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Multiple vaccinations and the risk of medically attended fever
Vaccine 28 (2010) 4169–4174
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Vaccine journal homepage: www.elsevier.com/locate/vaccine
Multiple vaccinations and the risk of medically attended fever夽 Nancy D. Lin a,b , Ken Kleinman a , K. Arnold Chan c , Stephen Soumerai a , Jyotsna Mehta a , John P. Mullooly e , David K. Shay f,1 , Margarette Kolczak f,2 , Tracy A. Lieu a,d,∗ , for the Vaccine Safety Datalink Team a
Department of Population Medicine, Harvard Pilgrim Health Care Institute and Harvard Medical School, Boston, MA, United States Center for Health Policy/Center for Primary Care and Outcomes Research, Stanford University, Stanford, CA, United States Harvard School of Public Health, Boston, MA, United States d Division of General Pediatrics, Children’s Hospital, Boston, MA, United States e Center for Health Research, Kaiser Permanente Northwest, Portland, OR, United States f Immunization Safety Office, Centers for Disease Control and Prevention, Atlanta, GA, United States b c
a r t i c l e
i n f o
Article history: Received 4 December 2009 Received in revised form 30 March 2010 Accepted 5 April 2010 Available online 18 April 2010 Keywords: Vaccines Immunizations Safety Adverse events Fever
a b s t r a c t Recent increases in the number of vaccinations recommended for infants have triggered concerns about the safety of multiple vaccinations. This study evaluated rates of medically attended fever after infant vaccination using computerized data from 1991 to 2000 from two large U.S. provider groups. The rate of medically attended fever within 7 days after vaccination was low (6.4 per 1000 vaccination visits) and did not increase during the decade. Higher rates of fever occurred during periods when a third dose of oral polio vaccine was used (1994–1995) and when a now-discontinued oral rotavirus vaccine was used (1998–1999). These findings offer reassurance that the multiple vaccinations introduced during the decade studied were not associated with increases in medically attended fever. © 2010 Elsevier Ltd. All rights reserved.
1. Introduction Between 1991 and 2000, the number of vaccinations recommended for U.S. children during the first year of life increased substantially. A child born in 1991 received seven or eight recommended vaccinations during the first year of life [1,2], while a child born in 2000 could receive up to fifteen vaccinations [3]. Although an Institute of Medicine report found the evidence insufficient to indicate that multiple immunizations lead to adverse immune response, parents and physicians have continued to express concern about the safety of multiple simultaneous vaccinations [4–6]. Fever is a powerful source of anxiety among parents [7] and is the most frequently reported adverse event following immu-
夽 The findings and conclusions in this manuscript are those of the author(s) and do not necessarily represent the official position of the Centers for Disease Control and Prevention. ∗ Corresponding author at: Department of Population Medicine, Harvard Pilgrim Health Care Institute and Harvard Medical School, 133 Brookline Ave., 6th Floor, Boston, MA 02215, United States. Tel.: +1 617 509 9949; fax: +1 617 859 8112. E-mail address: tracy [email protected] (T.A. Lieu). 1 Dr. Shay is now with the Influenza Division, Centers for Disease Control and Prevention. 2 Dr. Kolczak is deceased. 0264-410X/$ – see front matter © 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2010.04.014
nization among infants recorded by the Vaccine Adverse Event Reporting System [8]. While randomized controlled trials of the safety and effectiveness of new vaccines routinely evaluate the rate of fever after specific vaccinations, scant information exists on how often fever after vaccination leads to medical visits in clinical practice. It is also unknown whether the addition of multiple simultaneous immunizations during the past 15 years has led to changes in the rate of post-vaccination fever. This study was designed to help clinicians and policymakers by addressing these gaps in knowledge. Our aims were to (1) evaluate rates of medically attended fever after vaccination in the populations of two large provider groups; and (2) analyze whether several changes in vaccine policy during the 1990s and early 2000s that increased the number of recommended vaccinations a child could receive were associated with increased risk of medically attended fever among children. 2. Methods 2.1. Study population The study included the membership of two large provider groups: Harvard Pilgrim Health Care/Harvard Vanguard Medical Associates (Boston, MA) and Kaiser Permanente Northwest
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(Portland, OR). These sites have electronic medical records and participate in the Centers for Disease Control and Prevention Vaccine Safety Datalink Project, in which individual-level vaccination, demographic, and medical data are shared to facilitate vaccine safety research [9–11]. We studied infants who were born between January 1, 1991 and December 31, 2000 in one provider group (Group A) or between April 1, 1997 and December 31, 2000 in the second provider group (Group B). During these time periods, data on temperature at outpatient visits were routinely recorded in the electronic medical record of each provider group. We restricted our study population to children who were continuously enrolled from birth, who received at least one recommended vaccination during the first year of life, and who did not have a record of congenital or severe perinatal conditions (ICD-9 CM codes 767–779) during the first month of life. These criteria were applied to ensure that the most complete immunization history was recorded in the provider group information systems, and to restrict the study population to children who were likely to be vaccinated according to the recommended childhood immunization schedule. The study protocol was approved by the Institutional Review Boards at the participating provider groups and the Centers for Disease Control and Prevention. 2.2. Definition of medically attended fever Medically attended fever was defined as a temperature of 38 degrees Celsius or higher (≥100.4 degrees Fahrenheit) [12,13] that was recorded at an outpatient visit to a clinical provider. We included medically attended fevers within seven days of vaccination, and excluded fevers recorded on the day of vaccination because we could not determine whether the recorded fever preceded or followed the administered immunization(s). Seven-day follow-up was complete for all vaccination visits included in the study. 2.3. Definition of immunization policy cohorts We conducted the analysis using the immunization (birth) cohort as the main exposure of interest because using individual children’s actual immunization status as the predictor would have introduced confounding, since children who miss vaccinations usually differ from those who do not. Children were assigned to a distinct immunization policy exposure cohort based on the timing of their birth relative to changes to the childhood immunization schedule. Between January 1991 and December 2000, six changes in immunization policy affected either the number of vaccinations or number of vaccine injections recommended during the first year of life: (1) introduction of universal hepatitis B vaccination recommendations for all infants at the end of 1991 (“HB policy”) [14]; (2) the publication of a unified immunization schedule in January 1995 in which administration of the third dose of oral polio vaccine was recommended between 6 and 18 months of age (“OPV3 policy”) [15]; (3) replacement of diphtheria and tetanus toxoids and whole cell pertussis vaccine (DTwP) with an acellular pertussis formulation (DTaP) in October 1996 [16]; (4) replacement of oral polio vaccine (OPV) with inactivated (injected) polio vaccine (IPV) in February 1997 [17]; (5) temporary approval of oral rotavirus vaccine between August 1998 [18] and October 1999 [19] (“RV policy”); and (6) introduction of pneumococcal conjugate vaccine in February 2000 [3,20] (“PCV policy”) (Table 1). For each immunization policy change, three time points were identified empirically: the calendar quarter during which the new policy was introduced; the first calendar quarter during which 20% or more of the birth cohort adhered to the new policy; and the calendar quarter preceding the next change in immunization policy.
