ARTICLE

Antipyretic Agents for Preventing

Recurrences of Febrile Seizures
Randomized Controlled Trial
Teemu Strengell, MD; Matti Uhari, MD, PhD; Rita Tarkka, MD, PhD; Johanna Uusimaa, MD, PhD;
Reija Alen, MD; Pentti Lautala, MD, PhD; Heikki Rantala, MD, PhD

Objective: To evaluate the efficacy of different antipy-
retic agents and their highest recommended doses for
preventing febrile seizures.
Design: Randomized, placebo-controlled, double-
blind trial.
Setting: Five hospitals, each working as the only pedi-
atric hospital in its region.
Participants: A total of 231 children who experienced
their first febrile seizure between January 1, 1997, and
December 31, 2003. The children were observed for 2
years.
Interventions: All febrile episodes during follow-up were
treated first with either rectal diclofenac or placebo. Af-
ter 8 hours, treatment was continued with oral ibupro-
fen, acetaminophen, or placebo.
Main Outcome Measure: Recurrence of febrile
seizures.
Results: The children experienced 851 febrile episodes,
and 89 of these included a febrile seizure. Febrile seizure
recurrences occurred in 54 of the 231 children (23.4%).
There were no significant differences between the groups
in the main measure of effect, and the effect estimates were
similar, as the rate was 23.4% (46 of 197) in those receiv-
ing antipyretic agents and 23.5% (8 of 34) in those receiv-
ing placebo (difference, 0.2; 95% confidence interval, −12.8
to 17.6; P=.99). Fever was significantly higher during the
episodes with seizure than in those without seizure (39.7°C
vs 38.9°C; difference, 0.7°C; 95% confidence interval, −0.9°C
to −0.6°C; P⬍.001), and this phenomenon was indepen-
dent of the medication given.
Conclusions: Antipyretic agents are ineffective for the
prevention of recurrences of febrile seizures and for the
lowering of body temperature in patients with a febrile
episode that leads to a recurrent febrile seizure.
Trial Registration: clinicaltrials.gov Identifier:
NCT00568217
Arch Pediatr Adolesc Med. 2009;163(9):799-804

Author Affiliations:
Department of Pediatrics,
University of Oulu, Oulu
(Drs Strengell, Uhari, Tarkka,
Uusimaa, and Rantala);
Department of Pediatrics,
Satakunta Central Hospital,
Pori (Dr Tarkka); Division of
Pediatric Neurology,
Department of Pediatrics,
Central Hospital of Central
Finland, Jyväskylä (Dr Alen);
Department of Pediatrics,
Päijät-Häme Central Hospital,
Lahti (Dr Lautala); and
Department of Pediatrics, South
Carelian Central Hospital,
Lappeenranta (Dr Lautala),
Finland.
A
FEBRILE SEIZURE IS A SEI-
zure experienced in in-
fancy or childhood that is
associated with fever but
with no evidence of intra-
cranial infection, epilepsy, or any other de-
fined cause for the seizure. It occurs in 3%
to 5% of children aged 6 months to 6
years,1-4 and the recurrence rate is 20% to
30%.1-3,5 The most common cause of the
fever is a viral infection.4 The number of
febrile episodes, age, and family history of
febrile seizures are significant risk fac-
tors for further occurrence of febrile sei-
zures.4-6 Young age at the time of the first
febrile seizure increases the risk of recur-
rence, but not after adjustment for the
length of time at risk.6 Although frighten-
ing for the parents, febrile seizures in oth-
erwise healthy children have no adverse
long-term consequences.1,6-8
The general assumption has been that fe-
ver is the key factor in the initiation of a fe-
brile seizure, and it has, therefore, been sup-
posed that the administration of antipyretic
agents during febrile episodes will prevent
seizures and their recurrences by the low-
ering of the fever. This has not proved to
be the case in clinical trials, however.9,10
See also page 872
Antipyretic agents act mainly by the
alteration of prostaglandin synthesis. It
has been found in animal studies that
some prostaglandins inhibit seizures (eg,
prostaglandins D2, E1, and E2) and that
some provoke seizures (eg, prostaglan-
din F2␣).11 Elevated levels of prostagland-
ins E2 and F2␣ in the cerebrospinal fluid
have been found to be associated with
febrile seizures.12,13 Because antipyretic
agents have different effects on prosta-
glandin synthesis, it may be that some
would, in fact, provoke seizures.11

