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The Effect of Prophylactic Antipyretic Administration on
Post-Vaccination Adverse Reactions and Antibody
Response in Children: A Systematic Review
Rashmi Ranjan Das
1
*, Inusha Panigrahi
2
, Sushree Samiksha Naik
3
1Department of Pediatrics, All India Institute of Medical Sciences, Bhubaneswar, India, 2Department of Pediatrics, Post-Graduate Institute of Medical Education and
Research, Chandigarh, India, 3Department of Obstetrics and Gynecology, SCB Medical College and Hospital, Cuttack, India
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 ($38.0uC) 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.
Citation: Das RR, Panigrahi I, Naik SS (2014) The Effect of Prophylactic Antipyretic Administration on Post-Vaccination Adverse Reactions and Antibody Response
in Children: A Systematic Review. PLoS ONE 9(9): e106629. doi:10.1371/journal.pone.0106629
Editor: Caroline Quach, McGill University, Canada
Received May 22, 2014; Accepted August 8, 2014; Published September 2, 2014
Copyright: ß2014 Das 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.
Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its
Supporting Information files.
Funding: The authors have no support or funding to report.
Competing Interests: The authors have declared that no competing interests exist.
* Email: rrdas05@gmail.com
Introduction
Though routine vaccination is extremely beneficial for children,
one of the reasons for non-compliance of children is the adverse
effect of the previous vaccination [1,2]. Various side effects in the
form of local (skin indurations, swelling, rash, pain, or erythema at
injection site) and systemic reactions (fever, joint or muscle pain,
vomiting, diarrhea, fainting, seizures, or other central nervous
system effects) occur commonly after diphtheria, tetanus toxoids
and pertussis (DTP) vaccination [3,4]. Again, these reactions are
more common after vaccination with whole cell pertusis compo-
nent vaccine (DTwP) than with acellular pertusis component
vaccine (DTaP). When the reactions occur, they usually occur
within 24–48 hours following vaccination, are usually mild and
self limited, but can result in discomfort in the child [3,4]. It is a
common practice for many health providers to suggest that an
antipyretic be given preventively at the time of vaccine adminis-
tration [5].
If the reactogenicity of these vaccines are decreased in the
general population, parental anxiety could be relieved to some
extent. But there have been different schools of thought regarding
prophylactic antipyretic administration. A systematic review
conducted way back in 2007 concluded that parents be counseled
to monitor vaccine-related adverse reactions and to treat them if
and when they occur [6]. This review summarized the findings
pertaining only to DTP vaccination, and not to other childhood
vaccinations. Recent clinical trials have found that although febrile
reactions were significantly decreased by prophylactic antipyretics,
PLOS ONE | www.plosone.org 1 September 2014 | Volume 9 | Issue 9 | e106629
antibody responses to several vaccine antigens were reduced [7,8].
Meanwhile, the American Academy of Pediatrics (AAP) continues
to say that either prophylactic or therapeutic use of antipyretics
should not be withheld [9]. Therefore, the current systematic
review was planned to bridge this gap of information and provide
any recommendation on the use of prophylactic antipyretics post-
vaccination in children based on the available evidence.
Methods
The protocol was registered with PROSPERO (Registration
number: CRD42014009717).
Types of studies
Randomized controlled trials (RCTs)
Types of participants
Children of both sex and #6 year age undergoing routine
immunization were included. Children suffering from chronic
debilitating diseases, severe malnutrition (weight for height ,
3SD), and underlying immunodeficiency were excluded because of
unpredictability of the antibody response after immunizations.
Types of interventions
The intervention commenced either before, or after the child
had received any of the routine childhood vaccinations, and
consisted of prophylactic or preventive administration of antipy-
retics (either paracetamol or ibuprofen or both) or placebo/no
prophylactic antipyretics. All formulation, dose and schedule of
administration of antipyretics were considered.
Types of outcome measures
Primary outcome measures. (1) Febrile reactions $38.0uC
(100.4uF) in the first 24–48 hrs of primary and booster vaccina-
tions
(2) Antibody response rate [measured by geometric mean
concentration (GMC)] after primary (2, 3, and 4 or 3, 4, and 5
months) and booster vaccinations (12–15 months, and 40–48
months)
Secondary outcome measures. (1) High febrile reactions $
39.0uC in the first 24–48 hrs of primary and booster vaccinations
(2) Local symptoms (pain, redness, and swelling at the injection
site) after primary and booster vaccinations
(3) Systemic symptoms (temperature, irritability/fussiness,
drowsiness, diarrhea, vomiting, and loss of appetite) after primary
and booster vaccinations
(4) Nasopharyngeal carriage (NPC) rate of the organisms (S.
pneumoniae,H. influenzae, and others)
The same temperature cutoff was used to define the severity of
fever in almost all the trials. All routes of temperature (oral, rectal,
and axillary) measurements were considered.
Pain was graded as none, mild (light reaction to touch),
moderate (protesting in response to touch or pain with limb
movement), or severe (child resists limb movement or keeps limb
immobile).
Seroprotection: defined as an antibody concentration $0.1 IU/
mL for diphtheria and tetanus, 0.15 mg/mL for H. influenzae type
b, and 10 mIU/mL for Hepatitis B.
Seropositivity: defined as, 5 ELISA U/mL for antibodies to
acellular pertussis antigens; anti-pneumococcal serotypes 1, 4, 5,
6B, 7F, 9V, 14, 18C, 19F and 23F antibody concentrations $
0.2 mg/mL (for PCV10); anti-polio type 1, type 2 and type 3 titres
$8.