Table 1 Changes in the recommended childhood immunization schedule, 1991–2000. Year
Policy statement/action
1991 1991
Addition of Haemophilus influenzae type B vaccine Addition of universal hepatitis B vaccination recommendations Unified immunization schedule developed by the Advisory Committee on Immunization Practices, American Academy of Pediatrics, and American Academy of Family Practitioners Diphtheria and tetanus toxoids and acellular pertussis vaccine recommended in place of diphtheria and tetanus toxoids and whole cell pertussis vaccine Inactivated (injected) polio vaccine recommended for first 2 polio vaccinations, followed by oral polio vaccine for remaining doses Addition of oral rotavirus vaccine Withdrawal of oral rotavirus vaccine Temporary suspension of the birth dose of hepatitis B vaccine Addition of pneumococcal conjugate vaccine
1995
1996
1997
1998 1999
2000
The introduction of an immunization policy change was identified based on the earliest of three events: publication of a change to the national immunization recommendations; implementation of the new policy based on historical information from clinicians in the provider groups, when available; or the first appearance in the computerized data of the new vaccine or shift in vaccine timing. Time periods following introduction of each new policy up to the calendar quarter at which 20% or more of the birth cohort complied with the new policy were considered to be “transition periods” and were excluded from the analysis. Because recommendations to replace DTwP with DTaP and to replace OPV with IPV occurred in close succession, these two policies were considered jointly (“DTaP/IPV replacement”). In addition, rotavirus vaccine was never made available to the membership of Group B; therefore, a rotavirus policy period was not identified for this group. Finally, for both provider groups, we excluded the time period between September 1999 and January 2000, a span of time following the temporary suspension of the hepatitis B birth dose recommendations due to concerns about thimerosal in vaccines [21,22] when children might have experienced lingering disruptions in immunization scheduling. Fig. 1 delineates the transition and policy period cohorts for Groups A and B. 2.4. Statistical analysis All eligible infants were followed from birth and censored at the earlier of two time points: disenrollment from the provider group or their 1-year birthday. Most infants had several immunization visits during the 1-year observation period, and outcomes for the same infant were likely to be correlated. Odds ratios and 95% confidence intervals were calculated from logistic regression models, using generalized estimating equations (GEE) to account for potential correlation among observations for a given individual [23,24]. Multivariate models were adjusted for season of vaccination and age at vaccination. Season of vaccination was modeled using the sine and cosine function of the calendar month during which the vaccination visit occurred. Age at vaccination was characterized using six categories based on the approximate timing for recommended childhood immunization visits: birth or 1 month (0–<6 weeks), 2 months (6 weeks–3.5 months), 4 months (3.5–5.5 months), 6 months (5.5–7.5 months), 8 months (7.5–9.5 months), and 10 months (>9.5 months). Analyses were stratified by provider group because the two groups were likely to have differing baseline health care utiliza-
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Fig. 1. Immunization policy periods observed in Provider Groups A and B. The label for each policy period refers to the change in childhood immunization that occurred during that time period. “Pre-HB” refers to the time period during which only the DTwP, Hib, and OPV vaccinations were included in the national recommended childhood immunization schedule. “HB” refers to the addition of universal hepatitis B vaccination recommendations for all infants. “OPV3” refers to recommendations to administer a third dose of OPV between 6 and 18 months of age. “DTaP/IPV” refers to the replacement of DTwP with DTaP vaccine and replacement of OPV with IPV. “RV” refers to the introduction of rotavirus vaccine. “PCV” refers to the introduction of pneumococcal conjugate vaccine. Each dark area represents a transition period or the period when the hepatitis B birth dose was suspended. The study population for Provider Group B is restricted to birth cohorts born between April 1997 and December 2000, to correspond to the period of time during which information on the outcome, medically attended fever, was available.
tion behaviors for fever, as well as differing adoption patterns and responses to changes in childhood immunization policy. We additionally evaluated whether the association between risk for fever and immunization policy period varied across different age groups at vaccination. For the primary analyses in Group A, the HB policy period was chosen as the reference period because the basic combination of vaccinations recommended during this period remained consistent through the end of the study period and using the longer HB policy period would provide more stable estimates. To provide a consistent comparison across the two provider groups, odds ratios and 95% CIs for medically attended fever were calculated separately comparing the PCV policy period to the DTaP/IPV period for each provider group. We also conducted analyses using interrupted time series methods, which treat time periods as the unit of analysis and are often used to evaluate the effects of policy changes [25–27], as a comparison to the GEE methodology. However, given the brevity of the policy periods and strong seasonal variation observed in fever rates, we found that these two methodological approaches were not comparable. We therefore present only results from the GEE methodology, which allows for adjustment for season of vaccination at the level of the individual immunization visit. All analyses were performed using SAS software, Version 8.2 of the SAS System for Windows (SAS Institute, Cary, NC).
3. Results
Fig. 2. Trends in the number of vaccinations and vaccination visits during the first year of life, Provider Group A. —: Median number of vaccinations received during first year of life. --: Median number of vaccination visits during first year of life. . . .: 25th and 75th percentiles. Children were grouped by the calendar quarter of their birth. “Pre-HB”: period during which only DTwP, Hib, and OPV vaccinations were recommended. “HB”: addition of universal hepatitis B vaccination recommendations. “OPV3”: third dose of OPV recommended between 6 and 18 months. “DTaP/IPV”: replacement of DTwP with DTaP vaccine and replacement of OPV with IPV. “RV”: introduction of rotavirus vaccine. “PCV”: introduction of pneumococcal conjugate vaccine.
number of immunizations simultaneously administered at a given visit.
