A Randomized Placebo-Controlled Trial of Acetaminophen for Prevention of Post-Vaccination Fever in Infants

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DOI: 10.1371/journal.pone.0020102 · Source: PubMed
Abstract
Fever is common following infant vaccinations. Two randomized controlled trials demonstrated the efficacy of acetaminophen prophylaxis in preventing fever after whole cell pertussis vaccination, but acetaminophen prophylaxis has not been evaluated for prevention of fever following contemporary vaccines recommended for infants in the United States. Children six weeks through nine months of age were randomized 1:1 to receive up to five doses of acetaminophen (10-15 mg per kg) or placebo following routine vaccinations. The primary outcome was a rectal temperature ≥38°C within 32 hours following the vaccinations. Secondary outcomes included medical utilization, infant fussiness, and parents' time lost from work. Parents could request unblinding of the treatment assignment if the child developed fever or symptoms that would warrant supplementary acetaminophen treatment for children who had been receiving placebo. A temperature ≥38°C was recorded for 14% (25/176) of children randomized to acetaminophen compared with 22% (37/176) of those randomized to placebo but that difference was not statistically significant (relative risk [RR], 0.63; 95% CI, 0.40-1.01). Children randomized to acetaminophen were less likely to be reported as being much more fussy than usual (10% vs 24%) (RR, 0.42; 95% CI, 0.25-0.70) or to have the treatment assignment unblinded (3% vs 9%) (RR, 0.31; 95% CI, 0.11-0.83) than those randomized to placebo. In age-stratified analyses, among children ≥24 weeks of age, there was a significantly lower risk of temperature ≥38°C in the acetaminophen group (13% vs. 25%; p = 0.03). The results of this relatively small trial suggest that acetaminophen may reduce the risk of post-vaccination fever and fussiness. Clinicaltrials.gov NCT00325819.
A Randomized Placebo-Controlled Trial of
Acetaminophen for Prevention of Post-Vaccination Fever
in Infants
Lisa A. Jackson
1
*, Do Peterson
1
, John Dunn
1
, Simon J. Hambidge
2
, Maya Dunstan
1
, Patty Starkovich
1
,
Onchee Yu
1
, Joyce Benoit
1
, Clara P. Dominguez-Islas
1
, Barbara Carste
1
, Patti Benson
1
, Jennifer C.
Nelson
1,3
1 Group Health Research Institute, Seattle, Washington, United States of America, 2 Institute for Health Research, Kaiser Permanente Colorado and Denver Health
Community Health Services, Denver, Colorado, United States of America, 3 Department of Biostatistics, University of Washington, Seattle, Washington, United States of
America
Abstract
Background:
Fever is common following infant vaccinations. Two randomized controlled trials demonstrated the efficacy of
acetaminophen prophylaxis in preventing fever after whole cell pertussis vaccination, but acetaminophen prophylaxis has
not been evaluated for prevention of fever following contemporary vaccines recommended for infants in the United States.
Methods:
Children six weeks through nine months of age were randomized 1:1 to receive up to five doses of
acetaminophen (10–15 mg per kg) or placebo following routine vaccinations. The primary outcome was a rectal
temperature $38uC within 32 hours following the vaccinations. Secondary outcomes included medical utilization, infant
fussiness, and parents’ time lost from work. Parents could request unblinding of the treatment assignment if the child
developed fever or symptoms that would warrant supplementary acetaminophen treatment for children who had been
receiving placebo.
Results:
A temperature $38uC was recorded for 14% (25/176) of children randomized to acetaminophen compared with
22% (37/176) of those randomized to placebo but that difference was not statistically significant (relative risk [RR], 0.63; 95%
CI, 0.40–1.01). Children randomized to acetaminophen were less likely to be reported as being much more fussy than usual
(10% vs 24%) (RR, 0.42; 95% CI, 0.25–0.70) or to have the treatment assignment unblinded (3% vs 9%) (RR, 0.31; 95% CI,
0.11–0.83) than those randomized to placebo. In age-stratified analyses, among children $24 weeks of age, there was a
significantly lower risk of temperature $38uC in the acetaminophen group (13% vs. 25%; p = 0.03).
Conclusion:
The results of this relatively small trial suggest that acetaminophen may reduce the risk of post-vaccination
fever and fussiness.
