PEDIATRICS Vol. 122 No. 6 December 2008, pp. e1179-e1185 (doi:10.1542/peds.2008-1977)
ARTICLE |
A Population-Based, Postlicensure Evaluation of the Safety of a Combination Diphtheria, Tetanus, Acellular Pertussis, Hepatitis B, and Inactivated Poliovirus Vaccine in a Large Managed Care Organization
a UCLA Center for Vaccine Research, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Los Angeles, California
b Southern California Kaiser Permanente Health Care Plan, Los Angeles, California
c GlaxoSmithKline Biologicals, King of Prussia, Pennsylvania
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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BACKGROUND. Prelicensure studies of diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated polio virus vaccine suggested that there were higher rates of fever after its administration than when its component antigens were given separately.
METHODS. We conducted an open, controlled, cohort study to evaluate selected potential adverse events after receipt of diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliovirus vaccine in the Southern California Kaiser Permanente Health Care Plan. From April 2003 through June 2005, we identified 61004 infants who received 
1 dose of vaccine (120000 total doses). This group was compared with a previous cohort of 58251 age-, gender-, and medical center–matched infants (116637 doses) who received diphtheria, tetanus, acellular pertussis vaccine and separate doses of hepatitis B and inactivated poliovirus vaccines from January 2002 through March 2003. We compared the incidence of seizures, medically attended events that were associated with fever, and other selected adverse outcomes.
RESULTS. We identified 16 infants (8 with fever) who had a seizure in the diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliovirus cohort and 15 infants (6 with fever) among control subjects in the 8-day period after receipt of any dose of vaccine. The incidence of all seizures or seizures associated with fever was not significantly different between cohorts. The incidence of medically attended events that were associated with fever in the 4-day period after any dose of vaccine was also similar in both cohorts. As well, no significant differences between the diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliovirus and control cohorts, were noted in the incidence of allergic reactions within 48 hours of any dose of vaccine, outpatient visits within 21 days, hospitalizations within 21 days, or death within 1 year.
CONCLUSIONS. We did not observe a statistically significant increase in any of several clinically important safety events after diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliovirus vaccination compared with a historical cohort who received separate component vaccines.
Key Words: vaccine safety • DTaP-HepB-IPV vaccine
Abbreviations: DTaP-HepB-IPV—diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliovirus • SCKP—Southern California Kaiser Permanente Health Care Plan • PCV—pneumococcal conjugate vaccine • MAEF—medically attended event associated with fever • ICD-9—International Classification of Diseases, Ninth Revision • CI—confidence interval
The 2008 routine childhood immunization schedule for the United States targets prevention of 14 diseases, requiring up to 24 injections in the first 2 years of life.1 Delivering these vaccines is a logistic challenge for providers2 and has resulted in decreased acceptance by parents and some clinicians. Concern about the number of injections has advanced the development of combination vaccines that reduce the number of injections and increase vaccine coverage.3,4The Advisory Committee on Immunization Practices, the American Academy of Pediatrics, and the American Academy of Family Physicians recommend that combination vaccines be used preferentially if possible.5
In December 2002, a diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliovirus combination vaccine (DTaP-HepB-IPV; Pediarix [GlaxoSmithKline Biologicals, King of Prussia, PA]) was licensed in the United States for use in infants at 2, 4, and 6 months of age. Prelicensure evaluations of this vaccine included 
8100 infants and noted it to be immunogenic, generally safe, and unlikely to result in vaccine-associated serious adverse events.6–10 Some clinical trial data show an increased incidence of fever after DTaP-HepB-IPV vaccination, compared with separately administered vaccines.9–11 The clinical significance of this finding remains unclear.
Postlicensure safety evaluation of new vaccines is required to assess potential issues that may appear only when large populations are vaccinated after licensure and/or to validate prelicensure safety concerns. This study evaluated the DTaP-HepB-IPV vaccine in a large controlled cohort with emphasis on consequences of fever, including seizures.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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This was an open, controlled postlicensure cohort study that evaluated the safety of DTaP-HepB-IPV vaccine that was administered to infants at 2, 4, and 6 months of age. The UCLA Center for Vaccine Research managed all aspects of data collection, management, and analysis for this study. Immunizations, clinical care, and clinical medical chart maintenance were performed by the Southern California Kaiser Permanente Health Care Plan (SCKP). This study was approved by the institutional review board of both institutions.