Booster vaccine response to PT, FHA and PRN, one month
after the administration of the booster dose of DTPa combined
vaccine was defined as appearance of antibodies in subjects who
are seronegative (that is, with concentrations ,5 ELU/mL) just
before booster dose and at least two-fold increase of prevaccina-
tion antibody concentrations in those who are seropositive (that is,
with concentrations $5 ELU/mL) just before booster dose.
For comparison purpose, an acceptable decreased immunoge-
nicity of all the mentioned vaccines is that the final antibody
concentrations should not be below the above mentioned
seroprotective/seropositive titers after primary or booster vacci-
nation series.
Search methods for identification of studies
We searched the Cochrane Central Register of Controlled
Trials (CENTRAL, The Cochrane Library, Issue 3, March 2014),
which contains the Cochrane Acute Respiratory Infection (ARI)
Group and the Cochrane Infectious Diseases Group Specialized
Registers, Medline/Ovid (1970 – March 2014), Pubmed (1970 –
March 2014), and Embase (1988 – December 2013).
For these database searching, a combination of following search
terms were adopted: acetaminophen, paracetamol, ibuprofen,
analgesics, antipyretics, adverse reactions, vaccination, immuniza-
tion, DTwP, diphtheria tetanus–toxoid, whole-cell pertussis,
DTaP, acellular pertussis, Streptococcus pneumoniae,Haemophilus
influenzae type B, inactivated poliovirus, IPV, pneumococcal 7-
valent conjugate, pneumococcal 10-valent conjugate, pneumococ-
cal 13-valent conjugate, PCV, measles, mumps, rubella, MMR,
meningococcal conjugate, varicella zoster, hepatitis A, hepatitis B,
rotavirus, influenza, or pneumococcal polysaccharide. To identify
RCTs, which results had remained unpublished; we searched the
NIH clinical trial register (www.clinicaltrials.gov). Trials that
focused on the therapeutic effects of antipyretics post-vaccination
were excluded from the analysis. Articles obtained from this search
were cross-referenced and bibliographies were checked for all
relevant information. No language restrictions were applied. The
search details are given in Appendix S1.
Data extraction
Data extraction was done using a data extraction form that was
designed and pilot tested a priori. Two authors independently
extracted data from the included studies, including year, setting
(country, setting, type of participants, vaccination schedule
followed, type of vaccines administered), exposure/intervention
(type of antipyretic, dose and schedule of administration, protocol
deviation, type of placebo), results (outcome measures, effect,
significance), and sources of funding/support. Disagreements in
extracted data were resolved through discussion.
Assessment of risk of bias in included studies
Two review authors independently assessed the methodological
quality of the selected trials by using methodological quality
assessment forms. We undertook quality assessment of the trials
using the criteria outlined in the Cochrane Handbook for
Systematic Reviews of Interventions [10]. Any disagreements
between the two review authors were resolved by discussion with
the third author. Trials were assessed with respect to the extent to
which investigators minimised the potential for bias to occur and
addressed other issues in relation to methodological quality.
Publication bias that might affect the cumulative evidence was also
assessed.
Prophylactic Antipyretic for Immunization in Children
PLOS ONE | www.plosone.org 2 September 2014 | Volume 9 | Issue 9 | e106629
Table 1. Characteristics of included studies.
Study,
setting Participants, vaccination Intervention Outcomes measured Significant Finding
Ipp 1987;
Canada
(11)
DTwP (both primary and
booster). N= 452.
Age = 2–6 m, 18 m
Acetaminophen (P) 15
mg/kg/dose or placebo
(C) given 0–30 min before
vaccine, then 2 doses at
4 hr intervals.
Fever (.38.0uC), high
fever (.39.0uC), redness,
swelling, pain, drowsiness,
fussiness, vomiting, anorexia,
persistent crying unrelieved
by cuddling), unusual crying
(abnormal pitch).
Fever and high fever at 2–6 m; P vs
C: 26.6% vs 43.5% and 3.3% vs
12.7% (p,0.0005 for both).
Redness at 2–6 m; P vs C: 11.6% vs
20.4% (p,0.025). Pain (moderate
to severe) at 2–6 m; P vs C: 16.3%
vs 31.5% (p,0.001). Fussiness at 2–
6 m; P vs C: 34.8% vs 58.8% (p,
0.0001). Crying at 2–6 m; P vs C:
18.4% vs 30.1% (p,0.005).
Anorexia at 2–6 m; P vs C: 6.9% vs
13.9% (p,0.05).
Lewis 1988;
USA (12)
DTwP (both primary and
booster). N = 282.
Age = 2–6 m, 18 m, 4–6 y
Acetaminophen (P) 10
mg/kg or Placebo (C)
given with vaccine, then
3, 7, 12, and 18 hrs after
vaccination.
Fever ($38uC), redness,
swelling, induration, pain,
drowsiness, anorexia, fussiness,
vomiting, and crying
($30 min).
Fever at 2–6 m and overall, P vs C:
30% vs 53% and 32% vs 53% (p,
0.01 for both). Fussiness at 2–6 m
and overall, with P vs C: 46% vs
72% and 48% vs 70% (p,0.01 for
both).
Uhari 1988;
Finland (13)
DTwP (primary). N = 263.
Age = 5 m
Acetaminophen 75 mg
or Placebo 1 dose 4 hr
after vaccination
Fever (.37.5uC), fussiness,
local reactions (not specified),
drowsiness, diarrhea, and
vomiting
None.