Trial registration:
Clinicaltrials.gov NCT00325819
Citation: Jackson LA, Peterson D, Dunn J, Hambidge SJ, Dunstan M, et al. (2011) A Randomized Placebo-Controlled Trial of Acetaminophen for Prevention of
Post-Vaccination Fever in Infants. PLoS ONE 6(6): e20102. doi:10.1371/journal.pone.0020102
Editor: Zheng Su, Genentech Inc., United States of America
Received January 12, 2011; Accepted April 19, 2011; Published June 17, 2011
Copyright: ß 2011 Jackson et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: Financial support for this study was provided by the Centers for Disease Control and Prevention (CDC) (contract 200-2002-00732), through America’s
Health Insurance Plans. The CDC was involved in the development of the protocol and reviewed the manuscript, but neither the CDC nor AHIP was involved in
the data collection, data analysis, or the decision to submit the manuscript for publication.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: Jackson.L@ghc.org
Introduction
Fever is a relatively common adverse event following admin-
istration of vaccines routinely recommended for infants under one
year of age. For example, a randomized trial of seven-valent
pneumococcal conjugate vaccine given concomitantly with
diphtheria and tetanus toxoid and acellular pertussis (DTaP) and
other routinely recommended vaccines at two, four, and six
months of age reported that up to 24% of participants had a rectal
temperature $38uC and up to 2.5% had a rectal temperature
$39uC within 48 hours of vaccination.[1] Another trial of
pneumococcal conjugate vaccine given with a combination DTaP,
hepatitis B, inactivated poliovirus, and Haemophilus influenzae type b
(DTaP-HepB-IPV-Hib) vaccine at two, three, and four months of
age reported that up to 49% of participants had a rectal
temperature $38uC and up to 4.6% had a rectal temperature
$39uC within four days of vaccination.[2] Although significant
adverse events, such as febrile seizures, can occur, even in the
acellular pertussis vaccine era,[3,4] these events are infrequent and
post-vaccination fever in young infants is generally self-limited.
Post-vaccination fever can, however, lead to emergency room
visits and other medical utilization and can cause a parent to miss
time from work to care for the febrile child. Fever also results in
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discomfort for the child and may lead to disruption of sleep for
both the parents and the child. Lastly, the occurrence of post-
vaccination fever could potentially influence parents’ perception of
the safety of routine childhood immunizations.
Two randomized controlled trials conducted in the 1980s
reported reductions in risk of post-vaccination fever in infants two
through six months of age who received acetaminophen at the
time of whole cell pertussis vaccination, which was associated with
significant reactogenicity.[5,6] In those trials, acetaminophen
prophylaxis also led to reductions in the proportion of infants
with fussiness and persistent crying in the day following
vaccination. Prophylactic use of acetaminophen has not been
evaluated in infants receiving contemporary vaccines routinely
recommended for use in the United States.
We designed this randomized, placebo controlled trial to
evaluate the possible benefits of acetaminophen prophylaxis for
the prevention of post-vaccination fever and other outcomes,
including medical utilization and parents’ time lost from work,
among infants less than ten months of age receiving routinely
recommended vaccinations. The study sample size of 1000
children was selected to have 80% power to detect a 30%
reduction in risk of the primary outcome of rectal temperature
$38uC following vaccination. In 2009, during the enrollment
period of our trial, Prymula and colleagues reported the results of a
randomized trial of acetaminophen prophylaxis in infants in the
Czech Republic receiving a primary series of ten-valent pneumo-
coccal non-typeable Haemophilus influenzae protein D-conjugate
vaccine (PHiD-CV) co-administered with a combination DTaP-
HepB-IPV-Hib vaccine and oral human rotavirus vaccine.[7] The
trial included evaluations of immunogenicity and found signifi-
cantly lower immune responses to all ten pneumococcal vaccine
serotypes and to Hib polysaccharide, diphtheria, tetanus, and
pertactin antigens in the acetaminophen group. In light of these
unexpected findings indicating a detrimental effect of acetamin-
ophen prophylaxis on vaccine immune response, which could at
least theoretically have clinical implications, we elected to stop
enrollment in our trial. Here we report evaluation of the 352
children enrolled prior to study cessation.
Methods
The protocol for this trial and supporting CONSORT checklist
are available as supporting information; see Checklist S1 and
Protocol S1.