Study Population
The DTaP-HepB-IPV cohort included 61004 randomly selected infants who received a total of 120000 doses of DTaP-HepB-IPV vaccine (40000 infants for each dose of the primary series) from April 2003 to June 2005, had not reached their 9-month birthday, and had received 7-valent pneumococcal conjugate vaccine (PCV; Prevnar [Wyeth, Philadelphia, PA]) at the same visit. The historical cohort included a random sample of 58251 SCKP infants who received 1 dose of diphtheria, tetanus, acellular pertussis (DTaP; total of 116637 doses, distributed approximately equally across the 3 primary series doses) and with concomitant PCV between January 2002 and April 2003 (before the widespread availability of DTaP-HepB-IPV vaccine in the SCKP). This comparison cohort included infants who were age-, gender-, and area-matched to infants in the combination vaccine cohort. Given the random sampling strategy, any individual child may be included in 1, 2, or all 3 dose groups, by chance. In both groups, the 2-, 4-, and 6-month immunization dose windows were defined as follows: 42 to 83 days, 84 to 146 days, and >146 days, respectively (Fig 1). Infants were followed for the protocol-defined period of time for each adverse event under study or until SCKP membership ended.
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To assess medically attended events that were associated with fever (MAEF), we randomly selected a subset of each cohort by using computerized databases. From each cohort, we selected 7500 infants at each of the 3 primary series doses (
22500 doses) who were equally distributed by calendar year quartile. Clinic visit final diagnoses were screened for events that were not considered vaccine related or not related to the presence of fever (eg, broken leg) and were excluded (Fig 1).
Outcome Assessments
This study had 2 co-primary end points: (1) the incidence of seizures during the 8-day period after the primary doses of DTaP-HepB-IPV compared with the 8-day period after the primary doses of DTaP vaccine in the control cohort; and (2) the percentage of infants with a MAEF within 4 days of the first dose of DTaP-HepB-IPV compared with the 4-day period after the first dose of DTaP vaccine in the control cohort. By using computerized data, we identified all infants who received 1 dose of DTaP-HepB-IPV or DTaP in the primary series and concomitant vaccination with PCV. Participant visits were then identified by using automated databases that included hospitalization, emergency department, and outpatient clinic information. Outcomes data were available as International Classification of Diseases, Ninth Revision (ICD-9)-based diagnosis codes for each encounter (up to 10 discharge diagnoses per visit). The following specific ICD-9 codes were used: (1) seizures: 333.2, 345.x, 779.0, and 780.3; and (2) allergic reactions: 995.0, E948, E949, 995.3, 708.9, 978.4 to 978.9, 979.5, 979.6, 979.9, 999.5, E948.4 to E948.6, E948.8, E949.5, E949.6, and E949.9. Linkages were also made to California Department of Health Services death certificate information.
Medical visits for seizures (0–7 days) were ascertained by trained personnel by using standardized medical chart review. Initial screening was performed to confirm whether any vaccine was given before the identified medical visit, and, thereafter, the review excluded vaccine history (inclusion in the study or comparison cohort was completed with automated data). The presence of fever was ascertained by medical chart review and defined as a documented temperature of 38.0°C or by parental report taken by thermometer.12 We included seizures that were associated with fever and occurred <24 hours before onset or at the time of presentation to the health care provider for the seizure.
Identification of infants with fever was performed by standardized medical chart review of visits that occurred within 4 days of the 2-, 4-, and 6-month routine immunization visit for each cohort. Other outcomes including allergies (0–48 hours), outpatient visits (0–21 days), hospitalizations (0–41 and 42–365 days), and deaths (0–41 and 42–365 days) were identified by using computerized data. We obtained data from automated data and medical chart review.