Diez-
Domingo
1998;
Spain (14)
DTwP (primary). N = 256.
Age = 3 m, 5 m, 7 m
Ibuprofen prophylactically
(P) 20 mg/kg/day given in
3 equal doses at 8 hr intervals
or therapeutically (C) 7.5
mg/kg/dose when needed
for adverse reactions.
Fever ($38.0uC), pain, crying
(persistent or unusual),
drowsiness, fussiness,
vomiting, diarrhea, anorexia,
redness, edema, induration.
Temperature increase with age:
37.760.55, 37.960.68, and
38.060.92uC after 1st, 2nd, 3rd
doses (p = 0.001). Induration, P vs
C: 35.7% vs 44.4% (p,0.05). Pain, P
vs C: 37.5% vs 41.9% (p,0.05).
Crying, P vs C: 16. 3% vs 27.5% (p,
0.05). Drowsiness, P vs C: 30.1% vs
36.9% (p = 0.051). Fussiness, P vs C:
25.4% vs 37.7% (p,0.05).
Jackson
2006;
USA (15)
DTaP (booster). N = 372.
Age = 4–6 yrs
Acetaminophen 15 mg/kg
up to 450 mg, Ibuprofen
10 mg/kg up to 300 mg,
or Placebo given at vaccination;
2 doses following at
6 hr intervals.
Primary outcomes: local
reactions (area of redness or
discoloration in the vaccinated
limb during the 2 days after
vaccination, increase in
mid-limb circumference during
the 2 days after vaccination),
and a persistent reaction
(area of redness or discoloration
present on the third day after
vaccination). Secondary
outcomes: Fever $38.0uC
(during the next 2 days), local
reactions (area of redness or
discoloration in the vaccinated
limb during the next 6 days after
vaccination), itching (during next 6
days), and pain (during next 2 days).
None.
Yalcin 2008;
Turkey (16)
DTwP (booster).
N = 270.
Age = 15–20 m.
Acetaminophen (10 mg/kg)
along with vaccine (group 1),
2 hours after vaccination
(group 2), and after the
appearance of febrile reactions
or irritability (group 3, control).
In groups 1 and 2 in addition,
if the axillary temperature
was .38.0uC or if they were
irritable, acetaminophen
(10 mg/kg) was given, every
4 to 6 hr interval.
Local reaction (pain, redness
and induration at the injection
site), fever ($38.0uC), high
fever ($39.0uC), and systemic
reactions (drowsiness,
loss of appetite, vomiting,
diarrhea, and any other
adverse events)
None.
Prophylactic Antipyretic for Immunization in Children
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Table 1. Cont.
Study,
setting Participants, vaccination Intervention Outcomes measured Significant Finding
Prymula
2009;
Czech
Republic
(7)
Ten-valent pneumococcal
non-typeable H. influenzae
protein D-conjugate vaccine
(PHiD-CV) co-administered
with the hexavalent
diphtheria-tetanus-3-
component acellular
pertussis-hepatitis B-
inactivated poliovirus types
1, 2, and 3- H. influenzae type
b (DTPa-HBV/IPV/Hib) and
oral human rotavirus vaccines
(both primary & booster).
N = 459. Age = 9–16 wks,
12–15 m.
Three doses of paracetamol
given within the first 24 h
after each vaccine dose
(first dose immediately
after vaccination, second
and third administrations
were done at home every
6–8 hr). The dose was based
on bodyweight: 80 mg/dose
(53.3–34.3 mg/kg/24 h) for
infants .4.5 kg and ,7kg,
and 125 mg/dose
(#53.6 mg/kg/24 h) for
infants $7 kg. At booster
vaccination, the same dose
was given to infants .7kg
and ,9 kg, and those $9kg
received four administrations
of 125 mg/dose (#55.6
mg/kg/24 h).
Local symptoms (pain, redness,
and swelling at the injection
site), general symptoms
(fever $38.0uCand.39.5uC,
irritability/fussiness, drowsiness,
and loss of appetite), vomiting
and diarrhea. Immunogenicity
was studied by measuring the
antibody geometric mean
concentrations (GMCs) of
all vaccine types.
Antibody concentrations $
0.20 mg/mL against pneumococcus
serotype 6B; P vs C: 62.1% vs 75.6%
(p,0.05). Antipneumococcal
antibody GMCs against all ten
vaccine serotypes: significantly
lower in P group (p,0.05).
Percentage of children with
opsonophagocytic activity titres $
8 for serotypes 1, 5, and 6B; P vs C:
34.8% vs 55.1% (p,0.05), 79.9% vs
93% (p,0.05), 82.2% vs 93.2% (p,
0.05). Antiprotein D antibody GMC;
P vs C: 985.4 U/mL vs 1599.1 ELISA
U/mL (p,0.05). Seroprotection
rates against H. influenzae type b at
the 0.15 mg/mL, and 1.0 mg/mL
cut-offs; P vs C: 96.1% vs 100% (p,
0.05), and 73.9% vs 91.5% (p,
0.05). GMCs for antibodies against
H. influenzae type b, diphtheria,
tetanus, and pertactin: significantly
lower in P group (p,0.05). The
effect of prophylactic paracetamol
persisted after boosting similarly as
above.
Prymula
2013;
Czech
Republic
(8)
Ten-valent pneumococcal
non-typeable H. influenzae
protein D-conjugate vaccine
(PHiD-CV) (booster). N = 220.