Ethics statement
The study was conducted in compliance with the Helsinki
Declaration and was approved by the Institutional Review Boards
at Group Health and the Centers for Disease Control and
Prevention.
Study design and population
We conducted a randomized, observer and participant
blinded, placebo controlled trial of acetam inophen prophylaxi s
among children less than 10 months of age enrolled in Group
Health Cooperative, a managed care organization in Washing-
ton State. Children were eligible for enrollment if they were
expected to receive t wo or more injected vaccines at an
upcoming well chil d visit occurring after six weeks and before
10 months of age. Childre n less t han four months of age who had
a birth weight of ,2500 grams or gestational age of ,36 weeks
were excluded from enrollment but children four through nine
months of age could be enrolled regardless of birth weight or
gestational age.
Recruitment, enrollment, and randomization
Children potentially eligible for study participation were
identified from the Group Health data systems and parents were
mailed a letter providing information on the study and inviting
them to contact the study team if they were interested in more
information. If the child was confirmed to be eligible by phone
interview with the parents and by medical record review, a consent
form was mailed to the parents for them to sign and return.
After the parents returned the signed consent form, the child
was randomized with equal probability to receive acetaminophen
or placebo. The randomization sequence was generated by the
study biostatistician and provided to the study pharmacy. To
ensure balanced allocation, the randomization schedule was
generated with a variable block size of between six and twelve.
Neither the study biostatistician nor the study pharmacist was
involved with the enrollment of participants.
At a time proximate to the scheduled well child vaccination
visit, the parents were mailed an enrollment package that included
the bottle of study medication, two 3.0 mL medication syringes
graduated in 0.5 mL intervals, a digital thermometer, the study
diary, and the study medication dosing instructions.
Study drug, dosage, and timing
The liquid placebo and the acetaminophen suspension were
flavored to mask differences in taste and packaged by the study
pharmacy in identical containers identified only by study id
number. The acetaminophen suspension was formulated to
provide 160 mg of acetaminophen per 5 mL dose volume. The
parents were instructed to use the dosage table provided in the
enrollment package to identify the recommended dose volume
based on the child’s weight, which would provide between 10 mg
and 15 mg of acetaminophen per kilogram. Parents and study staff
members involved in recruitment, enrollment, and follow up were
blinded to study assignment.
Parents were encouraged to take the bottle of study medication
to the vaccination visit, and to give the first dose at that visit and
within an hour before or after the vaccinations. If the parent was
unable to give the first dose within an hour of vaccination, they
were asked to give the first dose as close as possible to the
vaccination, and within the allowable window of four hours before
through up to 24 hours after the vaccinations.
Following the initial dose, parents were instructed to give
subsequent doses no earlier than, but as close to, four hours
following the previous dose as possible. A maximum of five doses
of study medication should be given, and the last dose must be
given no later than 24 hours after the study vaccination regardless
of the total number of doses administered. If all doses were given
exactly on schedule, doses would be given at 0, 4, 8, 12, and
16 hours after vaccination.
Data collection
Parents completed a study diary and recorded the child’s weight
(measured at the vaccination visit), the time that vaccinations were
administered, and the timing and volume of each dose of study
medication administered. If they discontinued the study medica-
tion, they were asked to record the reason(s).
Parents were asked to take the child’s rectal temperature just
prior to administration of the second, third, fourth, and fifth doses
of study medication and to take a final rectal temperature
approximately 24 hours after vaccination, or four hours after the
final dose of study medication, whichever was later. At each study
medication dosage time, and at the time of the final temperature
assessment, parents were also asked to record the child’s level of
fussiness.
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Parents were also asked to record the relative amount of sleep
that each parent and the child had on the night following the
vaccinations and were asked to report whether they were
scheduled to work on the day of or the day following the child’s
vaccination visit and, if so, whether either parent missed work to
care for the child due to fever, fussiness, or possible vaccine
reaction. Parents were to record any use of medical services for
fever or other acute symptoms following the vaccination visit
through the next day. To judge the adequacy of the blinding
procedure, parents were also asked to indicate their guess as to
whether their child received acetaminophen or placebo.
Vaccinations given at the vaccination visit were identified from
Group Health immunization records.