An event on the day of vaccination was excluded when it occurred at the vaccination visit itself. Investigators determined the final clinical disposition of seizure and MAEF cases in a blinded manner (personal identifiers were redacted or physically separated from review materials). Chart-reviewed seizure events were classified according to criteria similar to those used in previous vaccine studies.13,14
Sample Size and Data Analysis
The sample size for this study was based on the expected incidence of seizures (from preliminary data) to be 1 to 2 per 10000 SCKP infants per year. A sample size of 40000 per group provided 80% power to detect a DTaP-HepB-IPV cohort seizure rate as low as 4 per 10000 people (a relative risk of 4 compared with the expected rate). For the MAEF end point, the projected sample size was based on preliminary data that 5.3% of SCKP infants accessed care in the 4-day period after the first dose at 2 months of age, assuming half of whom would have fever. These assumptions suggested that a subsample size of 7500 per dose per cohort would provide 80% power to detect an increase in the MAEF rate in the DTaP-HepB-IPV cohort of 1.5-fold.
The incidence of a given event was defined as either the ratio of the number of times the event occurred to the number of doses of the relevant vaccine (for events evaluated for a period specific to a particular vaccine dose) or the number of individuals who experienced at least 1 event to the number of individuals in a given cohort (for events evaluated across >1 dose [eg, hospitalizations, death]). In addition, we calculated the difference in incidence rates with the asymptotic 95% confidence intervals (CIs) for the incident safety variables between the DTaP-HepB-IPV and control cohorts. The exact 95% CIs for proportion within a group was calculated from Proc StatXact 7.0, assuming independence between doses (visits were randomly selected from each dose), and by using established methods.15,16 Asymptotic (Gaussian approximation) 95% CI was calculated to determine the difference in proportion between cohorts.17
A planned stratified analysis based on hepatitis B birth vaccination was not performed because 96% of participants in the DTaP-HepB-IPV cohort were not routinely administered a birth dose of hepatitis B vaccine. Conversely, before DTaP-HepB-IPV availability, 96% of DTaP recipients were given a birth dose of hepatitis B vaccine. A previous study noted that a birth dose of hepatitis B vaccine did not have an impact on subsequent reactogenicity of DTaP-HepB-IPV vaccine given at 2, 4, and 6 months of age.18
Because of matching, the distribution of age, gender, source of SCKP clinical care, and seasonality of immunizations was similar between groups. By design, all DTaP-HepB-IPV or DTaP vaccine doses were administered with concomitant PCV. More than 99% of participants had also received another vaccine in addition to PCV when they received the first and second doses of DTaP-HepB-IPV or DTaP vaccine. Approximately 40% of the infants received a concomitant vaccination in addition to PCV with the third dose of DTaP-HepB-IPV, in contrast to the control cohort, for which a concomitant vaccination in addition to PCV was administered to 99% of the infants along with their third dose of DTaP vaccine.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Seizures
We identified 16 seizure events in the 8-day postvaccination period (0.01% [95% CI: 0.01%–0.02%]) among infants who received DTaP-HepB-IPV, compared with 15 seizure events in the control group (0.01% [95% CI: 0.01%–0.02%]). In the DTaP-HepB-IPV cohort, 8 of the 16 seizure events were associated with fever at a frequency of 0.01% (95% CI: 0.00%–0.01%). In the control cohort, 6 of the 15 seizure events were associated with fever for a frequency of 0.01% (95% CI: 0.00%–0.01%). Neither of these comparisons was statistically significant, and, regardless of dose, the likelihood of a seizure event was similar in both groups. In addition, there was no significance difference in the rate of seizures (with or without fever) among those with underlying seizure disorders or a family history of seizures (Table 1).
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Medically Attended Events Associated With Fever
As shown in Table 2, 22500 infants (7500 per dose of the primary series) were selected from each cohort for medical chart review for this outcome. In each group,
11% of children had a clinic or emergency department visit in the 4-day period after any dose of vaccine. After exclusion of visits for events that were not biologically plausible as potential vaccine-related adverse events or not related to the presence of fever, 60% to 65% of the visits were selected for full chart review.
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We identified 60 MAEFs after any dose of vaccine for a rate of 0.27% (95% CI: 0.20%–0.34%) in the DTaP-HepB-IPV cohort and 48 MAEFs for a rate of 0.21% (95% CI: 0.16%–0.28%) in the historical cohort. This difference is not statistically significant. The infants in the DTaP-HepB-IPV and control groups presented with MAEF at similar frequencies to specific points of care including the outpatient clinic (72% and 75% of all MAEFs), emergency department (21% and 22%), or for hospitalization (4% and 7%), respectively. The final diagnoses for these MAEFs was varied, but for each group, "upper respiratory tract infection/viral illness/bronchitis/pneumonia" and "no known alternative cause for fever" were the most common and together accounted for >85% (Table 2).