3.1. Study population and trends in immunization practice Overall, 45,985 children met the study inclusion criteria and had a total of 192,930 vaccination visits. Exclusion of children born during the transition periods resulted in a population of 37,504 children with 158,518 vaccination visits. Fig. 2 illustrates how trends in immunization practices corresponded to changes in the recommended immunization schedule, using Group A as an example. The median number of vaccinations (including injections and oral vaccines) received by children in Group A during the first year of life increased from eight vaccinations (interquartile range (IQR): 8–8) among children born during the first quarter of 1991 to fourteen vaccinations (IQR: 12–15) following the introduction of PCV among children born during the second quarter of 2000. Between 1992 and 2000, the median number of visits in Group A stayed constant at five visits during the first 12 months of life. In Group B, the median number of vaccinations increased from 11 (IQR: 8–12) among children born during the second quarter of 1997 to 14 (IQR: 8–15) following the introduction of PCV, while the median number of vaccination visits during the first year of life remained at four visits throughout the study period. These findings suggest that additions to the childhood immunization schedule generally led to increases in the
3.2. Changes in multiple childhood immunization and risk for medically attended fever Overall, for every 1000 vaccination visits, 6.4 medically attended fevers were reported in the seven days following immunization. In Group A, unadjusted results indicated more fevers following vaccination during the OPV3, DTaP/IPV, and RV policy periods compared to the HB policy period (Table 2). We compared the policy periods while adjusting for season and age at vaccination (Table 3). In Group A, using the 1992–1993 hepatitis B policy period as the baseline, we observed an elevated but not statistically significant fever risk among children born during the DTaP/IPV period (OR = 1.22; 95% CI: 0.97–1.53) and the RV period (OR = 1.24; 95% CI: 0.94–1.62). Children were also at higher risk for medically attended fever in the OPV3 policy period (OR = 1.24, 95% CI: 1.05–1.46) compared to the HB policy period. In Group A, children born during the PCV period experienced similar risk for fever compared to the HB policy period (OR = 0.78, 95% CI: 0.50–1.23). Children born during the PCV period had no increase in the risk of medically attended fever compared with those born in the DTaP/IPV policy period. This finding held in both Group A (OR = 0.63, 95% CI: 0.38–1.04) and Group B (OR = 0.91, 95%
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Table 2 Rate of medically attended fever, unadjusted results. Site
Group A Group B
Rate of medically attended fever per 1000 vaccination visits during the given time period Pre-HB period
HB period
OPV3 period
DTaP/IPV period
RV period
PCV period
6.3
6.6
8.1
7.7 2.5
7.8
4.9 3.2
“Pre-HB”: period during which only DTwP, Hib, and OPV vaccinations were recommended. “HB”: addition of universal hepatitis B vaccination recommendations. “OPV3”: third dose of OPV recommended between 6 and 18 months. “DTaP/IPV”: replacement of DTwP with DTaP vaccine and replacement of OPV with IPV. “RV”: introduction of rotavirus vaccine. “PCV”: introduction of pneumococcal conjugate vaccine.
Table 3 Odds of medically attended fever after vaccination visits by infants aged 0–12 months during specific time periods from 1991 to 2000. Group
Policy period comparisons
OR
95% CI
Group A
Pre-HB period HB period (referent group) OPV3 period DTaP/IPV period RV period PCV period PCV period vs. DTaP/IPV period PCV period vs. DTaP/IPV period
0.84 1.00 1.24 1.22 1.24 0.78 0.63 0.91
(0.65, 1.08)
Group A Group B
(1.05, 1.46) (0.97, 1.53) (0.94, 1.62) (0.50, 1.23) (0.38, 1.04) (0.53, 1.56)
Based on generalized estimating equation models of 158,518 vaccination visits among 37,504 children, adjusted for seasonality and age at vaccination. “Pre-HB”: period during which only DTwP, Hib, and OPV vaccinations were recommended. “HB”: addition of universal hepatitis B vaccination recommendations. “OPV3”: third dose of OPV recommended between 6 and 18 months. “DTaP/IPV”: replacement of DTwP with DTaP vaccine and replacement of OPV with IPV. “RV”: introduction of rotavirus vaccine. “PCV”: introduction of pneumococcal conjugate vaccine.
CI: 0.53–1.56). 3.3. Stratification by age at vaccination Analyses stratified by age at vaccination identified a significant increase in risk for fever in Group A during the RV policy period at the 2-month (OR = 4.0; 95% CI: 1.9–8.6) and 4-month (OR = 1.8; 95%
CI: 1.1–3.1) immunization visits compared to the HB policy period (Fig. 3). A non-significant increase in risk for fever was also observed during the OPV3 period for all age strata. No significant differences or systematic patterns were observed for the other policy periods relative to the HB policy period. In both Groups A and B, children born in the PCV policy period experienced similar risk for fever compared with those born in the DTaP/IPV policy period. 4. Discussion This study indicates that medically attended fever following vaccination is rare. Our findings suggest that increases in the number of recommended vaccinations between 1991 and 2000 were not associated with corresponding increases in subsequent medical visits with fever among children. We did observe a significant excess risk for medically attended fever for 2- and 4-month olds during the time period of introduction of RotashieldTM , a now-discontinued form of oral rotavirus vaccine. This result was consistent with pre-licensure randomized controlled trials [18,28,29]. In contrast, no increase in fever has been noted in pre-licensure studies of RotateqTM or RotarixTM , the two currently recommended rotavirus vaccines [30]. We did not observe significant changes in the rates of medically attended fever after vaccination that coincided with any of the other time periods we studied. We observed a non-significant
Fig. 3. Time periods with different immunization policies and risk of medically attended fever, by recommended immunization visit, Provider Group A. Adjusted for seasonality. “Pre-HB”: period during which only DTwP, Hib, and OPV vaccinations were recommended. “HB”: addition of universal hepatitis B vaccination recommendations. “OPV3”: third dose of OPV recommended between 6 and 18 months. “DTaP/IPV”: replacement of DTwP with DTaP vaccine and replacement of OPV with IPV. “RV”: introduction of rotavirus vaccine. “PCV”: introduction of pneumococcal conjugate vaccine.