Age = 31–44 m.
Follow up study to Prymula
2009 (7). No paracetamol
used in the present study.
Antibody persistence,
immunological memory and
nasopharyngeal carriage
(NPC) evaluated in this
follow up study.
Induction of immunological
memory was shown irrespective of
prophylactic paracetamol (PP)
administration. Antibody GMCs
were lower in the PP group for
serotypes 1, 4, 7F and 9V.
Opsonophagocytic titres did not
differ significantly between the
two groups. No difference in the
rate of NPC of vaccine
pneumococcal serotypes and non-
vaccine and non-cross-reactive
serotypes were seen.
Prymula
2011;
Czech
Republic
(17)
PHiD-CV (booster). N = 748.
Age = 24–27 m.
Follow up study to Prymula
2009 (7). No paracetamol
used in the present study.
Nasopharyngeal carriage
(NPC) evaluated in this
follow up study.
Carriage prevalence of
pneumococcal vaccine serotypes;
P vs C: 7.4% vs 6.8%, which was
non-significant.
Jackson
2011;
USA (18)
DTaP, DTaP-HepB-IPV,
DTaP-IPV/Hib, HepB, Hib,
Hib-HepB, IPV, PCV7, TIV
(primary). N = 352.
Age = 6 wks–10 m.
Acetaminophen 10–15
mg/kg/dose. First dose
was given within an hr of
vaccination or within the
allowable window of 4 hrs
before through up to 24
hrs after the vaccinations.
A maximum of five doses
should be given.
Primary outcome: Fever $38.0uC
within 32 hrs following
vaccinations. Secondary
outcomes: medical utilization,
fussiness, parents’ time lost from
work, and treatment assignment
unblinded if child’s symptom
warrants supplementary
acetaminophen treatment.
Fussiness; P vs C: 10% vs 24% (p,
0.05). Unblinding of treatment
assignment; P vs C: 3% vs 9% (p,
0.05). Fever $38.0uC in infants $
24 wks age; P vs C: 13% vs 25%
(p = 0.03).
Hayat
2011;
India (19)
DTwP, (both primary
and booster). N = 302.
Age = 6–14 wks, 18 m.
Acetaminophen 10
mg/kg/dose. First dose 1
hour before and then
given at 6, 12 and 18
hours after vaccination.
Fever ($38.0uC), local
redness, local swelling/
induration, local pain, refusal
to feed, fussiness,
Fever $38.0uC; P vs C: 18.7% vs
55.3% (p,0.05). Fussiness; P vs C:
41.3% vs 74% (p,0.05).
Unblinding of treatment
assignment; P vs C: 3.3% vs 16.6%
(p,0.01).
Prophylactic Antipyretic for Immunization in Children
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Study descriptions
Information in relation to methodological quality, characteris-
tics of participants, interventions and outcome measures of each
trial is provided in Table 1 [7,8,11–21].
Data synthesis including assessment of heterogeneity
The data from various studies were pooled and expressed as,
odds ratio (OR) with 95% confidence interval (CI) for dichoto-
mous data, and mean difference (MD) with 95% CI for continuous
data. A p-value of ,0.05 was considered significant. Assessment of
heterogeneity was done by I-squared (I
2
) statistics. If there was a
high level of heterogeneity (.50%), we tried to explore this by
subgroup analysis if there were adequate number of trials. A fixed
effects model was initially conducted. If significant heterogeneity
existed among trials (.50%), potential sources of heterogeneity
were considered, and where appropriate, a random effects model
was used. RevMan (Review Manager) version 5.2 was used for all
the analyses [22].
Results
Description of studies
Of 2579 citations retrieved, full text of 26 articles were assessed
for eligibility (Figure 1). Out of these, a total of 14 articles were
excluded for the following reasons: non RCTs (n = 11), adult
participants (n = 03). Finally, 13 trials including 5077 children
were included in the review (Table 1) [7,8,11–21]. The included
trials were conducted in both developed (USA = 4, Czech
Republic = 3, Canada = 1, Germany = 1, Turkey = 1, Finland
= 1, and Spain = 1) and developing countries (India = 1). One
trial used ibuprofen [14], two used both paracetamol and
ibuprofen [15,21], and others used only paracetamol [7,8,11–
13,16–20]. The trials were heterogeneous regarding the dosage
schedule of intervention, the age of the enrolled children, type of
vaccine used, and the outcomes measured. 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].
Risk of bias in included studies
All the included trials had moderate to high risk of bias because
of the following reasons: open or single-blind nature, small sample
size, and other sources of bias.
Effect of prophylactic Paracetamol (PCM)
Primary outcome measures. (1) Febrile reactions $38.0uC
(100.4uF) in the first 24–48 hrs: Compared to the no prophylactic
PCM group, there was a significant reduction in the febrile
Table 1. Cont.
Study,
setting Participants, vaccination Intervention Outcomes measured Significant Finding
Rose
2013;
Germany
(20)
PCV-7 co-administered
with hexavalent vaccine
(DTPa-HBV-IPV/Hib)
(both primary and booster).
N = 301. Age = 56–112 days,
335–445 days
Paracetamol (125 mg or
250 mg suppositories,
based on body weight)
at vaccination, and at 6–8
hour intervals thereafter.
Children ,7 kg received
375 mg/day; children 7
to ,10 kg received 500
mg/day; and children $10
kg received 750 mg/day.
