Vaccine related reactogenicity for primary immunization: a randomized controlled trial of 23(wider) vs. 25(narrower) gauge needles with same lengths.

Abstract

To compare vaccine related reactogenicity during primary immunization in healthy infants using 23 vs. 25 gauge needles.
This randomized controlled trial was conducted in Vaccination Room of the Advanced Pediatrics Center. 155 participants for primary immunization were assigned to two intervention groups (23 vs. 25 gauge). Parent-reported local and systemic reactions were recorded daily for three days after the immunization.
Swelling (24%) and tenderness (21%) were the two most common parent-reported local symptoms followed by restriction of movements (18%) and redness (10%) on day 1. Any local reaction on day 1 was statistically similar in 25 gauge vs. 23 gauge group (RR 0.77; 95% CI: 0.32 to 1.82) (P = 0.54), but fever (day 1) showed higher trend in 23 gauge needle group (RR 2.24; 95% CI: 0.92-5.47) (P = 0.07). Furthermore, on analysis of serially reported local and systemic reactions for 3 consecutive days by generalized estimating equations, odds of redness, swelling, tenderness, restricted movement and fever were statistically similar between two needle groups. On the other hand, median (± SE) crying time (in seconds) was significantly prolonged in the 25 gauge needle (39 ± 2) as compared to 23 gauge group (30 ± 1.3) (log rank test, P = 0.001).
The use of same length needles with narrower (25) or wider (23) gauge did not show significant differences in local reactogenicity during primary immunization. Fever, however, was reduced marginally in 25 gauge group whereas crying duration was significantly shorter with 23 gauge needle. Finally, larger studies are needed to further evaluate objectively the outcome of reactogenicity.

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ORIGINAL ARTICLE
Vaccine Related Reactogenicity for Primary Immunization:
A Randomized Controlled Trial of 23(Wider) vs. 25
(Narrower) Gauge Needles with Same Lengths
Bhavneet Bharti & Anjum Grewal & Raman Kalia &
Pragya Pathak
Received: 6 March 2010 /Accepted: 2 August 2010 /Published online: 7 September 2010
# Dr. K C Chaudhuri Foundation 2010
Abstract
Objectives Tocomparevaccinerelated reactogenicityduring
primary immunization in healthy infants using 23 vs. 25
gauge needles.
Methods This randomized controlled trial was conducted in
Vaccination Room of the Advanced Pediatrics Center. 155
participants for primary immunization were assigned to two
intervention groups (23 vs. 25 gauge). Parent-reported local
and systemic reactions were recorded daily for three days
after the immunization.
Results Swelling (24%) and tenderness (21%) were the two
most common parent-reported local symptoms followed by
restriction of movements (18%) and redness (10%) on day 1.
Any local reaction on day 1 was statistically similar in 25
gaugevs.23gaugegroup(RR0.77;95%CI:0.32to1.82)(P=
0.54), but fever (day 1) showed higher trend in 23 gauge
needle group (RR 2.24; 95% CI: 0.92–5.47) (P=0.07).
Furthermore, on analysis of serially reported local and
systemic reactions for 3 consecutive days by generalized
estimating equations, odds of redness, swelling, tenderness,
restricted movement and fever were statistically similar
between two needle groups. On the other hand, median
(±SE) crying time (in seconds) was significantly prolonged in
the 25 gauge needle (39±2) as compared to 23 gauge group
(30±1.3) (log rank test, P=0.001).
Conclusions The use of same length needles with narrower
(25) or wider (23) gauge did not show significant differences
in local reactogenicity during primary immunization. Fever,
however, was reduced marginally in 25 gauge group whereas
crying duration was significantly shorter with 23 gauge
needle. Finally, larger studies are needed to further evaluate
objectively the outcome of reactogenicity.
Keywords Vaccine related reactogenicity.
Primary immunization
Introduction
Immunizationistheriteofpassageforeverychildattendingthe
pediatric practice. The local reactions and pain associated with
theseinjections,however,arewidelyrecognizedandaresource
of anxietyanddistress for parents andhealthcare providers.To
mitigate or reduce pain and reactogenicity in children, various
strategies have been rigorously evaluated in literature [1].
