for routine immunization of adults (including pregnant women) and children immunization of adults (including pregnant D. Summary: safety of vaccines used for routine Table Vaccine Adults Diphtheria Toxoid, and Toxoid, Tetanus Acellular Pertussis Tdap) (Td, Vaccines

9

Additional Findings From EPC Findings From Additional Many clinical trials reported that influenza vaccines clinical trials reported that influenza Many malaise, are associated with arthralgia, myalgia, AEs These and pain in the short term in adults. fever, graded mild was not considered serious; severity were were these events to moderate. Odds of experiencing patients than in 1.5 to 2 times higher in vaccinated not discussed people. Risk factors were unvaccinated in the trials. found an association A high-quality meta-analysis and GBS in H1N1 vaccine 2009 monovalent between results translate to about postvaccination; the 42 days cases per million vaccinated. 1.6 excess found inconsistent studies have Postlicensure vaccines with onset or associating influenza evidence of MS in adults. exacerbation found influenza studies have Postlicensure associated with increased risk are NOT vaccines in the events or cerebrovascular of cardiovascular elderly. that influenza shown studies have Postlicensure associated with increased risk of are NOT vaccines AEs in renal patients. serious associated with onset of type NOT MMR was high-quality 1 diabetes in adults large study: RR=0.71 (95% CI, 0.61 to epidemiological 0.83). ” a causal ” a causal ” of a causal relationship IOM Findings inadequate to accept or reject and children (continued) and children convincingly supports convincingly acceptance favors Two forms of were studied: live were studied: live vaccine forms of influenza Two (LAIV), and attenuated form, administered intranasally form (TIV), administered intramuscularly. inactivated Evidence “ vaccines and influenza relationship between or gelatin. to egg in people allergic anaphylaxis reduced manufacturers have in recent years, However, protein content. the egg Evidence “ with transient arthralgia in women. Evidence is “ relationship with MS onset, GBS, chronic arthralgia in and chronic arthritis in men. and arthropathy women,

: MS onset and : MS onset, GBS, : No association : Transient arthralgia : Arthralgia, myalgia, H1N1 : 2009 monovalent : No association with Strength of Evidence Strength EPC Conclusions and High pain at injection malaise, fever, in allergic Anaphylaxis site. persons. High with GBS vaccine High in the events cardiovascular elderly Insufficient exacerbation Moderate 1 diabetes Type with Moderate in women Insufficient chronic arthralgia in women, and chronic arthritis and in men arthropathy Table D. Summary: safety of vaccines used for routine immunization of adults (including pregnant women) immunization of adults (including pregnant D. Summary: safety of vaccines used for routine Table Vaccine Vaccines Influenza MMR Vaccine

10

Additional Findings From EPC Findings From Additional We found no placebo-controlled trials of the current We found trials AE data. (We formulation that reported of the current formulation that reported pneumonia or outcomes.) considered efficacy mortality; these were studies of pneumococcal polysaccharide Postlicensure not associated with was found vaccination vaccine in older adults. events increased risk of cardiovascular reported AEs were In some reports of clinical trials, such as “injection-related adverse in categories only or “serious events,” “systematic adverse events,” associated with was Vaccination events.” adverse injection site reactions. associated was In postlicensure studies, vaccination and allergic related to allergy with cellulitis possibly 1 to 7 days reactions such as redness and swelling AEs occurred in less than These mild postvaccination. in the younger more likely 1% of patients and were (aged 50-59) vaccinees. found no additional studies that met our inclusion We criteria. ” causal ” of a causal relationship IOM Findings inadequate to accept or reject and children (continued) and children favors rejection favors Not covered. AEs and older; adults 60 years Recommended for U.S. were not covered. specific to this age group Evidence “ tetanus containing diphtheria toxoid, vaccines between and acellular pertussis antigens and type 1 toxoid, diabetes. Evidence is “ and the following: vaccination relationships between infantile spasms, seizures, cerebellar ataxia, autism, MS relapse in children, myelitis, ADEM, transverse serum purpura, sickness, immune thrombocytopenic and SIDS.