Provisions for unblinding
The parents were instructed that if they or a health care provider
believed the child needed acetaminophen treatment for any reason,
the parent or health care provider could call study staff at any time
to request unblinding of the randomization assignment. Study staff
could unblind a child’s assignment by opening an individual, sealed
envelope labeled with the child’s study number. After unblinding,
study staff referred the parent to the consulting nurse or the child’s
physician for further clinical management, if needed, of the febrile
illness or other symptoms that led to the request for unblinding.
Primary and secondary outcomes
The primary outcome was a rectal temperature $38uC within
32 hours of vaccination. This time interval was chosen because it
corresponds to 8 hours after the latest possible administration of
the last dose of study medication (to be given no later than
24 hours after vaccination) and thus encompasses the maximum
window of expected activity of the study medication.
Secondary outcomes and their definitions are as follows. All
outcomes were specified a priori
Rectal temperature $39uC within 32 hours of vaccination.
Medical utilization. Telephone calls to the consulting nurse or
the child’s physician that were made due to concerns regarding an
acute illness, fever, or possible vaccine reaction and outpatient,
urgent care, and emergency room visits that were for evaluation of
an acute illness, fever, or a possible vaccine reaction, within
32 hours of vaccination.
Parent time lost from work. Parents were asked to report
whether they were scheduled to work on the day of the vaccination
visit, but following that visit, or the next day and, if so, whether
they had to miss work to care for their infant because of fever,
fussiness, or possible vaccine reaction on those days.
Time lost from sleep. Parents were asked about their sleep and
the child’s sleep on the night following the vaccinations. They were
asked to report whether they and the infant slept much less than
usual, less than usual, about the usual amount, more than usual, or
much more than usual on that night.
Infant fussiness. Parents were asked to record level of fussiness
(compared with the child’s usual) within 32 hours of vaccination,
using the categories much less than usual, less than usual, about
usual, more than usual, and much more than usual.
Unblinding of study drug assignment. The need for unblinding,
including the timing of and the precipitating reason, was assessed.
Sample size
Assuming that 40% of children in the placebo group would have
the primary outcome of temperature $38uC, a sample size of 897
would allow 80% power to detect a 30% reduction in risk of that
outcome in the treatment group. The sample size was inflated by
about 10% to account for failure to return study diaries for a final
intended sample size of 1000. As previously mentioned, the study
was stopped at about one-third of the intended enrollment and so
the sample size achieved did not allow adequate power to identify
the pre-specified 30% reduction in risk of the primary outcome.
Statistical analysis
The primary analysis included all participants who received at
least one dose of study drug and had study diary information
reported. Due to the bimodal age distribution of the study
population, exploratory age-stratified analyses of the age groups
,24 weeks and $24 weeks were also performed. The per protocol
population was defined by administration of the first dose of the
study medication within four hours before through one hour after
vaccination, and administration of at least two additional doses,
given at least 4 hours apart, within 24 hours of vaccination. The
results of the per protocol analyses were very similar to those of the
intent-to-treat analyses and are not presented.
Descriptive statistics including percentages for binary and
categorical variables and means and standard deviations for
continuously scored variables were computed by treatment group.
Relative risks of primary and secondary outcomes for treated
compared to untreated participants were estimated using unadjusted
Poisson regression. Robust inference was carried out using empirical
Huber-White (sandwich) standard errors because the Poisson model
assumption of mean and varia nce equality did not appear to hold.[8]
Statistical analyses were run using SAS 9.2 and STATA 11.0.
Results
A total of 374 children were randomized and mailed the study
product. Of those, 352, who were vaccinated between June 6,
2006 and September 28, 2009, received at least one dose of study
medication and had a completed study diary returned (Figure 1).
Those 352 children represent the intent to treat population
assessed in the primary study analyses. The age range of those
participants was 16 through 42 weeks with a bimodal distribution
reflecting ages grouped around the times of the four and six month
vaccinations (Figure 2). Other baseline characteristics are shown in
Table 1. A subgroup of 234 children (124 acetaminophen and 110
placebo) met the per protocol definition.
The first dose of study medication was given within one hour of
vaccination for 99% of subjects in each treatment group. In the
acetaminophen group, 98% received at least 2 doses, 94% at least
3 doses, 78% at least 4 doses, and 33% received 5 doses. In the
placebo group, 98% received at least 2 doses, 91% at least 3 doses,
76% at least 4 doses, and 31% received 5 doses.