These include the length of the needle, use of sucrose
analgesia, use of EMLA patch, picking up of the infant,
different injection techniques or different order of vaccines
[2–6]. Studies have shown that longer length of needle is
associated with reduced local reactogenicity, yet there are
only few studies comparing the gauge of needle [7, 8]. This
study, therefore, aimed to compare the reactogenicity after
immunization using same length needle with two different
bore sizes (23 vs. 25 gauge).
Material and Methods
This study was done in the Vaccination Room of a tertiary
pediatric hospital during months of January and February
2007.Healthyinfantsreceivingtheirfirst,secondorthirddose
of routine primary DPT/ DPT-Hib/ DPT-Hib-HepB vaccines
B. Bharti (*):A. Grewal
Department of Pediatrics, Advanced Pediatrics Center,
Postgraduate Institute of Medical Education & Research,
Chandigarh 160012, India
e-mail: bhavneetb@yahoo.com
R. Kalia:P. Pathak
National Institute of Nursing Education (NINE),
Chandigarh, India
Indian J Pediatr (2010) 77:1241–1246
DOI 10.1007/s12098-010-0173-3

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were eligible for the study. All the vaccines used had whole
cell pertussis vaccine asone ofthecomponentsofthe vaccine.
Subjects were excluded if they were preterm (gestational age
less than 37 weeks) or if they had any chronic or acute
illnesses.AspertheNationalImmunizationScheduleinIndia,
first vaccination is given at 6 weeks with subsequent three
vaccinations at 4 weeks interval. Infants were allocated to a
needle group according to a computer generated randomiza-
tion scheme. Allocations were concealed in sequentially
numbered opaque sealed envelopes. After the informed and
written parental consent had been obtained, the study nurse
allocated the next sequential participant number and opened
the appropriate envelopetodeterminetowhichneedlesizethe
infant had been randomized. Infants received all immuniza-
tions through the allocated needle size using standard
intramuscular injection technique (advocated for infants by
WHO). The vaccine was injected into the anterolateral thigh,
with the skin stretched flat between the thumb and forefinger
and the needle inserted at 90° and pushed down into the
muscle. Parents were not informed of the allocated needle
size. The entire vaccine procedure was videotaped using
digital camera (Nikon Coolpix 7900) 5 sec before the vaccine
was administered and continued till the baby stopped crying.
The total crying time was independently recorded by the
researcher blinded to the needle size. Assessment of pain was
done by using validated Modified behavioral Pain Scale
(MBPS) and Visual Analogue scale (VAS), the results of
which have already been reported [9].
Totalstudycohortparticipatingintheoriginaltrial(forpain
as well as crying time) was 320 infants out of which a
subgroup of 155 infants were further enrolled for the
outcomes of local and systemic reactions in the current study
(Fig. 1).
Study nurses instructed parents on how to report the
reactions after each immunization; this was initially validated
in 10 babies prior to the study. Parents reported pain, swelling,
and tenderness, restriction of movements, fever, and use of
medication for three days after vaccinations. They were also
asked to note the use of analgesics, and were requested to
respondtoquestionsonpresenceoflocalandgeneralreactions
dailyonphone.Onlythoseparentswhopossessedalandlineor
a mobile could therefore be followed up to ascertain the
outcomes of local or general reactions for 3 days after
vaccination.
Infants meeting the inclusion criteria
320 infants (165 in January 2007 and 155 in February
2007)
25 Gauge Needle
(161 infants)
23 Gauge Needle
(159 infants)
Randomization
Both these groups were evaluated for Crying time and Modified
Behavioral Pain Scale (MBPS)
155 infants in February 2007
enrolled for Reactogenicity
29 infants lost to follow-up
82 infants (25 gauge)73 infants (23 gauge)
Subgroup
II Part of the study
26 infants lost to follow-up
47 infants53 infants
Fig. 1 Schematicdiagramofstudypopulationrecruitmentandfollowup
Table 1 Comparison of baseline characteristics in infants immunized using two different gauges of needle
CharacteristicGroup 1(Gauge 25) N=82Group 2(Gauge 23) N=73P-value
Gender: Boys: Girls N (%)
Mean weight (SD) (95%CI)(kg)
Age N (%)
≤6 weeks
7–12 weeks
≥13 weeks
Dose distribution
First dose
Second dose
Third dose
48(58.5):34(41.5)
4.81(1.05) (4.58–5.04)
43(58.9):30(41.1)
5.13(1.15) (4.86–5.39)
0.96
0.08
43(52.4)
16(19.5)
23(28)
32(43.8)
24(32.9)
17(23.3)
0.16
47(53.3)
15(18.3)
20(24.4)
37(50.7)
20(27.4)
16(21.9)
0.44
• p value <0.05 is significant
1242 Indian J Pediatr (2010) 77:1241–1246

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Outcome Measures
The outcomes (binary) were local and systemic reactions
reported by parents for three consecutive days after the
immunization. Local reactions included presence or absence
of redness, swelling, tenderness or restriction of movements.