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 298 Children who had had their first febrile
seizure were assessed for eligibility

67 Were excluded
30 Did not meet inclusion criteria
37 Refused to participate

231 Were randomized

Randomly allocated groups

for rectal medication 117 Received diclofenac 114 Received placebo

Randomly allocated 76 (41 + 35) received 77 (39 + 38) received 78 (34 + 44) received
groups for oral mixture ibuprofen acetaminophen placebo

2 Did not want to continue 5 Did not want to continue 6 Did not want to continue 8 Did not want to continue 7 Did not want to continue 6 Did not want to continue
1 Was lost to follow-up 1 Was lost to follow-up 2 Were lost to follow-up 1 Had an afebrile 3 Dropped out for 1 Dropped out for
1 Had an afebrile 1 Received antiepileptics 1 Dropped out for convulsion unknown reason unknown reason
convulsion unknown reason 4 Dropped out for
unknown reason

31 Received diclofenac + 34 Received placebo + 29 Received diclofenac + 26 Received placebo + 34 Received diclofenac + 27 Received placebo +
ibuprofen ibuprofen acetaminophen acetaminophen placebo placebo

Figure 1. Profile of the trial. Patients who dropped out of the follow-up were included in the analyses as long as information was available from them.

We wanted to compare certain antipyretic agents and
their combinations to determine whether they could pre-
vent recurrences of febrile seizures. Two prostaglandin
inhibitors (diclofenac sodium and ibuprofen) were com-
pared in view of their slightly different effects on pros-
taglandin synthesis, whereas acetaminophen was
chosen because of its different mechanism compared
with the prostaglandin inhibitors.14 In previous trials in
which antipyretic agents had seemed to be ineffective,
the doses of the drugs had been relatively low: ibupro-
fen, 5 mg/kg, was administered up to 4 times a day10 and
acetaminophen, 10 mg/kg, up to 4 times a day.9 We chose
maximal dosages for the present trial. To ensure rapid
antipyresis, we decided to give the first drug, diclo-
fenac, rectally.
METHODS
The effects of antipyretic agents for treating febrile seizures were
evaluated in a placebo-controlled, double-blind, multicenter
study. Patients who had experienced their first febrile seizure
were recruited from 5 hospitals (Oulu, Satakunta, Central Fin-
land, Päijät-Häme, and South-Carelian), each of which served
in its area as the only pediatric hospital, between January 1,
1997, and December 31, 2003. The exclusion criteria were pre-
vious use of an anticonvulsant medication or a history of sei-
zures of any type.
The main outcome was the recurrence of febrile seizures in
the children allocated to the 3 oral treatment groups. Usually,
30.0% of children with febrile seizures will have a recurrence.
We considered that a 20% absolute decrease in the rate of re-
current seizures would be clinically important, and we calcu-
lated that a total of 186 individuals (62 per group) would be
required for a power of 80% and a type I error of 5%. The pro-
tocol was found to be ethically acceptable by the ethical com-
mittee of the University of Oulu Medical Faculty, and in-
formed consent was obtained from the parents. To allow for
the multiple comparison groups (placebo vs any of the anti-
pyretic agents and placebo vs each of the antipyretic agents)
and to obtain enough participants with febrile episodes (ie, at
risk of recurring febrile seizures), we decided to accept up to
230 children into the trial.
Patients were randomly allocated first into 2 groups (rectal
diclofenac vs placebo) and then into 3 groups (oral placebo vs
acetaminophen vs ibuprofen) (Figure 1). The allocation
sequence for rectal medications was generated by two of the
authors (M.U. and H.R.) by the use of random-number tables.
The allocation was performed as a block randomization with
permuted blocks with a block size of 4. Rectal diclofenac was
provided by Novartis Pharmaceuticals Corporation, Helsinki,
Finland, and rectal placebo by the University Pharmacy, Hel-
sinki, who labeled the drug containers in accordance with the
random numbers. The allocation for oral mixtures of acetami-
nophen, ibuprofen, and placebo was performed in a similarly
random fashion with a block size of 6 by Knoll Pharmaceuti-
cals, Nottingham, England, who provided these drugs. Partici-
pants were observed for 2 years. Parents were instructed to
measure the temperature of the child every time he or she had
any signs of infection and to begin administration of the study
medication immediately when the temperature was 38.0°C or