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decrease in rates of medically attended fever after PCV introduction, in contrast to pre-licensure studies which found an increase in fever after PCV vaccination [31]. The decrease we observed might be because our study was limited to a short time period during the early adoption of PCV. Alternatively, it might reflect a true effect. For example, physicians may have perceived that PCV would prevent invasive infections related to Streptococcus pneumoniae and be less likely to have parents bring a febrile child in for a visit and a potential fever work-up. Further study of fever after vaccines recommended subsequent to PCV7 introduction is warranted. For example, recent data suggest that the risk of febrile seizures is elevated after administration of measles–mumps–rubella–varicella (MMRV) vaccine, relative to measles–mumps–rubella and varicella vaccines administered separately on the same day [32]. This study is unique in using temperatures routinely recorded in the electronic medical record to collect information on fever. Historically, variation in the definition and identification of fever has made comparisons of vaccine safety difficult [12]. Using data from the electronic medical record, we were able to apply a standardized definition of fever at medical visits. Our methods provide an example of the research that is now becoming possible with the increasing adoption of electronic medical records. Our definition of fever has some limitations. Identifying cases of fever based on temperature taken at the office visit probably underestimates the true incidence of fever following vaccination. Children may have had fever that prompted a visit, but the fever may have resolved by the time of the visit [33]. In addition, the use of antipyretics reduces fever after vaccination [34], but we were not able to control for whether antipyretic medications such as Tylenol were given at the time of vaccination or recommended to be given at home to prevent fever or pain. Anecdotal reports suggest that such practices varied among the medical centers and clinicians in the provider groups in this study during the period we analyzed. This may explain why we did not observe a higher rate of visits for post-vaccination fever during the period when whole cell pertussis vaccine was routinely used. Another limitation is that we excluded fever recorded on the day of vaccination due to not being able to determine whether it occurred before or after the vaccination. This could have caused us to miss some fevers that began on the day of vaccination. This study evaluated whether rates of medically attended fever varied among children vaccinated during different time periods, and not whether administration of specific vaccinations to a given child affected that individual’s risk of medically attended fever. This approach has some limitations. National vaccine recommendations changed relatively rapidly during the 10 years evaluated, and the implementation of such policies in actual practice was also dynamic. In our preliminary analyses, we were able to use data from the provider groups in this study to empirically evaluate the percentage of infants who were receiving a new vaccine during each period, and we defined each vaccination policy as in use only after at least 20% of infants were being treated consistent with that policy. However, it is not possible to directly attribute observed changes in the rates of medically attended fever to specific immunization policies.
5. Conclusions Health care visits with documented fever after vaccination are rare, occurring in less than 1% of vaccination visits. Our findings provide reassurance that increases between 1991 and 2000 in the number of vaccines for routine use among children were not associated with increases in medically attended fever following vaccination in routine practice.
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Acknowledgements This study was supported by the Centers for Disease Control and Prevention, Atlanta, GA, via contract 200-2002-00732 (the Vaccine Safety Datalink Project) with America’s Health Insurance Plans. Dr. Lin’s effort was supported in part by the Agency for Healthcare Research and Quality, National Research Service Award, HS00002819. We gratefully acknowledge our colleagues at the Department of Population Medicine, especially Megan O’Brien, MPH, for local coordination of the VSD project, Richard Fox, MA, for his management of the automated analytic databases, Jonathan Finkelstein, MD, and Katherine Yih, PhD, for their thoughtful comments, and Richard Platt, MD, MPH, for his senior leadership of the project. We thank Ben Kruskal, MD, of Harvard Vanguard Medical Associates for providing useful historical context. Contributors: We appreciate the contributions of Karen Riedlinger, MPH, who prepared the analytic databases at Kaiser Permanente Northwest for this study. We appreciate the guidance of our other collaborators at the Centers for Disease Control and Prevention, including Robert Chen, MD, Robert Davis, MD, MPH, Frank DeStefano, MD, James Baggs, PhD, and Eric Weintraub, MPH. References [1] Hinman AR. Immunizations in the United States. Pediatrics 1990;86(December (6 Pt 2)):1064–6. [2] Haemophilus b conjugate vaccines for prevention of Haemophilus influenzae type b disease among infants and children two months of age and older. Recommendations of the immunization practices advisory committee (ACIP). MMWR Recomm Rep 1991;40(January (RR-1)):1–7. [3] Recommended childhood immunization schedule—United States, 2001. MMWR Morb Mortal Wkly Rep 2001;50(January (1)), 7–10, 19. [4] Poland GA, Jacobson RM. Understanding those who do not understand: a brief review of the anti-vaccine movement. Vaccine 2001;19(March (17–19)):2440–5. [5] Zimmerman RK, Schlesselman JJ, Baird AL, Mieczkowski TA. A national survey to understand why physicians defer childhood immunizations. Arch Pediatr Adolesc Med 1997;151(July (7)):657–64. [6] Gellin BG, Maibach EW, Marcuse EK. Do parents understand immunizations? A national telephone survey. Pediatrics 2000;106(November (5)):1097–102. [7] Crocetti M, Moghbeli N, Serwint J. Fever phobia revisited: have parental misconceptions about fever changed in 20 years? Pediatrics 2001;107(June (6)):1241–6. [8] Zhou W, Pool V, Iskander JK, English-Bullard R, Ball R, Wise RP, et al. Surveillance for safety after immunization: Vaccine Adverse Event Reporting System (VAERS)—United States, 1991–2001. MMWR Surveill Summ 2003;52(January (1)):1–24. [9] Chen RT, Glasser JW, Rhodes PH, Davis RL, Barlow WE, Thompson RS, et al. Vaccine Safety Datalink project: a new tool for improving vaccine safety monitoring in the United States. The Vaccine Safety Datalink Team. Pediatrics 1997;99(June (6)):765–73. [10] Chen RT, DeStefano F, Davis RL, Jackson LA, Thompson RS, Mullooly JP, et al. The Vaccine Safety Datalink: immunization research in health maintenance organizations in the USA. Bull World Health Organ 2000;78(2):186–94. [11] DeStefano F. The Vaccine Safety Datalink project. Pharmacoepidemiol Drug Saf 2001;10(August–September (5)):403–6. [12] Kohl KS, Marcy SM, Blum M, Connell Jones M, Dagan R, Hansen J, et al. Fever after immunization: current concepts and improved future scientific understanding. Clin Infect Dis 2004;39(August (3)):389–94. [13] Michael Marcy S, Kohl KS, Dagan R, Nalin D, Blum M, Jones MC, et al. Fever as an adverse event following immunization: case definition and guidelines of data collection, analysis, and presentation. Vaccine 2004;22(January (5–6)):551–6. [14] Hepatitis B virus: a comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination. Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR Recomm Rep 1991;40(November (RR-13)):1–25. [15] Recommended childhood immunization schedule—United States, 1995. Centers for Disease Control and Prevention. MMWR Recomm Rep 1995;44(June (RR-5)):1–9. [16] Pertussis vaccination: use of acellular pertussis vaccines among infants and young children. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 1997;46(March (RR-7)):1–25. [17] Poliomyelitis prevention in the United States: introduction of a sequential vaccination schedule of inactivated poliovirus vaccine followed by oral poliovirus vaccine. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 1997;46(January (RR-3)):1–25. [18] Rotavirus vaccine for the prevention of rotavirus gastroenteritis among children. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 1999;48(March (RR-2)):1–20.