Systemic reactions included presence or absence of fever and
the use of analgesics. Time to cessation of crying (total crying
time) was also compared between two groups.
Statistical Analysis
All data analysis was carriedout according toa pre-established
analysis plan. Differences between groups were analyzed
using the Student t test or chi-square test where appropriate.
Relative risks (RR) with their 95% Confidence Intervals (CI)
were also calculated. The crying time was also compared
using Kaplan Meier survival analysis with log rank test. The
generalized estimating equations (GEE) method, an extension
of the quasi-likelihood approach, was used to analyze the
outcomes of local and systemic reactions which were binary
(present/absent) in nature and correlated (observed longitudi-
nally daily for 3 days). The reductions in proportions of each
reaction over 3 days in overall cohort were compared using
Cochran’s Q test. All tests were 2-tailed and p-value <0.05
was taken as significant.
Results
The studycohortincluded155 infants out ofwhich there were
91 boys (58.7%). The age distribution showed 75(48.4%)
were ≤6 weeks old, 40(25.8%) were 7–12 weeks old, and 40
(25.8%) aged ≥13 weeks. The mean (SD) weight of enrolled
infants was 4.96(1.10) kg. In overall cohort, first, second and
third doses of vaccines were received by 84(54.2%), 35
(22.6%),and36(23.2%)infantsrespectively.Theflowchartin
Fig. 1 shows the enrollment, randomization and follow up of
participants through out the study. For outcome assessment,
only 100 infants were completely followed up (53 infants in
gauge 25 group and 47 infants in gauge 23 group) due to non
availability of landline or mobile phones. Any local reaction
was observed in 29% of the study infants on day 1. Swelling
(24%) and tenderness (21%) at the injection site were the two
most common parent-reported local symptoms followed by
restriction of movements (18%) and redness (10%). During
the 3-day follow-up period after vaccination, there was
significant reduction of swelling, redness, tenderness and
restricted movements (all values P<.01 using Cochran Q
tests). As far as systemic toxicity is concerned, 70% parents
reported fever on day 1 which almost disappeared (just 1%)
on day 3 following immunization. The use of analgesic
(Paracetamol) was reported in 84% of the infants. No serious
Table 2 Univariate comparison of local & systemic reactions in
infants immunized using two different gauges of needle
Reactogenicity Group 1(Gauge 25)
N=53(%)
Group 2(Gauge 23)
N=47(%)
P-value*
Local reactions
Redness
Day 1
Day 2
Day 3
Swelling
Day 1
Day 2
Day 3
Tenderness
Day 1
Day 2
Day 3
Restriction
Day 1
Day 2
Day 3
Systemic reaction
Fever
Day 1
Day 2
Day 3
Medication use
Day 1
Day 2
Day 3
4(7.5)
3(5.7)
1(1.9)
6(12.8)
4(8.5)
2(4.3)
0.38
0.57
0.48
11(20.8)
5(9.4)
2(3.8)
13(27.7)
8(17)
3(6.4)
0.42
0.26
0.55
8(15.1)
4(7.5)
2(3.8)
13(27.7)
7(14.9)
2(4.3)
0.12
0.24
0.90
8(15.1)
3(5.7)
2(3.8)
10(21.3)
5(10.6)
1(2.1)
0.42
0.36
0.63
33(62.3)
8(15.1)
0
37(78.7)
11(23.4)
1(2.1)
0.07
0.29
0.28
43(81.1)
13(24.5)
1(1.9)
41(87.2)
16(34)
5(10.6)
0.41
0.29
0.06
• p value <0.05 is significant (by Chi-square test)
Table 3 Reactogenicity parameters assessed longitudinally using Generalized Estimating Equations (GEE) Method
Reactogenicity ParameterB SEP-valueOdds ratio(OR) 95% CI for OR
Redness
Swelling
Tenderness
Restricted movement
0.44
−0.43
−0.57
−0.26
0.75
0.49
0.53
0.56
0.56
0.38
0.28
0.64
1.55
0.65
0.56
0.77
0.35–6.80
0.25–1.72
0.20–1.58
0.26–2.32
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adverse event was reported during the entire study period
(though the study did not aim to address safety issues).
