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a Group Health Center for Health Studies
d Department of Pediatrics, Group Health
b Departments of Epidemiology
c Biostatistics, University of Washington, Seattle, Washington
e Sanofi Pasteur Vaccines, Swiftwater, Pennsylvania
| ABSTRACT |
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METHODS. In this prospective assessment, parents reported signs and symptoms of adverse events for 7 days after vaccination. The relative risk of adverse events in relation to needle length (16 or 25 mm) and injection site (arm or thigh) was estimated in multivariate analyses that adjusted for age, gender, and BMI.
RESULTS. Of the 1315 study participants, 89% were vaccinated in the arm, and 67% were vaccinated with a 25-mm needle. Among children vaccinated in the arm, use of the shorter 16-mm needle was associated with a significantly higher risk of any redness,
5 cm of redness, persistent redness on day 2, and pain compared with vaccination with a 25-mm needle. Similar trends among the smaller group of children vaccinated in the thigh were also suggested but were not statistically significant. In analyses that were restricted to children vaccinated with a 25-mm needle, vaccination in the thigh versus arm was associated with a substantially lower risk of
5 cm of redness and a significantly lower risk of swelling and any itching but not with any difference in the risk of pain, irritability, or change in activity.
CONCLUSIONS. These findings suggest that a 25-mm needle should be used for the fifth diphtheria-tetanus-acellular pertussis vaccination regardless of injection site and that vaccination in the thigh is an option that may be considered by parents and providers who would like to decrease the risk of local reactions characterized by redness and swelling.
Key Words: vaccines adverse reactions
Abbreviations: DTaP—diphtheria-tetanus-acellular pertussis RR—relative risk CI—confidence interval DTP-IPV—whole-cell pertussis and inactivated polio vaccine ACIP—Advisory Committee on Immunization Practices AAP—American Academy of Pediatrics
The risk of local reactions increases with successive doses of diphtheria-tetanus-acellular pertussis (DTaP) vaccine, and these reactions are relatively common after the fifth DTaP vaccination.1–6 In infants vaccinated in the thigh with whole-cell pertussis vaccine, use of a shorter (16-mm) needle is associated with a higher frequency of local reactions when compared with the use of a longer (25-mm) needle.7–9 Whether needle length or other factors influence the risk of local reactions to DTaP vaccine in older children, most of whom are vaccinated in the arm, is not well defined. We conducted a prospective assessment of the safety of the fifth consecutive DTaP vaccination in children aged 4 to 6 years in which we collected information on needle length, needle gauge, injection site (arm versus thigh), and BMI to determine whether these factors influenced the frequency or severity of local reactions after the fifth DTaP vaccination.
| METHODS |
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Participants were enrolled from April 2001 through June 2004. In April 2003, a nested randomized, controlled trial of prophylaxis with acetaminophen or ibuprofen for prevention of injection-site reactions was initiated, the results of which have been reported.4 Because neither acetaminophen nor ibuprofen prophylaxis influenced the occurrence of injection-site reactions, the 364 children enrolled in the nested, randomly assigned trial were retained in the study population included in this report.
The study was conducted with approval by the Group Health Cooperative Institutional Review Board. Written informed consent was obtained from the child's parent or legal guardian before initiation of study activities.
Study Procedures and Data Collection
Children potentially eligible for the postlicensure assessment were identified from Group Health Cooperative computerized immunization records. Parents of these children were contacted, and if they were interested in participating, a study vaccination visit was scheduled at the child's usual clinic. At the scheduled vaccination visit, study staff collected baseline information, including height and weight. This study was designed to assess the safety of the fifth DTaP vaccine administered in the context of routine care, and for that reason the DTaP vaccine was administered (without other concomitant vaccinations) by Group Health Cooperative clinical staff who were not members of the study team, according to their usual practice. After vaccination, the vaccine administrator completed a log sheet indicating the site of administration and the needle length and gauge. The log sheet included preprinted options for common combinations of needle length and gauge, including 25-gauge, 1-in (25-mm) length and 26-gauge, 5/8-in (16-mm) length, with another space for entry of other combinations.
On the evening of vaccination and for the next 6 days, parents completed a study diary and recorded reactogenicity information, including oral temperature, circumference of the vaccinated limb at the midpoint, and maximum diameter of the area of redness or discoloration and of localized swelling. The diameters of maximum redness or discoloration and of swelling were categorized as not present, present and <2.5 cm in maximal diameter, between
2.5 and <5 cm in maximal diameter, or between
5 and <10 cm in maximal diameter,
10 cm and less-than-complete limb involvement, and complete thigh or upper arm involvement. Complete thigh involvement was defined as extending from the inguinal area to the knee, and complete upper arm involvement was defined as extending from the shoulder to the elbow.