: Infantile spasms, : Injection site : No association : No association Strength of Evidence Strength EPC Conclusions and High or with cardiovascular in the events cerebrovascular elderly Moderate reactions, reactions, allergic related to cellulitis possibly allergy Moderate with type 1 diabetes Insufficient seizures, cerebellar ataxia, autism, ADEM, transverse MS relapse, myelitis, serum sickness, immune purpura,thrombocytopenic and SIDS Table D. Summary: safety of vaccines used for routine immunization of adults (including pregnant women) immunization of adults (including pregnant D. Summary: safety of vaccines used for routine Table Vaccine Pneumococcal Polysaccharide Vaccine Adolescents and Children Diphtheria Toxoid, and Toxoid, Tetanus Acellular Pertussis- Containing Vaccines Tdap) Td, (DTap,

11

Additional Findings From EPC Findings From Additional Hep B vaccine in the first 6 months of life was in the first 6 months of life Hep B vaccine total IgE in a postlicensure associated with elevated historystudy of children with a family of food but not with clinical allergy. allergy, associated in 3 high-quality AEs were No serious clinical trials. was postlicensure study found HPV vaccine A large rheumatoid not associated with onset of juvenile This study reported arthritis or type 1 diabetes. an IRR of 1.29 (95% CI, 1.08 to 1.56) onset of a investigation disease. However, Hashimoto’s plausibility temporal relationship and biological of a safety signal. no consistent evidence revealed was postlicensure study found HPV vaccine A large syncope, associated with GBS, seizures, stroke, NOT thromboembolism. or venous clinical trials found HPV vaccination Several pain at injection associated with short-term severe associated with fever, also found vaccine Trials site. headache, nausea, and stomach ache. Black women including only A secondary analysis of receiving within 3 to 4 years became pregnant who in 2 trials reported a higher rate of HPV vaccine subjects. spontaneous abortion in vaccinated ” ” a ” causal favored acceptance favored ” of a causal relationship IOM Findings inadequate to accept or reject inadequate to accept or reject and children (continued) and children favors acceptance favors Not covered. Evidence “ and anaphylaxis. the HPV vaccine between Evidence is “ and the following: HPV vaccines relationships between optica, neuromyelitis myelitis, ADEM, transverse MS, GBS, chronic inflammatory demyelinating brachial neuritis, amyotrophic polyneuropathy, lateral sclerosis, transient arthralgia, pancreatitis, states. and hypercoagulable thromboembolic events, Although no epidemiological studies were identified by identified studies were Although no epidemiological “ the IOM, mechanistic evidence and the vaccine of a causal relationship between The IOM individuals. in yeast-sensitive anaphylaxis “ found evidence AEs. other causal relationship with any rejection” of a causal A 2002 IOM report “favors relationship with MS onset or exacerbation.

: ADEM, : Food allergy : Food : No association : No association : Anaphylaxis in : No association : Pain at injection site : Pain Strength of Evidence Strength EPC Conclusions and Moderate AEs in short term with serious Moderate rheumatoid with juvenile arthritis, type 1 diabetes, appendicitis, GBS, seizures, syncope, venous stroke, thromboembolism Moderate fever, persons with allergies, headache, mild gastrointestinal AEs, skin infection High Insufficient myelitis, transverse optica, MS, neuromyelitis disease, onset of Hashimoto’s chronic inflammatory polyneuropathy, demyelinating brachial neuritis, amyotrophic lateral sclerosis, transient arthralgia, pancreatitis, thromboembolic events, spontaneous abortion, and states hypercoagulable Insufficient Moderate with MS Table D. Summary: safety of vaccines used for routine immunization of adults (including pregnant women) immunization of adults (including pregnant D. Summary: safety of vaccines used for routine Table Vaccine HPV Vaccine Hepatitis B Vaccine

12

Additional Findings From EPC Findings From Additional One postlicensure study reported association between One postlicensure study reported association between to food and sensitivity in newborns polio vaccine allergens. vaccines In postlicensure studies, seasonal influenza serious adverse associated with any NOT were in the short term in children with malignancy, events cycle disorders, disease, or urea inflammatory bowel transplants. organ had received or children who vaccines and monovalent Both seasonal influenza associated with mild were H1N1 vaccine and disorders, such as vomiting gastrointestinal diarrhea, large in children the short term in several study found that postlicensure studies. One large were children (aged 5 to 8 years) vaccinated younger these symptoms than older to experience more likely (Children children (aged 9 to 17 years). vaccinated not included in that study). of age were under 5 years vaccines seasonal influenza and inactivated Both live symptoms in associated with influenza-like were children in the short term in multiple studies, while postlicensure U.S. A large not associated in others. TIV found study of children under age 5 years increased if associated with febrile seizures. Risk was administered concomitantly. PCV13 was ” a ” IOM Findings inadequate to accept or reject inadequate to accept or reject and children (continued) and children Not covered. The IOM committee studied seasonal influenza vaccine is administered in 2 The influenza vaccines. attenuated form, administered intranasally, forms: a live form, administered intramuscularly. and an inactivated “ Evidence was causal relationship in the pediatric population between seizures, vaccines and the following: seasonal influenza myelitis. ADEM, and transverse “ Evidence was LAIV and asthma a causal relationship between disease episodes. airway or reactive exacerbation