Laboratory or other diagnostic testing was performed for 18% of the postvaccination visits for patients in the DTaP-HepB-IPV cohort and for 21% of patients among control subjects. All of the bacterial cultures from cerebrospinal fluid,4 blood,10 and urine8 were negative. One infant in the DTaP-HepB-IPV cohort and 3 in the control cohort each had a cerebrospinal fluid evaluation; a definitive diagnosis was made for only 1 control infant (aseptic meningitis). Chest radiographs were performed for 5 infants in the DTaP-HepB-IPV cohort and 4 in the control cohort. Three radiographs (all in the DTaP-HepB-IPV cohort) were reported by the radiologist to be compatible with pneumonia.
Other Outcomes
Table 3 details the incidence of selected other outcomes, including allergic reactions, outpatient visits, hospitalizations, and deaths after any vaccine dose, according to study cohort. For each of these outcomes, the incidence between cohorts was not significantly different. In the DTaP-HepB-IPV cohort, there were 8 deaths for a crude mortality rate of 0.01% (95% CI: 0.01%–0.03%). The causes of death were liver necrosis (197 days after last DTaP-HepB-IPV vaccination); Pseudomonas septicemia (64 days); respiratory failure (273 and 358 days); primary cardiomyopathy (64 days); cystic fibrosis (52 days); pneumonia, organism unspecified (184 days); and aspiration pneumonia (47 days). None of the deaths seemed to be vaccine related as determined by the co-investigators. In both groups, the likelihood of a visit for an allergic reaction or of an outpatient visit for any reason slightly increased from dose 1 to dose 3 (data not shown), but the difference between cohorts was not significant.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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This study is the largest assessment of the safety of the DTaP-HepB-IPV combination vaccine and included >61000 infants who received a total of 120000 vaccine doses. We found no differences between the DTaP-HepB-IPV and control cohorts in the incidence of seizures (without or without fever), MAEF, allergies, outpatient visits, hospitalizations, or deaths after any dose of vaccine. We believe that these data provide reassuring information that the DTaP-HepB-IPV vaccine is generally safe and does not result in clinically relevant adverse events of any significant magnitude.
In the largest prelicensure US clinical study conducted with this vaccine, a statistically significant increase in the number of infants with temperature 38°C was observed in the group that received DTaP-HepB-IPV compared with those who received separately administered vaccines.9 These data led to concerns that postvaccination fever might result in clinically relevant consequences, such as seizures, medical visits, and/or diagnostic evaluation.6–9,19 This and other prospective prelicensure studies required parents to record daily temperatures regardless of clinical significance. In our study we evaluated this vaccine as used in routine clinical practice and the proportion of visits associated with postvaccination fever in each cohort was very small (<0.3%), the majority did not require diagnostic testing, and a cause of fever was rarely identified. There were no known differences in the approach to detection or evaluation of fever over time in the SCKP, and, given the size of each cohort, the impact of such potential imbalance between groups correlated to the observed outcomes is minimal. It is true, however, that we identified only participants who sought medical care and did not identify care received outside of the SCKP. In this study we did not observe an increase in clinical consequences of postvaccination fever after DTaP-HepB-IPV vaccination, such as seizures, medical visits to SCKP, and diagnostic testing; such postvaccination events therefore seem to be of little clinical significance.
There has been only 1 other postlicensure study of the safety of DTaP-HepB-IPV, and it evaluated the first dose only.11 The study was retrospective and observational and conducted at 5 inner-city practices to compare 1776 DTaP-HepB-IPV recipients with 2162 infants who received the antigens separately. Within 3 days of vaccination, infants in the DTaP-HepB-IPV group had significantly more emergency department visits (21 [1.2%] vs 12 [0.6%]) and complete blood counts obtained (10 vs 1) but no significant difference in the rate of documented fever. Infants in the DTaP-HepB-IPV cohort underwent more diagnostic evaluations than control subjects during the first 6 months of the study, but the rates were equivalent during the second 6 months of the study. During the second 6 months, significantly fewer infants who were younger than 8 weeks were vaccinated with DTaP-HepB-IPV, and less diagnostic testing was performed. The authors postulated that in this period, clinicians may have delayed DTaP-HepB-IPV vaccination to >8 weeks of age to avoid diagnostic testing, should fever occur.