Parents also recorded daily symptoms of pain of the vaccinated limb, graded as none, mild (light reaction to touch), moderate (protesting to touch or pain with limb movement), or severe (resists limb movement or keeps limb immobile), and itching of the vaccinated limb, graded as none, mild (child complains of itching or is noted to be scratching but no treatment given), moderate (treatment with cold packs or topical nonprescription medications), or severe (interferes with daily activities or sleep, topical prescription medication is used, or any oral medication is used for itching). Parents also recorded the presence or absence of unusually poor appetite, vomiting, or drowsiness, as well as the level of irritability or change in activity level, graded as none, mild (periodically more irritable than usual but normal activity), moderate (reduced activity or refusal to play), or severe (prolonged irritability or need for bed rest).
Study staff contacted parents by telephone to collect the diary information.
Statistical Methods
Binary variables were compared using Fisher's exact test, and continuous variables were compared using Student's t test, assuming unequal variances between 2 groups. For local reactions that occurred in
2% of each of the injection-site groups, multivariate analyses were performed to evaluate the association between needle length and the risk of local reactions. Because local reactions to the fifth DTaP vaccine were relatively common, we did not use logistic regression to model the risk of local reactions, because the odds ratios obtained from logistic regression models overestimate the relative risks of common outcomes. Instead, we modeled the probability of each local reaction as an exponential function of risk factors and used nonlinear least-squares estimation to obtain asymptotically unbiased estimates of the relative risks. To account for misspecification of the variance, we computed model-robust SEs.10 We adjusted for age at vaccination, gender, and BMI in all of the models. BMI was included in the models as a categorical variable with the referent group of 14.50 to 16.79 kg/m2 compared with <14.50 kg/m2 and
16.80 kg/m2. The cutoff values of 14.50 kg/m2 and 16.80 kg/m2 used to define BMI categories were based on the estimates of the 25th and the 85th percentiles of BMI for children 4.5 years of age, respectively.11 We evaluated the effect of needle length on each local reaction by BMI categories by testing for the interactions between BMI and needle length in the multivariate models. Association of needle gauge and risk of local reactions was also evaluated.
In addition to the primary analyses, secondary analyses were performed by excluding children enrolled in the nested, randomized trial evaluating prophylaxis with acetaminophen or ibuprofen for prevention of injection-site reactions. Those results were not substantively different from the primary analyses, and so only the results of the primary analyses are presented.
| RESULTS |
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In the multivariate analyses of children vaccinated in the arm, use of a 16-mm versus a 25-mm needle was associated with a significantly higher risk of any redness,
5-cm redness, persistent redness on day 3, and any pain (Table 3). In analyses stratified by the BMI categories shown in Table 1, the associations were generally consistent across BMI categories (data not shown). That is, the associations of use of the shorter needle with an increased risk of local reactions did not vary substantially by BMI category. Among the smaller group of children vaccinated in the thigh, there were no significant associations between needle length and risk of reactions in multivariate analysis, although there were nonsignificant trends for increased redness and swelling (Table 3).
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5 cm of swelling (RR: 1.49; 95% CI: 1.03–2.16), but there were no other differences between the 2 groups (data not shown).
Injection Site and Risk of Local Reactions After Vaccination With a 25-mm Needle
Because vaccination with a 25-mm needle was associated with a lower risk of local reactions, evaluations of the association of injection site and risk of reactions were conducted among the subgroup of children vaccinated with a 25-mm needle. In multivariate analyses adjusting for age, gender, and BMI, vaccination in the thigh was associated with a significantly lower risk of any redness,
5 cm redness, persistent redness on day 2, any swelling,
5 cm of swelling, and any itching compared with vaccination in the arm (Table 4). Vaccination in the thigh was not associated with a difference in risk of pain in the vaccinated limb or risk of irritability or change in activity.
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16.8 kg/m2 were at greater risk of any swelling and showed consistent trends toward a higher risk of redness than children with a lower BMI. There were also no consistent associations between BMI and risk of reactions. In analyses restricted to children with a BMI of 14.50 to 16.79 kg/m2 (which represented the majority of children in both the arm and thigh groups) who were vaccinated with a 25-mm needle, reactions characterized by redness were more common in children vaccinated in the arm, whereas the proportion reporting pain was similar in the 2 groups (Figure 1).
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| DISCUSSION |
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Three previous clinical trials have evaluated the association of needle length and risk of local reactions after thigh injections of whole-cell, pertussis-containing vaccines in children <2 years of age. The first was a nonrandomized study by Ipp et al9 in which 18-month-old children receiving a combination whole-cell pertussis and inactivated polio vaccine (DTP-IPV) were assigned sequentially to 1 of 3 groups: vaccination in the arm with a 16-mm needle, vaccination in the thigh with a 16-mm needle, or vaccination in the thigh with a 25-mm needle. Among children vaccinated in the thigh, use of a 16-mm needle was associated with a higher risk of local redness and swelling but with no difference in the risk of pain or decreased limb movement compared with use of a 25-mm needle (Table 5). 9 The other 2 studies were randomized trials conducted by Diggle and colleagues7,8 that compared the use of a 16- vs 25-mm needle for administration of whole-cell pertussis-Haemophilus influenzae type b vaccine in the thigh of children
4 months of age. Both of those studies also found significantly higher rates of local reactions in children vaccinated with the shorter needle.