: Food allergy : Food : Asthma : Mild : No association with any : No association with any symptoms : Influenza-like Strength of Evidence Strength EPC Conclusions and Insufficient Moderate disorders, gastrointestinal febrile seizures Low AEs in the short term serious in children with or who transplants organ received have Low Insufficient (with live exacerbation ADEM, vaccine), transverse myelitis Table D. Summary: safety of vaccines used for routine immunization of adults (including pregnant women) immunization of adults (including pregnant D. Summary: safety of vaccines used for routine Table Vaccine Inactivated Polio Polio Vaccines Influenza

13

Additional Findings From EPC Findings From Additional Four additional postmarketing studies were identified. studies were additional postmarketing Four associated with thrombocytopenic was Vaccination purpura in the short was term. MMR vaccination department associated with increased emergency this is indirect support of the visits within 2 weeks; vaccine is associated with findings that MMR IOM’s febrile seizures. meningococcal trials of quadrivalent new Two found no association with any vaccines conjugate AEs assessed. ” a ” ” causal relationships ” a causal ” of a causal relationship ” of a causal relationship ” a causal relationship IOM Findings nadequate to accept or reject inadequate to accept or reject convincingly supports convincingly acceptance favors rejection favors supports convincingly and children (continued) and children convincingly supports convincingly Evidence “ Evidence with febrile seizures and anaphylaxis. “ with measles inclusion body encephalitis in immunocompromised patients. Evidence “ MMR and transient arthralgia between Evidence “ MMR and autism. between Evidence is “i causal relationship with encephalitis, encephalopathy, afebrile seizures, cerebellar ataxia, acute disseminated optic myelitis, transverse encephalomyelitis, optica, MS onset, and chronic neuritis, neuromyelitis arthropathy. Evidence “ be may in children who relationship with anaphylaxis to ingredients.allergic Evidence is “ causal relationships between encephalitis, (unspecified) and the following: MS, GBS, myelitis, ADEM, transverse encephalopathy, and chronic headache. CIDP,

: Encephalitis, : Encephalitis, : Transient : Transient arthralgia : Thrombocytopenic : Anaphylaxis in : No association with in children Anaphylaxis : Strength of Evidence Strength EPC Conclusions and High autism spectrum disorders High febrile seizures with allergies, Moderate Moderate purpura Insufficient afebrile encephalopathy, seizures, meningitis, cerebellar ataxia, acute disseminated transverse encephalomyelitis, optic neuritis, myelitis, optica, MS neuromyelitis onset, and chronic arthropathy Moderate children with allergies Insufficient ADEM, encephalopathy, MS, GBS, myelitis, transverse chronic headache CIDP, Table D. Summary: safety of vaccines used for routine immunization of adults (including pregnant women) immunization of adults (including pregnant D. Summary: safety of vaccines used for routine Table Vaccine MMR Vaccine Meningococcal (MCV4, Vaccines MPSV)

14

Additional Findings From EPC Findings From Additional Association of DTaP-IPV-Hib vaccination with vaccination Association of DTaP-IPV-Hib found in a very large febrile seizures in children was Rate for first dose high-quality postlicensure study. estimated as 5.5 cases per 100,000 person/days. was estimated as 5.7 cases per Rate for second dose was 100,000 person/days. assessed studies have epidemiological Multiple large and and polio vaccine Hib, Hep B, Td, MMR, DTaP, found no association with childhood leukemia. have 1.8 million postlicensure study of over In a large recipients, purpura associated with vaccine was A in children aged 7 to hepatitis against vaccination in children varicella against vaccination 17 years, aged 11 to 17, and MMR in children from 12 19 based on 1 or 2 These results were months of age. According to the type/age group. cases per vaccine mild and acute. authors most cases were Safety Datalink Vaccine A recent study using the U.S. (VSD) found an association with febrile seizures. Estimated rate for 16-month-old patients is 13.7 cases per 100,000 doses for PCV13 without concomitant TIV TIV and 44.9 per 100,000 doses for concomitant and PCV13. IOM Findings and children (continued) and children Not covered. Not covered.