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 Table. Demographic Data of the 231 Children Allocated to Initially Receive Diclofenac or Placebo Suppositories and to Continue
Treatment With Acetaminophen, Ibuprofen, or Placebo Oral Mixture
Suppositories
Diclofenac
(n = 117)
Female sex, No. (%) 51 (43.6)
Age, mean (range), y 1.7 (0.4-3.9)
Type of first febrile seizure, No.
Simple 87
Complex 30
Family history of febrile seizures, No. 36
Family history of epilepsy, No. 4 5
Highest temperature during the first seizure, mean (SD), °C 39.8 (0.8)
higher. Treatment was started with a placebo or diclofenac
(1.5 mg/kg) suppository, and instructions were given for
treatment to be continued after 8 hours with an oral mixture
(placebo; acetaminophen, 15 mg/kg; or ibuprofen, 10 mg/kg,
each in correspondence with 0.5 mL of liquid) up to 4 times a
day for as long as the temperature remained greater than
38.0°C. The first antipyretic agent was given rectally to ensure
rapid effect. If the temperature rose above 40.0°C, parents
were allowed to give an extra dose of open-label acetamino-
phen. Parents were instructed not to use any external or other
cooling measures. Febrile seizures were treated with diazepam
rectioles. All the episodes were recorded in detail by the par-
ents by the use of a predesigned sheet that covered the symp-
toms experienced, the medications used, and the duration of
the episode. Study nurses contacted the families by telephone
at least once a month to ensure that we received information
about every febrile event, to ascertain any medication given to
the child, and to check the weight of the child. The dosage of
the mixtures was increased after each kilogram of body
weight gain. Parents were instructed to measure temperature
at least twice a day (on awakening and at bedtime), during
any episode of infection, and at the time of a seizure. Tem-
perature measurements were not standardized and were per-
formed either rectally or by the use of tympanic thermometry
in accordance with the preference of each family. In a case of
a nonfebrile seizure, the patient was excluded from any fur-
ther follow-up. At the end of follow-up, an electroencephalo-
gram and a neurological evaluation by a physician from the
team were conducted, with the examining physician being
unaware of the treatment given to the participants because all
the follow-up visits were completed before the code was
opened.
Differences between temperatures were compared by means
of a 1-way analysis of variance and paired and unpaired t tests.
Differences in the proportions of participants who experi-
enced seizure recurrences between treatment groups were tested
by the use of the standard normal deviate or binomial test.15
The effect of the type of the first febrile seizure on the number
of recurrences was analyzed by the use of the ␹2 test. Time to
the first recurrence in each treatment group was calculated, and
the equality of the cumulative Kaplan-Meier survival func-
tions across the groups was tested by the use of the log-rank
test. The possible interaction between the first randomization
and the oral treatment that followed was evaluated by analyz-
ing the significance of the interaction term in the logistic re-
gression analysis where recurrence was the end point. The data
were analyzed by the use of a statistical software program (SPSS
version 16.0.2; SPSS Inc, Chicago, Illinois). This study was ap-
proved by the ethics committee of the University of Oulu Medi-
cal Facility, Finland.
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Oral Mixture
Placebo Acetaminophen Ibuprofen Placebo
(n = 114) (n = 77) (n = 76) (n =78)
44 (38.6) 26 (33.8) 33 (43.4) 36 (46.2)
1.6 (0.4-4.0) 1.6 (0.4-3.0) 1.8 (0.7-4.0) 1.6 (0.6-3.8)
81 56 54 58
33 21 22 20
29 19 26 20
5 2 2
39.7 (0.7) 39.7 (0.8) 39.7 (0.7) 39.8 (0.7)
RESULTS
A total of 231 children, 95 girls and 136 boys aged 4
months to 4 years (mean, 1.7 years), were included in