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18 months of age. By extrapolation, these findings suggest that a longer needle should also be used for thigh injections in older children. This is consistent with current recommendations of both the Advisory Committee on Immunization Practices (ACIP) and the American Academy of Pediatrics (AAP).12,13
To our knowledge, our study is the first assessment of the association of needle length and risk of local reactions after deltoid vaccinations in either children or adults. Recommendations regarding needle length for deltoid injections in adults are based in part on the findings from a study by Poland et al14 that assessed deltoid fat pad thickness by ultrasound in 220 adult health care workers. Based on those measurements, the authors recommended that a 25-mm needle be used to ensure
5 mm of deltoid muscle penetration in men and that the needle length for women should be based on weight, with a 16-mm needle recommended for women <60 kg, a 25-mm needle for women between 60 and 90 kg, and a 31-mm needle for women
90 kg.
The current ACIP and AAP recommendations specify that a needle length of 16–25 mm should be used for deltoid site injections in toddlers and children.12,13 The ACIP recommendations include the caveat that a 16-mm needle is adequate only if the skin is stretched flat and the needle inserted at a 90° angle. Our evaluation of primarily 4-year-old children indicates that use of a 16-mm needle is associated with a higher frequency of local reactions than a 25-mm needle, which may indicate more consistent intramuscular penetration with the longer needle. These results suggest that a 16-mm needle should be avoided for administration of deltoid injections in children >4 years of age.
Both the ACIP and AAP recommendations indicate a preference for deltoid versus thigh as the site of administration for intramuscular vaccinations in children >2 years of age. Avoidance of thigh vaccination in older children is supported by the previously cited study conducted by Ipp et al,9 which included a comparison of local reactions after thigh and deltoid administration of DTP-IPV vaccine to children 18 months of age (Table 5). In that study, children vaccinated in the arm with a 16-mm needle were more likely to have local redness and swelling than children vaccinated in the thigh with a 25-mm needle. However, children vaccinated in the thigh were more likely to have decreased movement of the injected limb and severe pain than children vaccinated in the arm. Because of the greater frequency of discomfort and decreased movement of the extremity among children vaccinated in the thigh, the authors concluded that the deltoid muscle is preferable to the thigh for DTP-IPV vaccination at 18 months of age.
As with the study by Ipp et al,9 we found that redness and swelling were more common among children vaccinated in the arm compared with children vaccinated in the thigh. For example, among children vaccinated with a 25-mm needle, the risk of a local reaction with
5 cm of redness was 81% lower among children vaccinated in the thigh compared with the arm. In contrast to the study by Ipp et al,9 we found no difference in the frequency of pain, the frequency of irritability, or the change in activity level of moderate or greater severity (defined as reduced activity or refusal to play) by site of injection. This difference between our study and the previous study of whole-cell pertussis vaccine may be reflective of differences in the patterns of local reactions in toddlers compared with 4-year-old children, differences in the reactogenicity of whole-cell compared with acellular pertussis vaccines, or a combination of these factors.
We also found that, among children vaccinated with a 25-mm needle, reports of pain were less frequent in boys compared with girls. Because this finding is based on parental reports of the child's pain, we cannot determine whether boys experienced less pain than girls after vaccination or whether there was differential reporting of pain by parents based on the child's gender.
A limitation of our study is that needle length and injection site were not assigned at random, and the choice of injection site seemed to be related to the child's size. However, we were able to adjust for BMI in our analyses. In summary, we recommend avoiding a 16-mm needle for vaccine administration in children
4 years of age. In addition, our findings support the use of the thigh as an option for the fifth DTaP vaccination, because injection at this site may result in less redness and swelling after vaccination compared with the deltoid.
| ACKNOWLEDGMENTS |
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| FOOTNOTES |
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Address correspondence to Lisa A. Jackson, MD, MPH, Group Health Cooperative, 1730 Minor Ave, Suite 1600, Seattle, WA 98101. E-mail: jackson.l{at}ghc.org
Financial Disclosure: Dr Jackson received research funding for this study from Sanofi Pasteur Vaccines and is currently receiving research funding for another study from Sanofi Pasteur Vaccines, has served as a consultant to Sanofi Pasteur Vaccines in the past and is on the speaker's bureau for Sanofi Pasteur Vaccines, and has also received research funding from Wyeth Vaccines, ID Biomedical, GlaxoSmithKline Vaccines, and Novartis and has served as a consultant to Wyeth Vaccines and Novartis; and Drs Froeschle and Decker and Ms Maus are employed by Sanofi Pasteur Vaccines. The other authors have indicated they have no financial relationships relevant to this article to disclose.
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