: DTaP-IPV-Hib : DTaP-IPV-Hib A, MMR, : Hepatitis : No association of Strength of Evidence Strength EPC Conclusions and Moderate with febrile vaccination seizures High with childhood leukemia Hib, Hep B, Td, MMR, DTaP, and polio vaccines Moderate with vaccine and varicella purpura seizures Moderate: Febrile Table D. Summary: safety of vaccines used for routine immunization of adults (including pregnant women) immunization of adults (including pregnant D. Summary: safety of vaccines used for routine Table Vaccine Miscellaneous and Combination Vaccines Pneumococcal (PCV13) Conjugate

15

Additional Findings From EPC Findings From Additional In clinical trials, there was no association between no association between In clinical trials, there was (RotaTeq vaccines either of the 2 currently available AEs, including serious and Rotarix) any intussusception, in the long or short term Australia study in A high-quality epidemiological associated with intussusception was found RotaTeq the first of 3 required doses in following 1 to 21 days case-control studies Two infants 1 to 3 months of age. America found an association of conducted in Latin Rotarix with intussusception in children following U.S. Although 1 the first of 2 required doses. study found no association, a epidemiological Rapid Post-Licensure of the U.S. recent analysis Immunization Safety Monitoring (PRISM) program and Rotarix associated with found both RotaTeq intussusception in the short term. Estimated rate was and 5.1 1.1 to 1.5 cases per 100,000 doses of RotaTeq cases per 100,000 doses of Rotarix. IOM Findings and children (continued) and children Not covered.

: Intussusception Strength of Evidence Strength EPC Conclusions and Moderate Table D. Summary: safety of vaccines used for routine immunization of adults (including pregnant women) immunization of adults (including pregnant D. Summary: safety of vaccines used for routine Table Vaccine Rotavirus Vaccines: Vaccines: Rotavirus and RotaTeq Rotarix

16

Additional Findings From EPC Findings From Additional We identified 1 small trial in children with SLE; the We AEs. trial reported no association with and seasonal H1N1 vaccine Both monovalent containing H1N1 vaccine (inactivated) influenza not associated with serious adverse strains were in or their offspring women in pregnant events multiple trials and postlicensure studies. Studies risk of adverse report an association with lower outcomes. pregnancy ” a ” causal relationships IOM Findings inadequate to accept or reject convincingly supports convincingly and children (continued) and children Evidence “ and the following: vaccine varicella between VZV without other organ disseminated Oka VZV with subsequent disseminated Oka involvement; infection resulting in pneumonia, meningitis, with demonstrated or hepatitis in individuals vaccine strain viral reactivation immunodeficiencies; strain viral vaccine involvement; without other organ with subsequent infection resulting in reactivation meningitis or encephalitis; and anaphylaxis. is “ The evidence women. Results not specific to pregnant causal relationship between the vaccine and seizures, the vaccine causal relationship between GBS, small fiber myelitis, ADEM, transverse and of arthropathy, onset or exacerbation neuropathy, thrombocytopenia.

Seizures, ADEM, : No association : Anaphylaxis; : Anaphylaxis; Strength of Evidence Strength EPC Conclusions and High disseminated Oka VZV without other organ disseminated Oka involvement; VZV with subsequent infection resulting in pneumonia, meningitis, or hepatitis in with demonstrated individuals vaccine immunodeficiencies; without strain viral reactivation involvement; other organ strain viral reactivation vaccine with subsequent infection resulting in meningitis or encephalitis Insufficient: GBS, myelitis, transverse onset small fiber neuropathy, of arthropathy, or exacerbation thrombocytopenia Moderate events with serious adverse Table D. Summary: safety of vaccines used for routine immunization of adults (including pregnant women) immunization of adults (including pregnant D. Summary: safety of vaccines used for routine Table Vaccine Varicella Women Pregnant Vaccines Influenza polyneuropathy; CIDP = chronic inflammatory CI = confidence interval; demyelinating event; AE = adverse ADEM = acute disseminated encephalomyelitis; EPC = Evidence-based Practice Center; GBS Guillain-Barré = diphtheria, tetanus, and pertussis vaccine; syndrome; Hep B = hepatitis B; Hib Haemophilus DTaP vaccine; attenuated influenza E; IOM = Institute of Medicine; LAIV live IgE = immunoglobulin influenzae type B; HPV = human papillomavirus; Td = tetanus- MS = multiple sclerosis; SIDS sudden infantMMR = measles, mumps, rubella death syndrome; SLE = systemic lupus erythematosus; vaccine; vaccine; vaccine; IRR = incidence rate ratio; MCV meningococcal conjugate polio vaccine; IPV = inactivated influenza TIV = trivalent diphtheria; Tdap = tetanus, diphtheria, and acellular pertussis risk; RR = relative vaccine; PCV = pneumococcal conjugate vaccine; MPSV = meningococcal polysaccharide virus. VZV = varicella-zoster vaccine;