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Multiple vaccinations and the risk of medically attended fever夽 Nancy D. Lin a,b , Ken Kleinman a , K. Arnold Chan c , Stephen Soumerai a , Jyotsna Mehta a , John P. Mullooly e , David K. Shay f,1 , Margarette Kolczak f,2 , Tracy A. Lieu a,d,∗ , for the Vaccine Safety Datalink Team a
Department of Population Medicine, Harvard Pilgrim Health Care Institute and Harvard Medical School, Boston, MA, United States Center for Health Policy/Center for Primary Care and Outcomes Research, Stanford University, Stanford, CA, United States Harvard School of Public Health, Boston, MA, United States d Division of General Pediatrics, Children’s Hospital, Boston, MA, United States e Center for Health Research, Kaiser Permanente Northwest, Portland, OR, United States f Immunization Safety Office, Centers for Disease Control and Prevention, Atlanta, GA, United States b c
a r t i c l e
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Article history: Received 4 December 2009 Received in revised form 30 March 2010 Accepted 5 April 2010 Available online 18 April 2010 Keywords: Vaccines Immunizations Safety Adverse events Fever
a b s t r a c t Recent increases in the number of vaccinations recommended for infants have triggered concerns about the safety of multiple vaccinations. This study evaluated rates of medically attended fever after infant vaccination using computerized data from 1991 to 2000 from two large U.S. provider groups. The rate of medically attended fever within 7 days after vaccination was low (6.4 per 1000 vaccination visits) and did not increase during the decade. Higher rates of fever occurred during periods when a third dose of oral polio vaccine was used (1994–1995) and when a now-discontinued oral rotavirus vaccine was used (1998–1999). These findings offer reassurance that the multiple vaccinations introduced during the decade studied were not associated with increases in medically attended fever. © 2010 Elsevier Ltd. All rights reserved.
1. Introduction Between 1991 and 2000, the number of vaccinations recommended for U.S. children during the first year of life increased substantially. A child born in 1991 received seven or eight recommended vaccinations during the first year of life [1,2], while a child born in 2000 could receive up to fifteen vaccinations [3]. Although an Institute of Medicine report found the evidence insufficient to indicate that multiple immunizations lead to adverse immune response, parents and physicians have continued to express concern about the safety of multiple simultaneous vaccinations [4–6]. Fever is a powerful source of anxiety among parents [7] and is the most frequently reported adverse event following immu-
夽 The findings and conclusions in this manuscript are those of the author(s) and do not necessarily represent the official position of the Centers for Disease Control and Prevention. ∗ Corresponding author at: Department of Population Medicine, Harvard Pilgrim Health Care Institute and Harvard Medical School, 133 Brookline Ave., 6th Floor, Boston, MA 02215, United States. Tel.: +1 617 509 9949; fax: +1 617 859 8112. E-mail address: tracy [email protected] (T.A. Lieu). 1 Dr. Shay is now with the Influenza Division, Centers for Disease Control and Prevention. 2 Dr. Kolczak is deceased. 0264-410X/$ – see front matter © 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2010.04.014
nization among infants recorded by the Vaccine Adverse Event Reporting System [8]. While randomized controlled trials of the safety and effectiveness of new vaccines routinely evaluate the rate of fever after specific vaccinations, scant information exists on how often fever after vaccination leads to medical visits in clinical practice. It is also unknown whether the addition of multiple simultaneous immunizations during the past 15 years has led to changes in the rate of post-vaccination fever. This study was designed to help clinicians and policymakers by addressing these gaps in knowledge. Our aims were to (1) evaluate rates of medically attended fever after vaccination in the populations of two large provider groups; and (2) analyze whether several changes in vaccine policy during the 1990s and early 2000s that increased the number of recommended vaccinations a child could receive were associated with increased risk of medically attended fever among children. 2. Methods 2.1. Study population The study included the membership of two large provider groups: Harvard Pilgrim Health Care/Harvard Vanguard Medical Associates (Boston, MA) and Kaiser Permanente Northwest
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(Portland, OR). These sites have electronic medical records and participate in the Centers for Disease Control and Prevention Vaccine Safety Datalink Project, in which individual-level vaccination, demographic, and medical data are shared to facilitate vaccine safety research [9–11]. We studied infants who were born between January 1, 1991 and December 31, 2000 in one provider group (Group A) or between April 1, 1997 and December 31, 2000 in the second provider group (Group B). During these time periods, data on temperature at outpatient visits were routinely recorded in the electronic medical record of each provider group. We restricted our study population to children who were continuously enrolled from birth, who received at least one recommended vaccination during the first year of life, and who did not have a record of congenital or severe perinatal conditions (ICD-9 CM codes 767–779) during the first month of life. These criteria were applied to ensure that the most complete immunization history was recorded in the provider group information systems, and to restrict the study population to children who were likely to be vaccinated according to the recommended childhood immunization schedule. The study protocol was approved by the Institutional Review Boards at the participating provider groups and the Centers for Disease Control and Prevention. 2.2. Definition of medically attended fever Medically attended fever was defined as a temperature of 38 degrees Celsius or higher (≥100.4 degrees Fahrenheit) [12,13] that was recorded at an outpatient visit to a clinical provider. We included medically attended fevers within seven days of vaccination, and excluded fevers recorded on the day of vaccination because we could not determine whether the recorded fever preceded or followed the administered immunization(s). Seven-day follow-up was complete for all vaccination visits included in the study. 2.3. Definition of immunization policy cohorts We conducted the analysis using the immunization (birth) cohort as the main exposure of interest because using individual children’s actual immunization status as the predictor would have introduced confounding, since children who miss vaccinations usually differ from those who do not. Children were assigned to a distinct immunization policy exposure cohort based on the timing of their birth relative to changes to the childhood immunization schedule. Between January 1991 and December 2000, six changes in immunization policy affected either the number of vaccinations or number of vaccine injections recommended during the first year of life: (1) introduction of universal hepatitis B vaccination recommendations for all infants at the end of 1991 (“HB policy”) [14]; (2) the publication of a unified immunization schedule in January 1995 in which administration of the third dose of oral polio vaccine was recommended between 6 and 18 months of age (“OPV3 policy”) [15]; (3) replacement of diphtheria and tetanus toxoids and whole cell pertussis vaccine (DTwP) with an acellular pertussis formulation (DTaP) in October 1996 [16]; (4) replacement of oral polio vaccine (OPV) with inactivated (injected) polio vaccine (IPV) in February 1997 [17]; (5) temporary approval of oral rotavirus vaccine between August 1998 [18] and October 1999 [19] (“RV policy”); and (6) introduction of pneumococcal conjugate vaccine in February 2000 [3,20] (“PCV policy”) (Table 1). For each immunization policy change, three time points were identified empirically: the calendar quarter during which the new policy was introduced; the first calendar quarter during which 20% or more of the birth cohort adhered to the new policy; and the calendar quarter preceding the next change in immunization policy.