Baseline characteristics were comparable in two study
groups (Table 1). Table 2 shows the univariate analysis of
proportion of local and systemic reactions on each follow up
day in two study groups. The group of infants immunized
with 25 gauge needle showed marginally significant reduced
risk for any reaction (local/fever on day 1) with relative risk
(RR) of 0.40(95% CI; 0.15 to 1.03) (P-value 0.05).On
excluding fever, any local reaction on day 1 was lower but
statistically not different in 25 gauge as compared to 23
gauge group (RR 0.77; 95% CI: 0.32 to 1.82) (P-value 0.54).
The risk of fever (day 1) was marginally higher in 23 gauge
needle group (RR 2.24; 95% CI: 0.92–5.47) (P-value 0.07)
(Table 2). Accordingly there was a trend towards significance
for highermedicationuse (onday3)in23gauge needlegroup
as compared to gauge 25 needle group (p-values 0.06)
(Table 2). When stratified by dose schedule, RRs (95%
CIs) for any reaction (day 1) in 25 gauge group as compared
to 23 gauge group were 0.33(0.09 to 1.26) for first dose
(P-value 0.10), 0.58(0.10 to 3.50) for second dose (P-value
0.55) and 0.33(0.03 to 3.58) for third dose (P-value 0.35)
respectively. Though risk of any reactions (local/fever) was
lower for 25 gauge group in all 3 doses, but failed to reach
statistical significance.
On further analyzing the study results using generalized
estimating equations (GEE) method, the most useful method
for correlated binary or count variables, the outcomes of
redness, tenderness, swelling and restricted movements at
local site showed no significant difference between two
intervention groups when evaluated serially for 3 days
(Table 3). The odds ratios were estimated with 23 gauge
needlegroupasareferencecategory.Exceptfortheoutcomeof
redness where odds were increased in 25 gauge needle, other 3
outcomes (tenderness, swellingand restricted movement) were
showedreducedoddsin25gaugeneedlegroupascomparedto
23 gauge needle group. However, none of these odds ratios
reached statistical (all p-values >0.05) as well as clinical
significance (95% CIs crossing the value of 1). On further
analysis by GEE, other factors and covariates were also
analyzed in the GEE models to see their association with local
reaction outcomes. These results showed that odds of
developing redness in males (compared to females) were 3.56
higher (95% CI: 0.97–12.88) (p-value 0.05). In addition, odds
ratios(with95%CIs)forweight(kg)andage(inweeks)forthe
outcome of redness were 0.45(95%CI: 0.18–1.10) (p-value
0.08)and2.69(95%CI:0.94–7.67)(p-value0.07)respectively.
Outcome of cry duration was also compared between two
study groups. Table 4 gives the descriptive estimates of
‘crying duration’ in two study groups (sample size for this
outcome was 320 infants, originally enrolled for previously
published study). The median crying time was statistically
significantly longer with 25 gauge needle as compared to 23
gauge needle (log rank test; p-value 0.001). Figure 2 shows
Kaplan Meier Survival Analysis curves comparing cumulative
probability of “time to cry” in two study groups. At 30 after
receiving vaccine, 68.3% (SE 3.7%) infants in 25 gauge sec
group and 47.8%(SE 4%) infants in 23 gauge needle were still
crying, and by 60 sec after injection, only 21.1% (SE 3.2%) in
25 gauge needle group and 15.7% (SE 2.9%) in 23 gauge
needle were found crying. Finally at 90, 9.3% (SE 2.3%) in
gauge 25 group and none in 23 gauge sec needle group were
crying.