17 Discussion associated with serious conditions much as multiple sclerosis (MS), transverse myelitis, and acute disseminated In 2011, the IOM released “Adverse Effects of Vaccines: encephalomyelitis (ADEM). This leaves an important Evidence and Causality.” At the request of AHRQ and research gap. OASH, we assessed the additional evidence on the We identified a recent secondary analysis of data on safety of vaccines recommended for routine use among Black women who participated in two placebo-controlled adults, children, and pregnant women as of 2011. We trials of quadrivalent HPV vaccine () conducted conducted an extensive literature search for clinical trials in several countries. In women who became pregnant in and observational studies with strong study designs and the 4 years following the trial, there was a significantly analysis methods: cohort studies comparing vaccinated and higher rate of spontaneous abortion for women who were unvaccinated groups, case-control studies, self-controlled vaccinated.23 The authors state that the rate of “fetal loss” case series, and designs using multivariate risk factor was statistically similar for vaccinees and nonvaccinees; analyses. Our results support most findings of the IOM however, “fetal loss” included planned abortion. In report, add conclusions on some adverse events for which the vaccine group, 19 of 307 resulted in new evidence was identified, and include findings on spontaneous abortion, compared with 7 of 393 pregnancies additional vaccines. in the control group. Databases such as the Vaccine Safety Our findings may allay some patient, caregiver, and health Datalink (VSD) could be used to further investigate this care provider concerns. Strength of evidence is high signal in a much larger population. that vaccines against pneumonia and influenza are not Conclusions must be viewed in light of the important associated with cardiovascular or cerebrovascular events caveats below. in the elderly; many studies reported a decreased risk for vaccinated patients. Strength of evidence is high that Literature search procedures were extensive; however, MMR vaccine is not associated with the onset of autism in some unpublished trial results may not have been identified. children; this conclusion supports findings of all previous An independent Scientific Resource Center under contract reviews on the topic. There is moderate-strength evidence with AHRQ requested Scientific Information Packets from that HPV vaccine is not associated with appendicitis, vaccine manufacturers. (The research team was prohibited stroke, seizures, syncope, venous thromboembolism, onset from contacting manufacturers directly.) Only two of juvenile arthritis, or onset of type 1 diabetes and high- companies responded. strength evidence that MMR, DTaP (diphtheria, tetanus, We included trials of the formulations currently on the and pertussis), Td (tetanus-diphtheria), Hib (Haemophilus market in the United States. We tried to exclude Phase II influenzae type B), and hepatitis B vaccines are not studies that used dosages that were never licensed and/ associated with childhood leukemia. or formulations available only in foreign countries. Some Evidence of association with vaccines was found for studies reported the potency or formulation of the vaccines several serious AEs; however, these events were extremely in a different manner or unit than reported in the product rare. Absolute risk is extremely rare. Strength of evidence materials. Large epidemiological studies sometimes is high that 2009 monovalent H1N1 influenza vaccine included any available formulation of vaccines against a was associated with Guillain-Barré syndrome (GBS), but particular disease and did not stratify results by dosage results translate to about 1.6 additional cases per million or formulation. For example, the relationship between the persons vaccinated. Since 2010, U.S. seasonal influenza “seasonal influenza vaccine” and an AE could be studied vaccines have contained an H1N1 strain. No association over several years of data without addressing the changes in with GBS has been found for inactivated seasonal vaccine formulation over the seasons. (TIV). Strength of evidence is moderate for association Our findings are based on only the most rigorous study of vaccines against rotavirus with intussusception. designs to assess potential statistical associations; however, Although one U.S. epidemiological study found no these designs have limitations that must be considered. association, a recent analysis of the U.S. Post-Licensure Controlled trials often have insufficient sample size Rapid Immunization Safety Monitoring (PRISM) to identify very rare AEs and do not have extended 22 program found both RotaTeq and Rotarix associated with followup to identify long-term sequelae. In addition, intussusception in the short term. Estimated rate was 1.1 to trials may purposely exclude subjects such as the elderly, 1.5 cases per 100,000 doses of RotaTeq and 5.1 cases per pregnant women, and people with medical conditions 100,000 doses of Rotarix. who could be more susceptible to AEs. For this reason, Evidence is insufficient to make conclusions regarding any comprehensive review of vaccine safety also includes whether several routinely recommended vaccines are postlicensure studies, but these are not without limitations.