Children in the acetaminophen group were less likely to have
the primary outcome of temperature $38uC than children in the
placebo group, but this difference was not statistically significant
(p = 0.05) (Table 2). In analyses of the secondary outcomes,
children randomized to acetaminophen were less likely to be
reported as being much more fussy than usual or to have the
treatment assignment unblinded than those randomized to
placebo but there was no significant difference between the
groups for the other secondary outcomes. High fever (temperature
$39uC) was reported in only three (2%) placebo recipients. Febrile
seizure, which was assessed as a safety outcome, was not reported
in any participant. Of the 19 subjects with treatment assignment
unblinded, fever was indicated as a reason for unblinding for 11.
Of the remaining eight, seven were unblinded due to fussiness or
screaming and one because the child’s pediatrician requested
administration of acetaminophen due to history of seizure.
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In analyses stratified by age (,24 and $24 weeks), among children
in the older subgroup, there was a significant reduction in risk of
temperature $38uCintheacetaminophencomparedwiththe
placebo group (13% vs. 25%; p = 0.03) that was not found in the
younger age group (16% versus 18%; p = 0.8). In both age groups,
children randomized to acetaminophen tended to be less likely than
children randomized to placebo to be reported as being much more
fussy than usual ($24 weeks, 9% vs 23%; p = 0.004) (,24 weeks, 13%
vs 27%; p = 0.055). Among children in the placebo group, those $24
weeks of age were not significantly more likely than the younger group
to have a temperature $38uC (25% vs 18%; p = 0.31) or to be
reported as being much more fussy than usual (23% vs 27%; p = 0.56).
To assess the adequacy of the blinding of the study drug, parents
were asked to guess whether their child had received acetamin-
ophen or placebo. Fifty-seven percent of parents of children
assigned to acetaminophen and 53% of parents of children
assigned to placebo correctly guessed the study drug assignment.
These proportions were not different than those expected by
chance alone and suggested adequate blinding of the study drug.
Discussion
In this randomized placebo controlled trial of acetaminophen
prophylaxis among children less than 10 months of age, we found
suggestions of a benefit of acetaminophen in reducing the risk of
fever and increased fussiness following vaccination. Although the
risk of the primary outcome of temperature $38uC was lower in
the acetaminophen compared to the placebo group (15% versus
22%), this difference was not statistically significant in the primary
analysis of all subjects. A significantly lower risk of the primary
outcome was found in the subgroup analysis of infants $24 weeks
of age. Among all participants, children randomized to acetamin-
ophen were less likely to be described as much more fussy than
usual during the study period and to have had the study
assignment unblinded. Temperature $39uC was uncommon,
and was found in only 3 of 176 (2%) placebo recipients.
These possible benefits are consistent with the findings of two
randomized controlled trials of acetaminophen prophylaxis in
children receiving whole cell pertussis vaccine, which included
primarily children two through six months of age. In the trial by
Ipp, the risk of temperature $38uC was 39% lower in the
acetaminophen group (RR, 0.61; 95% CI, 0.47–0.81), with similar
reductions in fussiness/fretfulness and persistent crying.[5] In the
trial by Lewis, the risk of temperature $38uC was 43% lower in
the acetaminophen group (RR, 0.57; 95% CI, 0.41–0.79), with a
similar reduction in fussiness/fretfulness.[6] In both of those
studies, the risk of fever among placebo recipients was relatively
high. A temperature of $38uC was found in 43% of placebo
recipients in the Ipp study and 53% in the Lewis study and a
temperature $39uC was found in 13% of placebo recipients in the
Ipp study. The prevalence of fever is consistent with the higher
reactogenicity of whole cell pertussis vaccine formulations
Figure 1. Enrollment Flowchart.
doi:10.1371/journal.pone.0020102.g001
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compared with contemporary acellular pertussis vaccine formula-
tions. Unlike whole cell pertussis vaccines, DTaP vaccines do not
appear to be associated with a substantially increased risk of post-
vaccination febrile seizures.[9]
Our results are also consistent with the results of a recent
randomized, open label study of acetaminophen (paracetamol)
prophylaxis given with PhiD-CV and DTaP-HBV-IPV/Hib
vaccines administered at three, four, and five months of age
compared with no prophylaxis.[7] The primary outcome of rectal
temperature $38uC during the four days after any of those
vaccinations was significantly less common in the acetaminophen
group (42%) than the comparison group (66%).