We further stratified our total study cohort of 320
participants’ gender wise to study the duration of crying in
males and females separately. Our results showed that median
(SE) crying duration in seconds was statistically significantly
longer in girls who received 25 gauge needle (69±4.75 s) as
Fig. 2 Kaplan Meier Survival Analysis curves comparing cumulative
probability of “time to cry” in two study groups (p<.001)
Table 4 Comparison of total duration of crying in the two groups by log rank test
Duration of Cry (seconds) Median time (SE)95% CI P-value by Log Rank test
Group 1(gauge 25) N=161
Group 2(gauge 23) N=159
39 seconds (2 seconds)
30 seconds (1.3 seconds)
35–43 seconds
27–33 seconds
0.001
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compared to 23 gauge needle (50±4.75 s)(log rank test;
p-value 0.003). In contrast, male children did not show
statistically any significant difference in their median (SE)
crying time between 25 gauge needle (51±3.83 sec) and 23
gauge needle (48±3.83 sec) (log rank test; p-value 0.06).
Discussion
We found statistically no significant differences for any local
reactionsintwostudygroupsusinglongnarrow(25mm/25G)
vs. long wide (25 mm/23G). However, relative risk (RR) of
any reaction on day 1 (including local reactions and fever
together) was reduced with marginal statistical significance
(RR0.40;95%CI;0.15to1.03)(P-value0.05)inthegroupof
infants immunized with 25 gauge needle. Though occurrence
of any local reaction (day 1) was statistically similar, marginal
significance achieved for the higher overall reactionincidence
(23 gauge) could be easily attributed to higher risk of fever
(day1) in 23 gauge needle( RR 2.24; 95% CI: 0.92–5.47)
(P-value 0.07).
Some authors have suggested that the narrower 25 gauge
needle might produce an injection jet under greater pressure
and that this causes increased trauma and local reaction
rates [10, 11]. Though, our results provide an evidence to
support this claim as far as pain scores (previous results) and
duration of crying are concerned, yet current study has not
demonstrated statistically significant difference between two
needle gauges as far as local reactions are concerned. Notably,
this randomized controlled study design rules out the con-
foundingeffectoftheneedlelengthasitwassimilar(25mm)in
both the groups. There are likely to be potential disparities in
uniform reporting or coding of local reactions by parents,
making generalizability of our results difficult. In our study,
parents reported difficulty in objectively measuring the
swelling as well as induration. Therefore, we adopted a binary
strategy (presence or absence) of reporting all local and
systemicreactionswithclusteringofmild,moderateandsevere
reaction in a single group. Using this methodology, only 29%
ofourparentsreportedanylocalreactioninourcohortwhereas
some studies had reported local reactions as high as 65% [8].
Differences in the local and systemic reactions have been
mainly observed with different vaccines(whole cell vs.
acellular pertussis vaccine), site of administration (thigh vs.
deltoid) , length of the needle and successive doses of vaccine
[12]. The risk of local reactions has been shown to increase
with successive doses of diphtheria-tetanus acellular pertussis
vaccine especially after the booster dose. In contrast, our study
results did not demonstrate any significant differences in the
proportion of infants experiencing local reactions when
stratified by dose schedule of vaccine in our study [8].
Previously, three studies had compared the incidence of local
reactionsbasedondifferentlengthsoftheneedle,includingone
nonrandomizedandtworandomizedtrials.Theyallfavoredthe
useoflonger(25mm)needleforintramuscularinjectionsinthe
anterolateral part of thigh. Similarly, all the infants in our study
werevaccinatedusing25mmneedle,thismightexplainoverall
lower incidence of reactogenicity in our study. Overall reaction
rates have been shown to decrease with time with maximum
reactiononfirstday.Consistentwithliterature,wetooobserved
reduction in the frequency of local reactions progressively on
follow up for next three days after vaccination.
Interestingly, when effect of gender was evaluated for the
total crying duration, it was significantly more in females as
compared to males [9]. Though no study has compared the
gender differences in crying time, Jackson et al had reported
reduced pain in boys as compared to girls [8].
Themainlimitationofthisstudyissignificantlosstofollow
up (33% infants) because of non availability of telephones
(mobile or landline) to contact the parents reducing the power
of study. Ownership of a phone is increasing day by day in the
developing countries and probably a fresh study or random-
ization after ensuring the availability of phone would decrease
the attrition of infants as observed in the present study
In conclusion, the use of same length needles with
narrower (25) or wider (23) gauge did not show significant
differences in local reactogenicity during primary immuniza-
tion. Systemic toxicity in the form of fever, however, was
reduced marginally with use of 25 gauge needle whereas
crying duration was significantly shorter with 23 gauge
needle. Finally, larger studies are needed to further evaluate
objectively the outcome of reactogenicity.
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