Fever ($38.0uC, .39.0uC,
.40.0uC) tenderness, redness,
swelling, rash irritability,
drowsiness, decreased
appetite, persistent
inconsolable crying,
decreased activity.
Fever $38.0uC (primary); P vs C:
43% vs 75.4% (p,0.05). Fever .
39.0uC (booster); P vs C: 2.6% vs
12.2% (p,0.05). Rash (second
dose, primary); P vs C: 6.8%
vs15.7% (p = 0.04). Irritability
(second and third dose, primary); P
vs C: 47.2% vs 62.1% (p = 0.019)
and 42.2% vs 58.5% 9 (p = 0.01 3).
Drowsiness (first dose, primary); P
vs C: 50.4% vs 64.7% (p = 0.019).
Decreased appetite (second dose,
primary); P vs C: 26.6% vs 42.7%
(p = 0.011). Persistent inconsolable
crying (first dose, primary); P vs C:
9.5% vs 20% (p = 0.031). Persistent
inconsolable crying (booster); P vs
C: 7.8% vs 17.1% (p = 0.05).
Decreased activity (second and
third dose, primary); P vs C: 31% vs
48% (p = 0.007) and 23.3% vs 40%
(p = 0.007). Decreased activity
(booster); P vs C: 29% vs 48.3%
(p = 0.005).
Wysocki
2014;
USA (21)
PCV13 co-administered
with DTaP/IPV/Hib/HBV
(primary). N = 908.
Age = 2–4 and 12 months.
Paracetamol (15 mg/kg/dose)
at vaccination, at 6–8 hr, and
12–16 hr. Ibuprofen (10 mg/kg/
dose) at vaccination, at 6–8 hr,
and 12–16 hr. Five groups (2
groups received paracatemol or
ibuprofen at vaccination and
thereafter, 2 groups did not
receive paracatemol or
ibuprofen at vaccination but
thereafter, one control group
did not receive any of these).
Antibody/immune response
to all the administered
vaccine antigens.
Pneumococcal anticapsular IgG
geometric GMCs were significantly
(p,0.0125) lower in G3 (received
paracetamol at vaccination) versus
G5 (control) for 5 of 13 serotypes
after the primary series. Pertussis
FHA and tetanus IgG GMC were
significantly lower among G4
(received ibuprofen at vaccination)
versus G5 (control) after the
primary series. No differences were
observed for any antigens after the
toddler dose.
doi:10.1371/journal.pone.0106629.t001
Prophylactic Antipyretic for Immunization in Children
PLOS ONE | www.plosone.org 5 September 2014 | Volume 9 | Issue 9 | e106629
reactions of $38.0uC (100.4uF) in the first 24–48 hrs in the
prophylactic PCM group, both after primary [OR, 0.35; 95%CI,
0.26–0.48] (Figure 2) and booster [OR, 0.60; 95%CI, 0.39–0.93]
(Figure 3) vaccinations. However, because of a high degree of
heterogeneity (.50%), these results should be interpreted with
caution.
(2) Antibody response rate (measured by GMCs) after primary
vaccination (3, 4, and 5 months age): There was significant
difference in the GMC of the anti-pneumococcal IgG antibody
between the prophylactic PCM group and no prophylactic PCM
group, for all the vaccine serotypes: serotype 1 [MD 20.53
(95%CI, 20.71 to 20.35)], serotype 4 [MD 20.8 (95%CI, 21.08
to 20.52)], serotype 5 [MD 20.62 (95%CI, 20.87 to 20.37)],
serotype 6B [MD 20.2 (95%CI, 20.29 to 20.11)], serotype 7F
[MD 20.59 (95%CI, 20.83 to 20.35)], serotype 9V [MD 20.46
(95%CI, 20.65 to 20.27)], serotype 14 [MD 21.28 (95%CI,
21.79 to 20.77)], serotype 18C [MD 21.47 (95%CI, 21.82 to
21.12)], serotype 19F [MD 22.13 (95%CI, 22.93 to 21.33)],
and serotype 23F [MD 20.27 (95%CI, 20.43 to 20.11)].
Regarding other vaccinations, there was significant difference in
the GMC of the anti-PRP [MD 21.99 (95%CI, 22.76 to 21.22)],
anti-diphtheria [MD 20.89 (95%CI, 21.27 to 20.51)], anti-
tetanus [MD 21.04 (95%CI, 21.34 to 20.74)], anti-pertactin
[MD 227.9 (95%CI, 238.65 to 217.15)] between the prophy-
lactic PCM group and no prophylactic PCM group. The GMC of
anti-PT, anti-FHA, anti-HBs, and anti-polio (type 1,2,3) did not
show any significant difference between the prophylactic PCM
group and no prophylactic PCM group. Though the GMC of all
pneumococcal vaccines serotypes and some other vaccines
decreased after prophylactic PCM, still the level of GMC in the
prophylactic PCM group was well above the seroprotection level.
(3) Antibody response rate (measured by GMCs) after first
booster vaccination (12–15 months age): There was significant
difference in the GMC of the anti-pneumococcal IgG antibody
between the prophylactic PCM group and no prophylactic PCM
group, for all the vaccine serotypes: serotype 1 [MD 20.96
(95%CI, 21.37 to 20.55)], serotype 4 [MD 21.22 (95%CI,
21.84 to 20.6)], serotype 5 [MD 21.38 (95%CI, 21.91 to
Figure 1. Study flow.
doi:10.1371/journal.pone.0106629.g001
Prophylactic Antipyretic for Immunization in Children
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20.85)], serotype 6B [MD 21.11 (95%CI, 21.5 to 20.72)],
serotype 7F [MD 21.24 (95%CI, 21.81 to 20.67)], serotype 9V
[MD
21.55 (95%CI, 22.17 to 20.93)], serotype 14 [MD 21.38
(95%CI, 22.28 to 20.48)], serotype 18C [MD 22.03 (95%CI,
22.99 to 21.07)], serotype 19F [MD 21.55 (95%CI, 23.08 to
20.02)], and serotype 23F [MD 20.93 (95%CI, 21.5 to 20.36)].