18 People who avoid (whether purposely or or provide enough information for our investigators to not) may differ from those who receive vaccinations determine severity. Future studies of vaccines should report in terms of race, sex, age, socioeconomic status, and results with more granularity. preexisting medical conditions, and these differences may Children and Adolescents be associated with health outcomes. Observational studies attempt to control for such potential confounders by using There is insufficient evidence to determine any matched cohorts or multivariate regression analysis; still, potential association between trivalent inactivated some factors such as environmental exposures may be vaccine and asthma exacerbation, acute disseminated unmeasured or challenging to adequately control for. The encephalomyelitis, and transverse myelitis. self-controlled case series was developed specifically Febrile seizures were associated with MMR, influenza, to assess the safety of vaccines; this method eliminates and pneumococcal conjugate vaccines. Younger age was confounding by all time-independent variables by using associated with increased risk in several studies. Large- cases as their own controls and predefined “time windows” scale epidemiological studies could determine other patient before and after vaccination. This design has been used to risk factors. study purpura, febrile seizures, intussusception, and autism in children. The SCCS assumption of no temporal shifts A large U.S. postlicensure study found associations is difficult to justify in very young children, as any patient between both Rotarix and RotaTeq and intussusception in characteristics that change with time will not be adequately the short term following vaccination; patient risk factors controlled for. were not reported. There may be important AE signals not identified in this Strong evidence for a lack of association of HPV report that warrant future research. Passive surveillance vaccines with several serious medical conditions (juvenile systems such as the U.S. Vaccine Adverse Event Reporting rheumatoid arthritis, type 1 diabetes, GBS) has been found System16 are crucial in identifying signals regarding in large postlicensure studies. However, there is insufficient AEs postlicensure, but they are not designed to assess a evidence regarding other serious conditions such as MS, statistical association so were excluded from this project. chronic inflammatory demyelinating polyneuropathy, The research gaps below are based on the study designs amyotrophic lateral sclerosis, and pancreatitis. Importantly, that met our inclusion criteria. a recent analysis of long-term followup data from Black women enrolled in two trials of Gardasil showed a possible Research Gaps increased risk of miscarriage of pregnancies within 4 years of vaccination. Large datasets from U.S. managed Adults care organizations include medical records on both There was insufficient evidence to determine whether immunization and pregnancy, so they could be used to influenza vaccines are associated with onset or investigate any potential association. exacerbation of MS. There is insufficient evidence to determine the possible The unknown association regarding MS and GBS and association, if any, between vaccines such as DTaP, vaccines for MMR and hepatitis A also presents a research meningococcal vaccine, and varicella vaccine and the onset gap; the IOM found evidence inadequate to accept or reject of conditions such as ADEM, transverse a causal relationship. As these medical conditions are myelitis, MS, and GBS. Large-scale epidemiological extremely rare, “insufficient” evidence determination may studies could provide additional data; however, as these be unavoidable despite additional research. medical conditions are extremely rare, it may not be possible to reach a level of evidence beyond “insufficient.” A recent meta-analysis on 2009 monovalent H1N1 vaccine provided high-strength evidence of association with GBS Pregnant Women in adults. As the vaccine is associated with only 1.6 excess There is moderate strength of evidence that inactivated cases per million vaccinated, it will be very difficult to influenza vaccine is not associated with serious adverse assess risk factors. events in pregnant women or their offspring. Given the Some published vaccine trials were not specific in reporting 2013 recommendation to administer the Tdap vaccine AEs. Broad categories such as “injection-related adverse during every pregnancy, passive surveillance systems events,” “systemic adverse events,” “one or more adverse should be monitored regularly for AEs in this population. events,” or “serious adverse events” were reported rather A reliable system of tracking when in pregnancy the than specific AEs. In addition, many studies reported vaccine was given is extremely important. In addition, in on a list of predefined AEs but did not rate the severity any study of vaccines and pregnancy, followup of newborns