the trial; 63 children (27.3%) had experienced a com-
plicated febrile seizure, and 27 of these had had more than
1 seizure episode during a 24-hour period when present-
ing with their index febrile seizure (Table). A further
31 of the 63 individuals had had a seizure lasting more
than 15 minutes, and 15 children had had an asymmetri-
cal seizure. Of the 231 participants, 181 completed the
2-year follow-up (Table and Figure 1). Those who
dropped out of the follow-up prematurely were in-
cluded in the analyses for as long as they participated in
the trial because we used Kaplan-Meier analyses and, thus,
we did not do any imputations for the dropouts (Table).
Children who refused to participate and those who dis-
continued the study prematurely were not different from
those who participated in the entire follow-up period. A
total of 191 participants had 851 febrile episodes during
follow-up, and there were 40 participants in whom no
febrile episodes occurred. A total of 89 recurrent febrile
seizures occurred in 54 of 231 participants (23.4%). One
patient had as many as 7 recurrences. Febrile seizures re-
curred in 8 of 34 children (23.5%) who received pla-
cebo only and in 46 of 197 (23.4%) who received any of
the antipyretic agents of the trial (difference, 0.2; 95%
confidence interval [CI], −12.8 to 17.6; P=.99). For each
febrile episode, recurrences of febrile seizures occurred
in 7.4% of those in the placebo group and in 10.9% in
the other groups. There were no significant differences
between groups in the main measure of effect, and the
effect estimates were similar. All the antipyretic agents
were ineffective in the prevention of recurrences of fe-
brile seizures (Figure 2 and Figure 3). The interac-
tion term between the first randomization and the fol-
lowing oral treatment was not significant (P =.90).
The recurrence rate of febrile seizures did not differ
between children whose initial febrile seizure was simple
vs complex (P = .38). During the 2-year follow-up pe-
riod, there were 23 complicated recurrences in 17 indi-
viduals, with the highest number in a single patient being
3. The recurrent seizures took place predominantly dur-
ing the first 2 days of the febrile episode, and the mean
duration of the seizures was 5.7 minutes. Seven partici-
WWW.ARCHPEDIATRICS.COM
 The maximum temperature measured during a fe-
1.0 brile episode was higher in those that led to a febrile sei-
0.9 zure (39.7°C) than in those that did not (38.9°C; differ-
Cumulative State Without Recurrence ence, 0.7°C; 95% CI, −0.9°C to −0.6°C; P ⬍ .001)
0.8
(Figure 4). All the antipyretic drugs were ineffective in
0.7 the lowering of the temperature during an episode that
0.6
led to a febrile seizure, and there were no significant dif-
ferences between the treatment groups (Figure 4). On
0.5
the other hand, all the antipyretic agents were effective
0.4 in the lowering of the fever in episodes that did not lead
0.3
to a febrile seizure (Figure 4).
The seizures started slightly earlier in the group whose
0.2
Placebo medication was initiated with a suppository that con-
0.1
Diclofenac tained diclofenac than in the placebo group (5 children
in the diclofenac group and 2 in the placebo group ex-
0.0
0 2 4 6 8 10 12 14 16 18 20 22 24 perienced the seizure during the 8 hours after receiving
Time, mo the rectal medication but before administration of the oral
medication), and the children in the diclofenac group had
Figure 2. State of cumulative nonrecurrence: comparison between the rectal a slightly higher fever during the first day of the febrile
diclofenac and placebo groups. episode that led to a febrile seizure (38.6°C for the pla-
cebo group and 39.0°C for the diclofenac group; differ-
ence, −0.4°C; 95% CI, −0.7°C to −0.1°C; P=.01), but there
1.0
were no differences between the oral medication groups.
0.9 There were no differences between any of the groups in
the maximum temperature during the whole febrile epi-
Cumulative State Without Recurrence