In that study, a unexpected detrimental effect of acetaminophen
prophylaxis on immune responses to vaccine antigens was found.
Although most children who received acetaminophen achieved an
immune response believed to correlate with protection, the
responses, as measured by ELISA or by an opsonophagocytic
assay, to the pneumococcal serotypes included in the vaccine
tended to be lower in the acetaminophen group. In addition, there
were lower immune responses to Hib polysaccharide, diphtheria,
tetanus, and pertactin antigens in the acetaminophen group. Post
hoc analyses of previous vaccine clinical trials, with information on
concomitant acetaminophen use, also found similar trends for an
association of acetaminophen exposure and reduced responses to
pneumococcal conjugate vaccine.[7]
Although the clinical relevance of these findings is not known, the
study authors, and the authors of the accompanying editorial,[10]
interpreted the findings as arguing against routine acetaminophen
prophylaxis at the time of vaccination. We agreed that, in the
absence of additional information, the potential benefit of
acetaminophen prophylaxis in reducing the risk of fever and
associated adverse events following contemporary infant immuni-
zations appears to be outweighed by the potential harmful effects of
acetaminophen prophylaxis on vaccine immune responses and we
stopped enrollment in our trial after the publication of the paper by
Prymula and colleagues in October 2009. Subsequent to that time,
we used Group Health databases to identify study participants who
had been hospitalized for any reason between the time of study
enrollment and their second birthday and identified 14 children
Figure 2. Distribution of participant age in weeks at the vaccination visit.
doi:10.1371/journal.pone.0020102.g002
Table 1. Baseline characteristics and vaccinations received by
study group.
Acetaminophen
N = 176
Placebo
N = 176
Age in weeks,
mean (SD)
24.8 (4.7) 24.2 (4.7)
Age 16–23 weeks, % 31 36
24–42 weeks, % 69 64
Female, % 44 54
Weight in lbs,
mean (SD)
16.7 (2.3) 16.5 (2.1)
Number of injected
vaccines administered, %
23 3
315 16
469 69
513 11
60 1
Vaccines administered, %
DTaP 62 61
DTaP-HepB-IPV 19 16
DTaP-IPV/Hib 17 21
HepB 11 11
Hib 75 74
Hib-HepB 2 3
IPV 60 61
PCV7 98 98
TIV 11 10
DTaP, Diphtheria and tetanus toxoids and acellular pertussis vaccine; HepB,
hepatitis B vaccine; IPV, inactivated poliovirus vaccine; Hib, Haemophilus
influenzae type b conjugate vaccine; PCV7, pneumococcal conjugate vaccine
(7-valent); TIV, trivalent inactivated influenza vaccine.
doi:10.1371/journal.pone.0020102.t001
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who had been hospitalized during that period. We evaluated the
discharge diagnoses assigned to the 14 hospitalizations and
identified none that appeared due to a potentially vaccine
preventable infection, such as pneumococcal or Hib infection.
Conclusions
In summary, the results of this trial that included about one
third of the predefined sample size suggest a benefit of
acetaminophen prophylaxis in reducingfeveramonginfants
receiving DTaP vaccine and other currently recommended
vaccines. New inf ormation d emonstrating an adverse effect of
acetaminophen prophylaxis on vaccine immune res ponse, as
well as data indicating that the risk of febrile seizures, a more
serious complica tion of po st-vaccination fever, i s not increased
following administration of DTaP vaccine, indicates that
acetaminophe n prophyl axis should no t be routin ely used for
prevention of post-vaccination fever. Future evaluations of
acetaminophen o r ot her an ti-inflammato ry drug s given in
association with vaccinations should include evaluations of
vaccine immune response.
The findings and conclusions in this report are those of the
authors, and do not necessarily represent the official position of the
Centers for Disease Control and Prevention.
Supporting Information
Checklist S1 CONSORT checklist.
(DOC)
Protocol S1 Protocol for this trial.
(DOC)
Author Contributions
Conceived and designed the experiments: LAJ JD SJH MD PS OY BC PB
JCN. Performed the experiments: JAH MD PS JB BC PB JCN. Analyzed
the data: LAJ DP OY CPD JCN. Contributed reagents/materials/analysis
tools: LAJ DP OY CPD JCN. Wrote the paper: LAJ DP OY CPD JCN.