19 should be sufficiently long, as not all adverse effects may Independent abstraction and systematic reassessment of be apparent immediately after birth. The need for large the studies included in the IOM consensus report “Adverse numbers of pregnant exposures is particularly important Effects of Vaccines: Evidence and Causality” may be a given the relatively low frequency of some birth defects useful future endeavor. Odds ratios could be calculated and the need to define which are associated with vaccine. for each event reported in each trial and postlicensure In addition, little is known about the patient factors that study and, where appropriate, meta-analysis conducted to may influence the effect of the vaccine. Another unknown calculate overall odds ratios for each AE and each vaccine is how vaccination in pregnancy may affect the newborn’s type. If the additional studies were abstracted, the totality /reaction to newborn vaccinations. The of data abstracted could be statistically analyzed to explore Vaccines and Medications in Pregnancy Surveillance additional hypotheses and issues beyond the scope of the System (VAMPSS) has components to monitor safety current report. of maternally administered vaccines and their effect on recipients and their offspring. VAMPSS is a collaboration References of the American Academy of Allergy, Asthma & 1. Ten great public health achievements--United States, ; the Organization of Teratology Information 1900-1999. MMWR Morb Mortal Wkly Rep. 1999 Apr Specialists (OTIS) Research Center at the University of 2;48(12):241-3. PMID: 10220250. San Diego; and the Slone Center 2. National, state, and local area vaccination coverage among (SEC) at Boston University. The U.S. Department of Health children aged 19-35 months - United States, 2011. MMWR and Human Services Biomedical Advanced Research and Morb Mortal Wkly Rep. 2012 Sep 7;61:689-96. PMID: Development Authority contracted VAMPSS to perform 22951450. safety monitoring of H1N1 influenza vaccine administered 3. National and state vaccination coverage among adolescents during the 2009 pandemic. As this report was being aged 13-17 years - United States, 2011. MMWR Morb finalized, a VAMPSS study on the safety of H1N1 was Mortal Wkly Rep. 2012 Aug 31;61:671-7. PMID: 22932301. released;24,25 the authors found no meaningful evidence 4. Adult vaccination coverage--United States, 2010. MMWR of increased risk of major birth defects, miscarriage, or low Morb Mortal Wkly Rep. 2012 Feb 3;61(4):66-72. PMID: birth weight for gestational age. Existing Federal systems 22298302. such as the VSD and/or PRISM could potentially be used as well. 5. Influenza vaccination coverage among pregnant women- -United States, 2010-11 influenza season. MMWR Morb General Methodological Observations Mortal Wkly Rep. 2011 Aug 19;60(32):1078-82. PMID: 21849964. Advanced health information technology systems that contain both vaccination and health outcome records can be 6. Wakefield AJ, Murch SH, Anthony A, et al. Ileal-lymphoid- nodular hyperplasia, non-specific colitis, and pervasive used to conduct high-quality epidemiological studies. In the developmental disorder in children. Lancet. 1998 Feb United States, the VSD contains data obtained through such 28;351(9103):637-41. PMID: 9500320. systems at nine very large managed care organizations. The 7. Retraction--Ileal-lymphoid-nodular hyperplasia, non-specific FDA’s Mini-Sentinel program PRISM system also conducts colitis, and pervasive developmental disorder in children. active surveillance using electronic health care databases Lancet. 2010 Feb 6;375(9713):445. PMID: 20137807. from managed care organizations. Nations with single- payer health care systems often have electronic registries 8. Freed GL, Clark SJ, Hibbs BF, et al. Parental vaccine safety concerns. The experiences of pediatricians and family that allow very large epidemiological studies of entire physicians. Am J Prev Med. 2004 Jan;26(1):11-4. PMID: populations. Studies using these databases have greater 14700706. validity than studies that rely on surveys that use patient/ 9. Advisory Committee on Immunization Practices. parent recall for ascertainment of vaccination or health Recommended adult immunization schedule: United States, outcome. Not only are such surveys subject to recall bias, 2011. Ann Intern Med. 2011;154(154):168-73. but there may be no way of determining the formulation or brand of vaccination. 10. Centers for Disease Control and Prevention. ACIP Recommendations Advisory Committee for Immunization Observational studies should be powered adequately to Practices (ACIP). www.cdc.gov/vaccines/pubs/acip-list.htm. determine risk factors such as demographic and health Accessed April 2012. characteristics of patients. Analysis should be stratified 11. Centers for Disease Control and Prevention. Guidelines for by formulation and brand of vaccine, if possible. This is Vaccinating Pregnant Women. www.cdc.gov/vaccines/pubs/ especially true for influenza vaccine, which differs from preg-guide.htm. Accessed April 2012. season to season.