Regarding other vaccinations, there was significant difference in
the GMC of the anti-diphtheria [MD 22.2 (95%CI, 23.82 to
20.58)], anti-tetanus [MD 22.2 (95%CI, 23.25 to 21.15)]
between the prophylactic PCM group and no prophylactic PCM
group. The GMC of anti-PRP, anti-PT, anti-FHA, anti-pertactin,
anti-HBs, and anti-polio (type 1,2,3) did not show any significant
difference between the prophylactic PCM group and no prophy-
lactic PCM group. Though the GMC of all pneumococcal
vaccines serotypes and some other vaccines decreased after
prophylactic PCM, still the level of GMC in the prophylactic
PCM group was well above the seroprotection level.
(4) Antibody response rate (measured by GMCs) after second
booster vaccination (40–48 months age): There was significant
difference in the GMC of the anti-pneumococcal IgG antibody
between the prophylactic PCM and no prophylactic PCM group,
for the following vaccine serotypes: serotype 1 [MD 24.27
(95%CI, 26.75 to 21.79)], serotype 4 [MD 24.78 (95%CI,
28.16 to 21.4)], serotype 5 [MD 23.69 (95%CI, 26.67 to
20.71)], serotype 7F [MD 22.92 (95%CI, 24.74 to 21.1)],
serotype 9V [MD 24.59 (95%CI, 27.4 to 21.78)], serotype 14
[MD 26.7 (95%CI, 213.35 to 20.05)], serotype 18C [MD
212.54 (95%CI, 222.1 to 22.98)]. The GMC of the anti-
pneumococcal IgG antibody for serotypes 6B, 19F, and 23F did
not show statistically significant difference between the prophy-
lactic PCM and no prophylactic PCM group. No study reported
this outcome for other vaccinations.
Secondary outcome measures. (1) High febrile reactions $
39.0uC in the first 24–48 hrs: compared to the placebo group,
there was a significant reduction in the high febrile reactions of $
39.0uC in the first 24–48 hrs in the prophylactic PCM group after
primary [OR, 0.31; 95%CI, 0.18–0.52], but not booster [OR,
0.63; 95%CI, 0.35–1.11] vaccinations.
(2) Pain of all grades: compared to the no prophylactic PCM
group, there was a significant reduction in the pain of all grades in
the prophylactic PCM group, both after primary [OR, 0.57;
95%CI, 0.47–0.7] and booster [OR, 0.64; 95%CI, 0.48–0.84]
vaccinations.
(3) Pain of moderate to severe grade: compared to the no
prophylactic PCM group, there was a significant reduction in the
pain of moderate to severe grade in the prophylactic PCM group
after primary [OR, 0.39; 95%CI, 0.26–0.58], but not booster
[OR, 0.59; 95%CI, 0.24–1.45] vaccinations.
(4) Local redness: compared to the no prophylactic PCM group,
there was a significant reduction in the local redness in the
prophylactic PCM group after primary [OR, 0.81; 95%CI, 0.68–
0.95], but not booster [OR, 0.93; 95%CI, 0.73–1.18] vaccina-
tions.
(5) Local swelling/induration: compared to the no prophylactic
PCM group, there was a significant reduction in the local
swelling/induration in the prophylactic PCM group after primary
[OR, 0.78; 95%CI, 0.66–0.92], but not booster [OR, 0.90;
95%CI, 0.68–1.19] vaccinations.
(6) Persistent cry: compared to the no prophylactic PCM group,
there was a significant reduction in the rate of persistent cry in the
prophylactic PCM group, both after primary [OR, 0.55; 95%CI,
0.39–0.77] and booster [OR, 0.44; 95%CI, 0.22–0.87] vaccina-
tions.
(7) Irritability/fussiness: compared to the no prophylactic PCM
group, there was a significant reduction in the irritability/fussiness
in the prophylactic PCM group, both after primary [OR, 0.36;
95%CI, 0.29–0.45] and booster [OR, 0.66; 95%CI, 0.48–0.91]
vaccinations.
(8) Drowsiness: compared to the no prophylactic PCM group,
there was a significant reduction in the drowsiness in the
prophylactic PCM group after primary [OR, 0.82; 95%CI,
0.70–0.96], but not booster [OR, 0.99; 95%CI, 0.76–1.3]
vaccinations.
(9) Anorexia/loss of appetite: compared to the no prophylactic
PCM group, there was a significant reduction in the anorexia/loss
of appetite in the prophylactic PCM group after primary [OR,
0.61; 95%CI, 0.49–0.77], but not booster [OR, 0.85; 95%CI,
0.64–1.14] vaccinations.
(10) Vomiting: There was no significant difference between the
prophylactic PCM and the no prophylactic PCM group regarding
the reduction of vomiting.
(11) Diarrhea: There was no significant difference between the
prophylactic PCM and the no prophylactic PCM group regarding
the reduction of diarrhea.