Table 1 Changes in the recommended childhood immunization schedule, 1991–2000. Year
Policy statement/action
1991 1991
Addition of Haemophilus influenzae type B vaccine Addition of universal hepatitis B vaccination recommendations Unified immunization schedule developed by the Advisory Committee on Immunization Practices, American Academy of Pediatrics, and American Academy of Family Practitioners Diphtheria and tetanus toxoids and acellular pertussis vaccine recommended in place of diphtheria and tetanus toxoids and whole cell pertussis vaccine Inactivated (injected) polio vaccine recommended for first 2 polio vaccinations, followed by oral polio vaccine for remaining doses Addition of oral rotavirus vaccine Withdrawal of oral rotavirus vaccine Temporary suspension of the birth dose of hepatitis B vaccine Addition of pneumococcal conjugate vaccine
1995
1996
1997
1998 1999
2000
The introduction of an immunization policy change was identified based on the earliest of three events: publication of a change to the national immunization recommendations; implementation of the new policy based on historical information from clinicians in the provider groups, when available; or the first appearance in the computerized data of the new vaccine or shift in vaccine timing. Time periods following introduction of each new policy up to the calendar quarter at which 20% or more of the birth cohort complied with the new policy were considered to be “transition periods” and were excluded from the analysis. Because recommendations to replace DTwP with DTaP and to replace OPV with IPV occurred in close succession, these two policies were considered jointly (“DTaP/IPV replacement”). In addition, rotavirus vaccine was never made available to the membership of Group B; therefore, a rotavirus policy period was not identified for this group. Finally, for both provider groups, we excluded the time period between September 1999 and January 2000, a span of time following the temporary suspension of the hepatitis B birth dose recommendations due to concerns about thimerosal in vaccines [21,22] when children might have experienced lingering disruptions in immunization scheduling. Fig. 1 delineates the transition and policy period cohorts for Groups A and B. 2.4. Statistical analysis All eligible infants were followed from birth and censored at the earlier of two time points: disenrollment from the provider group or their 1-year birthday. Most infants had several immunization visits during the 1-year observation period, and outcomes for the same infant were likely to be correlated. Odds ratios and 95% confidence intervals were calculated from logistic regression models, using generalized estimating equations (GEE) to account for potential correlation among observations for a given individual [23,24]. Multivariate models were adjusted for season of vaccination and age at vaccination. Season of vaccination was modeled using the sine and cosine function of the calendar month during which the vaccination visit occurred. Age at vaccination was characterized using six categories based on the approximate timing for recommended childhood immunization visits: birth or 1 month (0–<6 weeks), 2 months (6 weeks–3.5 months), 4 months (3.5–5.5 months), 6 months (5.5–7.5 months), 8 months (7.5–9.5 months), and 10 months (>9.5 months). Analyses were stratified by provider group because the two groups were likely to have differing baseline health care utiliza-
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Fig. 1. Immunization policy periods observed in Provider Groups A and B. The label for each policy period refers to the change in childhood immunization that occurred during that time period. “Pre-HB” refers to the time period during which only the DTwP, Hib, and OPV vaccinations were included in the national recommended childhood immunization schedule. “HB” refers to the addition of universal hepatitis B vaccination recommendations for all infants. “OPV3” refers to recommendations to administer a third dose of OPV between 6 and 18 months of age. “DTaP/IPV” refers to the replacement of DTwP with DTaP vaccine and replacement of OPV with IPV. “RV” refers to the introduction of rotavirus vaccine. “PCV” refers to the introduction of pneumococcal conjugate vaccine. Each dark area represents a transition period or the period when the hepatitis B birth dose was suspended. The study population for Provider Group B is restricted to birth cohorts born between April 1997 and December 2000, to correspond to the period of time during which information on the outcome, medically attended fever, was available.
tion behaviors for fever, as well as differing adoption patterns and responses to changes in childhood immunization policy. We additionally evaluated whether the association between risk for fever and immunization policy period varied across different age groups at vaccination. For the primary analyses in Group A, the HB policy period was chosen as the reference period because the basic combination of vaccinations recommended during this period remained consistent through the end of the study period and using the longer HB policy period would provide more stable estimates. To provide a consistent comparison across the two provider groups, odds ratios and 95% CIs for medically attended fever were calculated separately comparing the PCV policy period to the DTaP/IPV period for each provider group. We also conducted analyses using interrupted time series methods, which treat time periods as the unit of analysis and are often used to evaluate the effects of policy changes [25–27], as a comparison to the GEE methodology. However, given the brevity of the policy periods and strong seasonal variation observed in fever rates, we found that these two methodological approaches were not comparable. We therefore present only results from the GEE methodology, which allows for adjustment for season of vaccination at the level of the individual immunization visit. All analyses were performed using SAS software, Version 8.2 of the SAS System for Windows (SAS Institute, Cary, NC).
3. Results
Fig. 2. Trends in the number of vaccinations and vaccination visits during the first year of life, Provider Group A. —: Median number of vaccinations received during first year of life. --: Median number of vaccination visits during first year of life. . . .: 25th and 75th percentiles. Children were grouped by the calendar quarter of their birth. “Pre-HB”: period during which only DTwP, Hib, and OPV vaccinations were recommended. “HB”: addition of universal hepatitis B vaccination recommendations. “OPV3”: third dose of OPV recommended between 6 and 18 months. “DTaP/IPV”: replacement of DTwP with DTaP vaccine and replacement of OPV with IPV. “RV”: introduction of rotavirus vaccine. “PCV”: introduction of pneumococcal conjugate vaccine.
number of immunizations simultaneously administered at a given visit.