References
1. Black S, Shinefield H, Fireman B, Lewis E, Ray P, et al. (2000) Efficacy, safety
and immunogenicity of heptavalent pneumococcal conjugate vaccine in
children. Northern California Kaiser Permanente Vaccine Study Center Group.
Pediatr Infect Dis J 19: 187–195.
Table 2. Primary and secondary outcomes by study group.
Acetaminophen
N = 176
Placebo
N = 176 Relative risk (95% CI) P value**
%%
Primary outcome
Rectal temperature $38uC* 14 22 0.66 (0.41, 1.01) 0.053
Secondary outcomes
Rectal temperature $39uC* 0 2 -- 0.08
F
Study assignment unblinded 3 9 0.31 (0.12, 0.84) 0.02
Medical utilization 3 6 0.45 (0.16, 1.28) 0.14
Infant fussiness (maximum recorded)
About usual or less than usual 42 38 Reference
More than or much more than
usual
58 62 0.94 (0.79, 1.11) 0.45
Much more than usual 10 24 0.40 (0.25, 0.70) 0.001****
Parent sleep**
About usual or more than usual 73 77 Reference
Less than or much less than
usual
27 23 1.20 (0.85, 1.80) 0.33
Much less than usual 3 5 0.62 (0.21, 1.88) 0.40****
Infant sleep
About usual or more than usual 78 81 Reference
Less than or much less than usual 22 19 1.15 (0.76, 1.75) 0.51
Much less than usual 2 2 1.00 (0.25, 3.94) 1.00****
Missed work, among parents scheduled to work
{
4 1 2.94 (0.60, 14.34) 0.18
F
Fisher’s exact test.
*Temperature values were missing for one subject in the acetaminophen group and two subjects in the placebo group; the analyses included N = 175 in the
acetaminophen group and N = 174 in the placebo group.
**If two parents reported, selected parent with the least amount of sleep.
***P-values from Poisson regression with robust variance unless otherwise indicated.
****All other less extreme Likert categories as reference.
{
N = 143 in the acetaminophen group and 140 in the placebo group.
doi:10.1371/journal.pone.0020102.t002
Acetaminophen and Post-Vaccination Fever
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Acetaminophen and Post-Vaccination Fever
PLoS ONE | www.plosone.org 7 June 2011 | Volume 6 | Issue 6 | e20102
    • "Children >1 months (not neonates) were included in the studies. Isolated DTwP vaccine was used in six trials [11]–[14], [16], [19], isolated DTaP in one trial [15], and rest others used combination vaccine [7], [8], [17], [18], [20], [21]. "
    [Show abstract] [Hide abstract] ABSTRACT: Background Prophylactic antipyretic administration decreases the post-vaccination adverse reactions. Recent study finds that they may also decrease the antibody responses to several vaccine antigens. This systematic review aimed to assess the evidence for a relationship between prophylactic antipyretic administration, post-vaccination adverse events, and antibody response in children. Methods A systematic search of major databases including MEDLINE and EMBASE was carried out till March 2014. Randomized controlled trials (RCTs) comparing prophylactic antipyretic treatment versus placebo post-vaccination in children ≤6 years of age were included. Two reviewers independently applied eligibility criteria, assessed the studies for methodological quality, and extracted data [PROSPERO registration: CRD42014009717]. Results Of 2579 citations retrieved, a total of 13 RCTs including 5077 children were included in the review. Prophylactic antipyretic administration significantly reduced the febrile reactions (≥38.0°C) after primary and booster vaccinations. Though there were statistically significant differences in the antibody responses between the two groups, the prophylactic PCM group had what would be considered protective levels of antibodies to all of the antigens given after the primary and booster vaccinations. No significant difference in the nasopharyngeal carriage rates (short-term and long-term) of H. influenzae or S. pneumoniae serotypes was found between the prophylactic and no prophylactic PCM group. There was a significant reduction in the local and systemic symptoms after primary, but not booster vaccinations. Conclusions Though prophylactic antipyretic administration leads to relief of the local and systemic symptoms after primary vaccinations, there is a reduction in antibody responses to some vaccine antigens without any effect on the nasopharyngeal carriage rates of S. pneumoniae & H. influenza serotypes. Future trials and surveillance programs should also aim at assessing the effectiveness of programs where prophylactic administration of PCM is given. The timing of administration of antipyretics should be discussed with the parents after explaining the benefits & risks.