We did not detect a significant difference between study groups in the incidence of seizures (with or without fever) after any dose of DTaP-HepB-IPV. This is consistent with prelicensure data.6–9 Seizures have been associated with receipt of DTaP, measles-mumps-rubella vaccine,20 and measles-mumps-rubella-varicella vaccine,21 particularly in association with fever. The cause of this phenomenon remains obscure, but generally most seizures in infants are associated with fever, and fever probably precipitates most vaccine-associated seizures as well, which are generally not serious. Seizures remain important to monitor, however, in subsequent vaccine safety studies given the morbidity with which they may be associated.
Several other end points that were not subjected to medical chart review had similar incidence in the 2 study groups (allergic reactions, outpatient visits, hospitalizations, and deaths). The absolute rates for these end points, for both groups, were low. Use of computerized data for evaluating outpatient visits and hospitalizations is problematic, however, because these end points are nonspecific and provide little information as to the potential relationship to previous vaccination, yet, as a general indicator of health care use after vaccination, the data are reassuring. Importantly, none of the deaths in the DTaP-HepB-IPV group seemed to be vaccine related, and observed mortality rates were comparable to what would be expected in this infant population.22
Ideally, one would evaluate the safety of a vaccine independent of other vaccines, but this is often not feasible before licensure and impossible after licensure (requires withholding vaccines). In our study, in addition to PCV, 40% of the infants in the DTaP-HepB-IPV cohort received another vaccine with the third dose, in contrast to 99% in the control cohort. This is expected because most of the infants in both cohorts received a Haemophilus influenzae type b–meningococcal protein conjugate vaccine (which does not require a third dose at 6 months of age), and the infants in the DTaP cohort required IPV and/or hepatitis B vaccines in addition to DTaP. Because others have shown that separate receipt of these antigens may increase reactogenicity,8,23 this had the potential for introducing bias favoring the DTaP-HepB-IPV vaccine for this dose. It has also been shown that PCV, when administered with other immunizations, is associated with increased rates of fever,24 but all patients in both groups received concomitant PCV; therefore, our safety data reflect a "real world" experience in which infants receive >1 immunization at the same time yet during the primary series may receive different vaccine antigens depending on local supply, physician preferences, and/or practice-specific financial considerations.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Data from this large study indicate that the incidences of seizures (with or without fever), MAEF, and other clinically relevant adverse events are not increased as a result of the routine use of DTaP-HepB-IPV vaccine at 2, 4, and 6 months of age, compared with separate administration of the component vaccines.
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ACKNOWLEDGMENTS |
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This study was supported by GlaxoSmithKline Biologicals and National Institute of Allergy and Infectious Diseases, National Institutes of Health contract N01 AI 25463.
We gratefully acknowledge the hard work of the following, without whom this study would not have been completed: Zendi Solano, Oliver DelaCruz, Cathy Martinez, Monique Bryher, Susan Partridge, and Craig Cheetham.
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FOOTNOTES |
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Accepted Sep 2, 2008.
Address correspondence to Kenneth M. Zangwill, MD, Harbor-UCLA Medical Center, Liu Research Building, 1124 W Carson St, Torrance, CA 90502. E-mail: kzangwill{at}labiomed.org
These data were presented, in part, at the National Immunization Conference; Atlanta, GA; March 17–20, 2008.
This trial has been registered at www.clinicaltrials.gov (identifier NCT00146835).
Financial Disclosure: Exclusive of research funding for this trial specifically, Dr Zangwill, Ms Erikson, Dr Lee, Ms Lee, Dr Marcy, and Dr Ward have not received financial support from GlaxoSmithKline Biologicals, the manufacturer of the vaccine evaluated in this clinical trial. Drs Friedland, Weston, and Howe are employees of GlaxoSmithKline Biologicals.
| What's Known on This Subject There are no population-based, postlicensure data on this vaccine. This trial is the definitive Food and Drug Administration–mandated phase IV study of this vaccine.
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| What This Study Adds This study provides clinicians and policy makers with information on the safety of the DTaP-HepB-IPV vaccine (Pediarix). No comparable data are currently available.
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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics
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