3.1. Study population and trends in immunization practice Overall, 45,985 children met the study inclusion criteria and had a total of 192,930 vaccination visits. Exclusion of children born during the transition periods resulted in a population of 37,504 children with 158,518 vaccination visits. Fig. 2 illustrates how trends in immunization practices corresponded to changes in the recommended immunization schedule, using Group A as an example. The median number of vaccinations (including injections and oral vaccines) received by children in Group A during the first year of life increased from eight vaccinations (interquartile range (IQR): 8–8) among children born during the first quarter of 1991 to fourteen vaccinations (IQR: 12–15) following the introduction of PCV among children born during the second quarter of 2000. Between 1992 and 2000, the median number of visits in Group A stayed constant at five visits during the first 12 months of life. In Group B, the median number of vaccinations increased from 11 (IQR: 8–12) among children born during the second quarter of 1997 to 14 (IQR: 8–15) following the introduction of PCV, while the median number of vaccination visits during the first year of life remained at four visits throughout the study period. These findings suggest that additions to the childhood immunization schedule generally led to increases in the
3.2. Changes in multiple childhood immunization and risk for medically attended fever Overall, for every 1000 vaccination visits, 6.4 medically attended fevers were reported in the seven days following immunization. In Group A, unadjusted results indicated more fevers following vaccination during the OPV3, DTaP/IPV, and RV policy periods compared to the HB policy period (Table 2). We compared the policy periods while adjusting for season and age at vaccination (Table 3). In Group A, using the 1992–1993 hepatitis B policy period as the baseline, we observed an elevated but not statistically significant fever risk among children born during the DTaP/IPV period (OR = 1.22; 95% CI: 0.97–1.53) and the RV period (OR = 1.24; 95% CI: 0.94–1.62). Children were also at higher risk for medically attended fever in the OPV3 policy period (OR = 1.24, 95% CI: 1.05–1.46) compared to the HB policy period. In Group A, children born during the PCV period experienced similar risk for fever compared to the HB policy period (OR = 0.78, 95% CI: 0.50–1.23). Children born during the PCV period had no increase in the risk of medically attended fever compared with those born in the DTaP/IPV policy period. This finding held in both Group A (OR = 0.63, 95% CI: 0.38–1.04) and Group B (OR = 0.91, 95%
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Table 2 Rate of medically attended fever, unadjusted results. Site
Group A Group B
Rate of medically attended fever per 1000 vaccination visits during the given time period Pre-HB period
HB period
OPV3 period
DTaP/IPV period
RV period
PCV period
6.3
6.6
8.1
7.7 2.5
7.8
4.9 3.2
“Pre-HB”: period during which only DTwP, Hib, and OPV vaccinations were recommended. “HB”: addition of universal hepatitis B vaccination recommendations. “OPV3”: third dose of OPV recommended between 6 and 18 months. “DTaP/IPV”: replacement of DTwP with DTaP vaccine and replacement of OPV with IPV. “RV”: introduction of rotavirus vaccine. “PCV”: introduction of pneumococcal conjugate vaccine.
Table 3 Odds of medically attended fever after vaccination visits by infants aged 0–12 months during specific time periods from 1991 to 2000. Group
Policy period comparisons
OR
95% CI
Group A
Pre-HB period HB period (referent group) OPV3 period DTaP/IPV period RV period PCV period PCV period vs. DTaP/IPV period PCV period vs. DTaP/IPV period
0.84 1.00 1.24 1.22 1.24 0.78 0.63 0.91
(0.65, 1.08)
Group A Group B
(1.05, 1.46) (0.97, 1.53) (0.94, 1.62) (0.50, 1.23) (0.38, 1.04) (0.53, 1.56)
Based on generalized estimating equation models of 158,518 vaccination visits among 37,504 children, adjusted for seasonality and age at vaccination. “Pre-HB”: period during which only DTwP, Hib, and OPV vaccinations were recommended. “HB”: addition of universal hepatitis B vaccination recommendations. “OPV3”: third dose of OPV recommended between 6 and 18 months. “DTaP/IPV”: replacement of DTwP with DTaP vaccine and replacement of OPV with IPV. “RV”: introduction of rotavirus vaccine. “PCV”: introduction of pneumococcal conjugate vaccine.
CI: 0.53–1.56). 3.3. Stratification by age at vaccination Analyses stratified by age at vaccination identified a significant increase in risk for fever in Group A during the RV policy period at the 2-month (OR = 4.0; 95% CI: 1.9–8.6) and 4-month (OR = 1.8; 95%
CI: 1.1–3.1) immunization visits compared to the HB policy period (Fig. 3). A non-significant increase in risk for fever was also observed during the OPV3 period for all age strata. No significant differences or systematic patterns were observed for the other policy periods relative to the HB policy period. In both Groups A and B, children born in the PCV policy period experienced similar risk for fever compared with those born in the DTaP/IPV policy period. 4. Discussion This study indicates that medically attended fever following vaccination is rare. Our findings suggest that increases in the number of recommended vaccinations between 1991 and 2000 were not associated with corresponding increases in subsequent medical visits with fever among children. We did observe a significant excess risk for medically attended fever for 2- and 4-month olds during the time period of introduction of RotashieldTM , a now-discontinued form of oral rotavirus vaccine. This result was consistent with pre-licensure randomized controlled trials [18,28,29]. In contrast, no increase in fever has been noted in pre-licensure studies of RotateqTM or RotarixTM , the two currently recommended rotavirus vaccines [30]. We did not observe significant changes in the rates of medically attended fever after vaccination that coincided with any of the other time periods we studied. We observed a non-significant
Fig. 3. Time periods with different immunization policies and risk of medically attended fever, by recommended immunization visit, Provider Group A. Adjusted for seasonality. “Pre-HB”: period during which only DTwP, Hib, and OPV vaccinations were recommended. “HB”: addition of universal hepatitis B vaccination recommendations. “OPV3”: third dose of OPV recommended between 6 and 18 months. “DTaP/IPV”: replacement of DTwP with DTaP vaccine and replacement of OPV with IPV. “RV”: introduction of rotavirus vaccine. “PCV”: introduction of pneumococcal conjugate vaccine.