    Full-text · Article · Sep 2014
    • "Paracetamol significantly reduced the incidence of all systemic reactions after at least one dose during the infant series; but again, there were no significant differences between groups after the toddler dose except for the assessment of decreased activity, which was observed less frequently in the paracetamol group. Our data are generally consistent with that of other studies4567, but not with studies where a single dose of paracetamol was administered, which reported no significant impact on any reactions [8,9]. In all studies, paracetamol generally seemed to have less impact after the toddler dose. "
    [Show abstract] [Hide abstract] ABSTRACT: In two clinical trials, low-grade fever was observed more frequently after coadministration than after separate administration of two recommended routine pediatric vaccines. Since fever is an important issue with vaccine tolerability, we performed this open-label study on the efficacy and safety of prophylactic use of paracetamol (acetaminophen, Benuron®) in children administered routine 7-valent pneumococcal conjugate vaccine (PCV-7) coadministered with hexavalent vaccine (diphtheria-tetanus-acellular pertussis-hepatitis B, poliovirus, Haemophilus influenzae type b vaccine [DTPa-HBV-IPV/Hib]) in Germany. Healthy infants (N = 301) who received a 3-dose infant series of PCV-7 and DTPa-HBV-IPV/Hib plus a toddler dose were randomly assigned 1:1 to prophylactic paracetamol (125 mg or 250 mg suppositories, based on body weight) at vaccination, and at 6–8 hour intervals thereafter, or a control group that received no paracetamol. Rectal temperature and local and other systemic reactions were measured for 4 days post vaccination; adverse events were collected throughout the study. In the intent-to-treat population, paracetamol reduced the incidence of fever ≥38°C, but this reduction was only significant for the infant series, with computed efficacy of 43.0% (95% confidence interval [CI]: 17.4, 61.2), and not significant after the toddler dose (efficacy 15.9%; 95% CI: −19.9, 41.3); results were similar in the per protocol (PP) population. Fever >39°C was rare during the infant series, such that there were too few cases for assessment. After the toddler dose, paracetamol effectively reduced fever >39°C, reaching statistical significance in the PP population only (efficacy 79%; 95% CI: 3.9, 97.7). Paracetamol also reduced reactogenicity, but there were few significant differences between groups after any dose. No vaccine-related serious adverse events were reported. Paracetamol effectively prevented fever and other reactions, mainly during the infant series. However, as events were generally mild and of no concern in either group our data support current recommendations to administer paracetamol to treat symptoms only and not for routine prophylaxis. Trial registration NCT00294294
    Full-text · Article · Jun 2013
  • [Show abstract] [Hide abstract] ABSTRACT: OBJECTIVE: To assess the efficacy of paracetamol (acetaminophen) for neonatal pain relief. STUDY DESIGN: Randomized, double-blind placebo-controlled trial in 3 Swiss university hospitals. Term and near-term infants (n = 123) delivered by forceps or vacuum were randomized to receive 2 suppositories with paracetamol (60/80/100 mg in infants <3000 g/3000-4000 g/>4000 g birth weight) or placebo at 2 and 8 hours of life. Pain and discomfort during the first 24 hours was assessed by the échelle de douleur et d'inconfort du nouveau né [neonatal pain and discomfort scale] score. The response to the subsequent heel prick for metabolic screening at days 2-3 of life was investigated by the Bernese Pain Scale for Neonates (BPSN). RESULTS: The échelle de douleur et d'inconfort du nouveau né [neonatal pain and discomfort scale] pain scale ratings after assisted vaginal delivery were low and declined within 4 hours of life (P < .01) irrespective of paracetamol administration. At 2-3 days of life, BPSN scores after heel prick were significantly higher in infants who had received paracetamol, compared with controls, both when BPSN were scored by nurses at the bedside (median [IQR] 4 [2-7] vs 2 [0-5], P = .017) or off-site from videos (4 [2-8] vs 2 [1-7], P = .04). Thirty-five of 62 (57%) infants treated with paracetamol cried after heel prick, compared with 25 of 61 (41%) controls (P = .086). CONCLUSIONS: Infants born by assisted vaginal delivery have low pain scores in the immediate period after birth. Paracetamol given to newborns soon after birth may aggravate a subsequent stress response.
    Full-text · Article · Jul 2012
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