(12) Any severe symptom: compared to the no prophylactic
PCM group, there was a significant reduction in any severe
symptom in the prophylactic PCM group after booster [OR, 0.38;
95%CI, 0.20–0.71], but not primary [OR, 0.81; 95%CI, 0.58–
1.12] vaccinations.
(13) Nasopharyngeal carriage (NPC) rate of the organisms (S.
pneumoniae,H. influenzae, and others)
Figure 2. Prophylactic paracetamol: febrile reactions
$
38.06C (100.46F) in the first 24–48 hrs after primary vaccination.
doi:10.1371/journal.pone.0106629.g002
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There was no significant difference either in the pneumococcal
carriage rate (any serotype, vaccine serotypes, or any cross-reactive
serotype) or in the H. influenza carriage rate between the
prophylactic PCM and the no prophylactic PCM group. The
significant finding of post-booster non-typeable H. influenzae
carriage rate [OR, 0.61; 95%CI, 0.39–0.95] might be due to
chance or inadequate randomization.
(14) Days of parental work loss
There was no significant difference between the prophylactic
PCM and no prophylactic PCM group for the days of parental
work loss.
Effect of prophylactic Ibuprofen (IB)
Primary outcome measures. (1) Febrile reactions $38.0uC
(100.4uF) in the first 24–48 hrs: there was no significant difference
between the prophylactic IB and no prophylactic IB groups
regarding the reduction of febrile reactions $38.0uC (100.4uF) in
the first 24–48 hrs of primary and booster vaccinations.
Secondary outcome measures. (1) High febrile reactions $
39.0uC in the first 24–48 hrs: there was no significant difference
between the prophylactic IB and no prophylactic IB group
regarding the reduction of febrile reactions $39.0uC in the first
24–48 hrs of primary vaccination.
(2) Pain all grades: compared to the prophylactic IB group, there
was a significant increase in the pain of all grades in the no
prophylactic IB group after primary [OR, 1.52; 95%CI, 1.13–
2.04], but not booster [OR, 0.97; 95%CI, 0.55–1.7] vaccinations.
(3) Pain (moderate to severe): compared to the prophylactic IB
group, there was a significant increase in the moderate to severe
pain in the no prophylactic IB group after primary [OR, 1.73;
95%CI, 1.1–2.72], but not booster [OR, 0.95; 95%CI, 0.41–2.24]
vaccinations.
(4) Local redness: There was no significant difference between
the prophylactic IB and no prophylactic IB group regarding the
reduction of local redness after primary and booster vaccinations.
(5) Swelling/induration: compared to the prophylactic IB
group, there was a significant increase in the swelling/induration
in the no prophylactic IB group after primary [OR, 1.44; 95%CI,
1.06–1.94] vaccination.
(6) Prolonged cry: There was no significant difference between
the prophylactic IB and no prophylactic IB group regarding
prolonged cry after primary vaccination.
(7) Irritability/fussiness: There was no significant difference
between the prophylactic IB and no prophylactic IB group
regarding irritability/fussiness after primary vaccination.
(8) Drowsiness: compared to the prophylactic IB group, there
was a significant increase in drowsiness in the no prophylactic IB
group after primary [OR, 1.36; 95%CI, 1.00–1.86] vaccination.
(9) Anorexia/loss of appetite: There was no significant
difference between the prophylactic IB and no prophylactic IB
group regarding anorexia/loss of appetite after primary vaccina-
tion.
(10) Vomiting: There was no significant difference between the
prophylactic IB and no prophylactic IB group regarding vomiting
after primary vaccination.
(11) Diarrhea: There was no significant difference between the
prophylactic IB and no prophylactic IB group regarding diarrhea
after primary vaccination.
Effect of prophylactic PCM and prophylactic IB
Primary outcome measure. (1) Antibody response rate
(measured by GMCs) after primary vaccination (2, 3, 4, and 12
month age): This was reported in one trial [presented as
conference abstract]. The trial employed 5 groups (Table 1),
and the results were as follows. Pneumococcal anticapsular IgG
GMCs were significantly lower (p,0.0125) in G3 (received
paracetamol at vaccination and thereafter) versus G5 (no
antipyretic) for 5 of 13 serotypes after the primary series. Pertussis
FHA and tetanus IgG GMC was significantly lower among G4
(received ibuprofen at vaccination and thereafter) versus G5 (no
antipyretic) after the primary series. No differences were observed
for any antigens after the toddler dose. The trial concluded that
prophylactic PCM may interfere with primary series immune
response to pneumococcal antigens. Prophylactic IB did not
interfere with pneumococcal responses, but may reduce response
to pertussis FHA and tetanus antigens. These effects were not
observed following the toddler dose. The clinical significance of
these findings is unclear.
Publication bias
To assess whether there was a bias in the published literature,
funnel plot was constructed using the OR and 1/SE values
obtained from studies measuring the primary outcome (febrile
reactions of $38.0uC in the first 24–48 hrs of PCM administra-
tion). In the absence of a publication bias, such a plot is expected
to have a shape resembling an inverted funnel [23]. From the
asymmetry of funnel plot generated, the possibility of publication
bias in the analysis cannot be ruled out (Figure 4).
Figure 3. Prophylactic paracetamol: febrile reactions
$
38.06C (100.46F) in the first 24–48 hrs after booster vaccination.
doi:10.1371/journal.pone.0106629.g003
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Discussion
Summary of evidence
Prophylactic antipyretic administration significantly reduced the
febrile reactions of $38.0uC after primary and booster vaccina-
tions. Though there were statistically significant differences in the
antibody responses between the two groups (being lower in the
prophylactic PCM group), the prophylactic PCM group had what
would be considered protective levels of antibodies (GMCs) to all
of the antigens given after the primary and booster vaccinations.