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decrease in rates of medically attended fever after PCV introduction, in contrast to pre-licensure studies which found an increase in fever after PCV vaccination [31]. The decrease we observed might be because our study was limited to a short time period during the early adoption of PCV. Alternatively, it might reflect a true effect. For example, physicians may have perceived that PCV would prevent invasive infections related to Streptococcus pneumoniae and be less likely to have parents bring a febrile child in for a visit and a potential fever work-up. Further study of fever after vaccines recommended subsequent to PCV7 introduction is warranted. For example, recent data suggest that the risk of febrile seizures is elevated after administration of measles–mumps–rubella–varicella (MMRV) vaccine, relative to measles–mumps–rubella and varicella vaccines administered separately on the same day [32]. This study is unique in using temperatures routinely recorded in the electronic medical record to collect information on fever. Historically, variation in the definition and identification of fever has made comparisons of vaccine safety difficult [12]. Using data from the electronic medical record, we were able to apply a standardized definition of fever at medical visits. Our methods provide an example of the research that is now becoming possible with the increasing adoption of electronic medical records. Our definition of fever has some limitations. Identifying cases of fever based on temperature taken at the office visit probably underestimates the true incidence of fever following vaccination. Children may have had fever that prompted a visit, but the fever may have resolved by the time of the visit [33]. In addition, the use of antipyretics reduces fever after vaccination [34], but we were not able to control for whether antipyretic medications such as Tylenol were given at the time of vaccination or recommended to be given at home to prevent fever or pain. Anecdotal reports suggest that such practices varied among the medical centers and clinicians in the provider groups in this study during the period we analyzed. This may explain why we did not observe a higher rate of visits for post-vaccination fever during the period when whole cell pertussis vaccine was routinely used. Another limitation is that we excluded fever recorded on the day of vaccination due to not being able to determine whether it occurred before or after the vaccination. This could have caused us to miss some fevers that began on the day of vaccination. This study evaluated whether rates of medically attended fever varied among children vaccinated during different time periods, and not whether administration of specific vaccinations to a given child affected that individual’s risk of medically attended fever. This approach has some limitations. National vaccine recommendations changed relatively rapidly during the 10 years evaluated, and the implementation of such policies in actual practice was also dynamic. In our preliminary analyses, we were able to use data from the provider groups in this study to empirically evaluate the percentage of infants who were receiving a new vaccine during each period, and we defined each vaccination policy as in use only after at least 20% of infants were being treated consistent with that policy. However, it is not possible to directly attribute observed changes in the rates of medically attended fever to specific immunization policies.
5. Conclusions Health care visits with documented fever after vaccination are rare, occurring in less than 1% of vaccination visits. Our findings provide reassurance that increases between 1991 and 2000 in the number of vaccines for routine use among children were not associated with increases in medically attended fever following vaccination in routine practice.
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Acknowledgements This study was supported by the Centers for Disease Control and Prevention, Atlanta, GA, via contract 200-2002-00732 (the Vaccine Safety Datalink Project) with America’s Health Insurance Plans. Dr. Lin’s effort was supported in part by the Agency for Healthcare Research and Quality, National Research Service Award, HS00002819. We gratefully acknowledge our colleagues at the Department of Population Medicine, especially Megan O’Brien, MPH, for local coordination of the VSD project, Richard Fox, MA, for his management of the automated analytic databases, Jonathan Finkelstein, MD, and Katherine Yih, PhD, for their thoughtful comments, and Richard Platt, MD, MPH, for his senior leadership of the project. We thank Ben Kruskal, MD, of Harvard Vanguard Medical Associates for providing useful historical context. Contributors: We appreciate the contributions of Karen Riedlinger, MPH, who prepared the analytic databases at Kaiser Permanente Northwest for this study. We appreciate the guidance of our other collaborators at the Centers for Disease Control and Prevention, including Robert Chen, MD, Robert Davis, MD, MPH, Frank DeStefano, MD, James Baggs, PhD, and Eric Weintraub, MPH. References [1] Hinman AR. Immunizations in the United States. Pediatrics 1990;86(December (6 Pt 2)):1064–6. [2] Haemophilus b conjugate vaccines for prevention of Haemophilus influenzae type b disease among infants and children two months of age and older. Recommendations of the immunization practices advisory committee (ACIP). MMWR Recomm Rep 1991;40(January (RR-1)):1–7. [3] Recommended childhood immunization schedule—United States, 2001. MMWR Morb Mortal Wkly Rep 2001;50(January (1)), 7–10, 19. [4] Poland GA, Jacobson RM. Understanding those who do not understand: a brief review of the anti-vaccine movement. Vaccine 2001;19(March (17–19)):2440–5. [5] Zimmerman RK, Schlesselman JJ, Baird AL, Mieczkowski TA. A national survey to understand why physicians defer childhood immunizations. Arch Pediatr Adolesc Med 1997;151(July (7)):657–64. [6] Gellin BG, Maibach EW, Marcuse EK. Do parents understand immunizations? A national telephone survey. Pediatrics 2000;106(November (5)):1097–102. [7] Crocetti M, Moghbeli N, Serwint J. Fever phobia revisited: have parental misconceptions about fever changed in 20 years? Pediatrics 2001;107(June (6)):1241–6. [8] Zhou W, Pool V, Iskander JK, English-Bullard R, Ball R, Wise RP, et al. Surveillance for safety after immunization: Vaccine Adverse Event Reporting System (VAERS)—United States, 1991–2001. MMWR Surveill Summ 2003;52(January (1)):1–24. [9] Chen RT, Glasser JW, Rhodes PH, Davis RL, Barlow WE, Thompson RS, et al. Vaccine Safety Datalink project: a new tool for improving vaccine safety monitoring in the United States. The Vaccine Safety Datalink Team. Pediatrics 1997;99(June (6)):765–73. [10] Chen RT, DeStefano F, Davis RL, Jackson LA, Thompson RS, Mullooly JP, et al. The Vaccine Safety Datalink: immunization research in health maintenance organizations in the USA. Bull World Health Organ 2000;78(2):186–94. [11] DeStefano F. The Vaccine Safety Datalink project. Pharmacoepidemiol Drug Saf 2001;10(August–September (5)):403–6. [12] Kohl KS, Marcy SM, Blum M, Connell Jones M, Dagan R, Hansen J, et al. Fever after immunization: current concepts and improved future scientific understanding. Clin Infect Dis 2004;39(August (3)):389–94. [13] Michael Marcy S, Kohl KS, Dagan R, Nalin D, Blum M, Jones MC, et al. Fever as an adverse event following immunization: case definition and guidelines of data collection, analysis, and presentation. Vaccine 2004;22(January (5–6)):551–6. [14] Hepatitis B virus: a comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination. Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR Recomm Rep 1991;40(November (RR-13)):1–25. [15] Recommended childhood immunization schedule—United States, 1995. Centers for Disease Control and Prevention. MMWR Recomm Rep 1995;44(June (RR-5)):1–9. [16] Pertussis vaccination: use of acellular pertussis vaccines among infants and young children. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 1997;46(March (RR-7)):1–25. [17] Poliomyelitis prevention in the United States: introduction of a sequential vaccination schedule of inactivated poliovirus vaccine followed by oral poliovirus vaccine. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 1997;46(January (RR-3)):1–25. [18] Rotavirus vaccine for the prevention of rotavirus gastroenteritis among children. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 1999;48(March (RR-2)):1–20.
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