20 12. Institute of Medicine. Adverse Effects of Vaccines: Evidence 25. Chambers CD, Johnson D, Xu R, et al. Risks and safety of and Causality. Washington, DC: The National Academy pandemic h1n1 influenza vaccine in pregnancy: birth defects, Press; 2011. spontaneous abortion, preterm delivery, and small for gestational age infants. Vaccine. 2013 Oct 17;31(44):5026- 13. Higgins JPT, Green S, eds. Cochrane Handbook for 32. PMID: 24016809. Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration; 2011. Addendum www.cochrane-handbook.org. 14. Mann CJ. Observational research methods. Research design This evidence report summarizes scientific data on the II: cohort, cross sectional, and case-control studies. Emerg safety of vaccines currently recommended in the United Med J. 2003 Jan;20(1):54-60. PMID: 12533370. States. High strength of evidence was found for an 15. Whitaker HJ, Farrington CP, Spiessens B, et al. Tutorial in association of measles-mumps-rubella (MMR) vaccine biostatistics: the self-controlled case series method. Stat with febrile seizures in children under age 5 (Key Question Med. 2006 May 30;25(10):1768-97. PMID: 16220518. 2c). On May 19, 2014 (while this evidence report was 16. Haber P, Iskander J, Walton K, et al. Internet-based reporting in press), an important study investigating the timing of to the Vaccine Adverse Event Reporting System: a more MMR and MMRV (measles-mumps-rubella-varicella) timely and complete way for providers to support vaccine vaccine and risk of febrile seizures1 was published. We felt safety. Pediatrics. 2011 May;127(Suppl 1):S39-S44. this information warranted inclusion in this review of the PMID: 21502243. evidence. 17. Institute of Medicine. The Childhood Immunization Schedule and Safety: Stakeholder Concerns, Scientific Researchers conducted a self-controlled case series analysis Evidence, and Future Studies. Washington, DC: The using records from over 300,000 U.S. children from the National Academies Press; 2013.. (VSD). They found timing was unrelated to risk of post-vaccination seizure in infants, but 18. National Institutes of Health, National Cancer Institute. Common Terminology Criteria for Adverse Events found that delaying measles containing vaccines past 15 (CTCAE). Version 4.0. May 28, 2009. months results in a higher risk of seizures. 19. Santaguida PL, Raina P. The Development of the McHarm According to the study’s authors, these adverse events are Quality Assessment Scale for Adverse Events: Delphi very rare, and occurred at the rate of about 1 per 100,000 Consensus on Important Criteria for Evaluating Harms. person-days at seven months of age, compared to a high of 2008. http://hiru.mcmaster.ca/epc/mcharm.pdf. Downloaded five per 100,000 person-days at 17 months of age. December 2008. Reference 20 Owens DK, Lohr KN, Atkins D, et al. AHRQ series paper 5: grading the strength of a body of evidence when comparing 1. Hambidge S J, Newcomer SR, Narwaney KJ, et al. Timely medical interventions--Agency for Healthcare Research versus delayed early childhood vaccination and seizures. and Quality and the effective health-care program. J Clin Pediatrics. 2014 Jun;133(6):e1492-e1499. PMID: 24843064. Epidemiol. 2010 May;63(5):513-23. PMID: 19595577. Full Report 21. Balshem H, Helfand M, Schunemann HJ, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol. 2011 Apr;64(4):401-6. PMID: 21208779. This executive summary is part of the following document: Maglione MA, Gidengil C, Das L, Raaen L, Smith A, Chari 22. Yih K, Lieu T, Kulldorff M, et al. Intussusception Risk R, Newberry S, Hempel S, Shanman R, Perry T, Goetz After Rotavirus Vaccination in U.S. Infants. Mini-Sentinel MB. Safety of Vaccines Used for Routine Immunization in Coordinating Center; June 2013. www.mini-sentinel.org/ work_products/PRISM/Mini-Sentinel_PRISM_Rotavirus- the United States. Evidence Report/Technology Assessment and-intussusception-Report.pdf. Accessed June 2013. No. 215. (Prepared by the Southern California Evidence- based Practice Center under Contract No. 290-2007-10062- 23. Clark LR, Myers ER, Huh W, et al. Clinical trial experience I.) AHRQ Publication No. 14-E002-EF. Rockville, MD: with prophylactic human papillomavirus 6/11/16/18 vaccine in young black women. J Adolesc Health. Agency for Healthcare Research and Quality; July 2014. 2013 Mar;52(3):322-9. PMID: 23299013. www.effectivehealthcare.ahrq.gov/reports/final.cfm. DOI: https://doi.org/10.23970/AHRQEPCERTA215. 24. Louik C, Ahrens K, Kerr S, et al. Risks and safety of pandemic H1N1 influenza vaccine in pregnancy: exposure prevalence, preterm delivery, and specific birth defects. Vaccine. 2013 Oct 17;31(44):5033-40. PMID: 24016804.

AHRQ Pub. No. 14-E002-1-EF July 2014 22