There was a significant reduction in the local and systemic
symptoms after primary, but not booster vaccinations (except for
any severe symptom, that had a significant reduction after booster
but not primary vaccinations).
The present review does not find a strong evidence to support
the conclusion of a well conducted RCT that questioned the
administration of prophylactic PCM during administration of
childhood vaccines. This RCT had concluded that although
febrile reactions significantly decreased, prophylactic administra-
tion of PCM at the time of vaccination should not be routinely
recommended since antibody responses to several vaccine antigens
were reduced [7]. However, since the antibody response (GMC)
was not reduced below seroprotection level, it is unlikely that
prophylactic PCM would have any detrimental effect for
individual child concerned. The same has been endorsed by
AAP in their guidelines [9]. Regarding the new trial studying the
effect of PCM and IB simultaneously, the results are more
complicated, as it found differential effect of the antipyretics on the
vaccine antigen responses [21].
The present review finds a benefit in favour of prophylactic
antipyretic administration on both local and systemic symptoms
post-vaccination, although the analyses included trials using mostly
DTwP (6 trials) instead of DTaP (3 trials), the later being less
reactive. The results of the RCT that has sparked the debate about
the beneficial role of prophylactic antipyretic though cannot be
ignored, but cannot be accepted with foolproof at the same time
[7]. This is because of the following four points. First, there is only
a small decrease in the GMC of vaccine antibody titers that may
be of statistically significant but the clinical/epidemiological
relevance is not clear. The latter is supported by the fact that, in
spite of being a common practice for administration of prophy-
lactic antipyretics after immunizations for decades, there have
been significant reductions in invasive disease due to S.
pneumoniae and H. influenzae type b serotypes. Second, the
follow up study to the above RCT has shown that regardless of the
administration of prophylactic PCM, there was no effect on the
nasopharyngeal carriage rate post-booster vaccination [8]. Third,
the development of fever or increase in the temperature post-
vaccination due to the release of endogenous cytokines (IL 1, TNF
a), has been considered as a marker of immune response to
respected vaccines. Fourth, the potential interference between
different vaccines when co-administered with or without antipy-
retics should also be taken into consideration. For example, 30–
60% lower anti-HBs GMTs occur when co-administered with
HPV vaccines and that without antipyretics, which might further
diminish the magnitude of the immune response. It has also been
seen that the acellular pertussis vaccine is much less immunogenic
than the whole cell, and PCV13 develops lower IgG concentra-
Figure 4. Funnel plot for assessing publication bias by including studies reporting the primary outcome.
doi:10.1371/journal.pone.0106629.g004
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PLOS ONE | www.plosone.org 9 September 2014 | Volume 9 | Issue 9 | e106629
tions than PCV7 to the common serotypes. If this is already the
case, adding prophylactic PCM that could lower the immune
response even lower, could be a problem. If there is already herd
immunity, maybe a small decrease in efficacy at the individual
level will take a long time to be noticed, and would raise the need
for better surveillance programs for vaccine-preventable diseases
in all countries. Because of these later two findings, there is
concern that prophylactic antipyretic might decrease the post-
vaccination immune response further.
Besides these, the findings of another RCT [24] reporting about
the infant sleep after immunization and relation of acetaminophen
(paracetamol) use need mention here. This RCT found that
paracetamol use post-immunization (not prophylactic) was asso-
ciated with increase in the infant sleep duration. As sleep
deprivation before or after has been associated with decreased
antibody formation post-immunization in adults, this study
postulates that use of acetaminophen post-immunization might
facilitate the immune response. But this study neither studied the
effect of prophylactic antipyretic nor measured the antibody
response.
Limitations
Only two trials (from the same country) studied the antibody
response (one trial) and carriage rate (one trial) as a result the data
could not be pooled. Studies used different doses/schedules of
antipyretic administration resulting in significant heterogeneity in
the pooled result. The age of the participants or timing of
administration also markedly differed among the studies. Only one
study from developing country (India) made it difficulty in
generalizing the present review findings.
Further area of research
Future trials should focus on the timing (before, with or after)
and route (oral or rectal) of administration of paracetamol as well
as on the subgroup of infants (term or preterm) for any correlation
with the immune response. As there was no trial examining the
prophylactic effect of ibuprofen on post-vaccination antibody
response, future trials should focus on this. Any post-vaccination
decrease in antibody titer noted in future studies should be
correlated with the natural history of that particular disease. The
mechanism underlying the decrease in immune/antibody response
should also be explored. Immune response to varicella, hepatitis A,
measles, MMR, and flu vaccine should also be studied, if feasible.
Trials should also be conducted in developing countries where
over-the-counter use of antipyretics (including prophylactic) are
common. Other confounding factors that might affect the
antibody response (e.g., infant sleep post-immunization) should
also be studied.
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 surveil-
lance 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.
Supporting Information
Checklist S1 PRISMA checklist.
(DOC)
Appendix S1 Detailed search strategy.
(DOC)
Author Contributions
Conceived and designed the experiments: RRD IP SSN. Performed the
experiments: RRD IP SSN. Analyzed the data: RRD SSN. Contributed
reagents/materials/analysis tools: RRD IP. Contributed to the writing of
the manuscript: RRD IP SSN.
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