0.8
sode that led to a seizure or in the temperature mea-
0.7
sured at the time of the seizure (Figure 4). All the neu-
0.6 rologic and electroencephalographic findings after
0.5
follow-up were normal, and no adverse effects were
reported.
0.4

0.3
0.2
0.1
0.0
0 2 4 6
Figure 3. State of cumulative nonrecurrence: comparison between the oral
medication groups.
pants (5 in the diclofenac group and 2 in the placebo
group) experienced their seizures during the 8 hours af-
ter receiving the rectal medication but before adminis-
tration of the oral medication. Forty-seven of the 54 chil-
dren (87.0%) with seizures had received their oral
medication before the seizure. A total of 142 partici-
pants received extra antipyretic agents from their par-
ents during febrile episodes because of a persistent high
temperature despite use of the trial medication. The dis-
tribution of children who received extra antipyretic agents
did not differ between study groups (54%-71%; P =.32),
but children with recurrences more often received extra
antipyretic agents (51 of 54 [94.4%]) during their fe-
brile episodes than those without recurrences (91 of 134
[67.9%]) (difference, 28; 95% CI, 16 to 37; P ⬍.001).
Two individuals were excluded from the trial because
of an afebrile seizure and 1 because of the initiation of an-
tiepileptic medication by her physician owing to epilepti-
form discharges in her electroencephalogram during follow-
up. All of them had had a complicated first seizure.
COMMENT
Placebo
Acetaminophen
Ibuprofen
We found that all the antipyretic agents tested were in-
effective in the prevention of recurrent febrile seizures
8 10 12 14 16 18 20 22 24
Time, mo
and in the lowering of the raised temperature during a
febrile episode that led to a recurrent febrile seizure. The
fever was significantly higher during episodes that led
to a seizure regardless of the patient or the medication.
Thus, we found no evidence that antipyretic agents could
significantly reduce the risk of seizure recurrence, a find-
ing that is in accordance with those of previous random-
ized trials.9,10 Also, antipyretic instruction, which in-
cludes the use of antipyretic agents (either aspirin or
acetaminophen), and the sponge bathing of the child have
been ineffective in the prevention of the recurrence of
febrile seizures.16 Consequently, indications for the use
of antipyretic agents should be the same for children with
or without previous febrile seizures.
The 3 antipyretic agents used in this trial have differ-
ent effects on prostaglandin synthesis. Ibuprofen is a more
potent inhibitor of cyclooxygenase-1 than of cyclooxy-
genase-2, whereas diclofenac inhibits both enzymes.17 The
exact mechanism of acetaminophen is not known, but
it seems to act preferentially in the central nervous sys-
tem, lowering prostaglandin E2 levels during fever.14 Theo-
retically, the inhibition of different prostaglandins may
have opposite effects on seizure recurrence, which may
produce some dilutional bias in these results.
The sample size calculation was based on a consider-
ation that a 20% absolute decrease in the rate of recurrent

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 42.5
41.5
Temperature, °C
40.5
39.5
38.5
37.5
A B C A
Placebo
Participants, No. 17 16 46 20
Febrile episodes, No. 30 67 149 33
Figure 4. Maximum fever measured during a febrile episode leading to a seizure in children with recurrences (A), during an episode that does not lead to a seizure
in those with recurrences (B), and during an episode in those without seizure recurrences (C), in the oral antipyretic drug treatment groups. The horizontal bars
denote means.
seizures would be clinically important. These results do not
exclude the possibility of a lesser effect that could be de-
tected with a greater sample size. Participation in this study
was relatively good, and the dropout rate was acceptable
and similar in each treatment group (Figure 1). Parents were
allowed to give their child an extra dose of open-label acet-
aminophen if his or her temperature rose above 40.0°C.
This might cause some dilutional bias but, because the dis-
tribution of extra acetaminophen was comparable in each
treatment group, we assert that this kind of bias does not
materially affect the results.
It has been often stated that the fever in children prone
to febrile seizures should be treated very early to pre-
vent the seizures, although there is no evidence that a
rapid rise in temperature provokes seizures.18 The pres-
ent study indicates that early aggressive use of antipy-
retic agents does not prevent seizures because most of
the children (87.0%) who had a recurrence had re-
ceived their oral medication and all had received their
rectal medication before the recurrent seizure. On the
other hand, children with recurrences in the present study
had received extra antipyretic agents more often than those
without recurrences, which further indicates the inef-
fectiveness of antipyretic agents in the prevention of fe-
brile seizures.
Previous studies have been criticized because of the
relatively low doses of antipyretic agents used and the
possibly slow onset of the effect of the drug because of
oral administration.9,10 In addition, only one antipyretic
drug was compared with the placebo in each trial. Herein,
we used the highest recommended doses, administra-
tion was started rectally to ensure a rapid effect, and an-
tipyretic agents with different mechanisms of action were
used. Despite this, all the antipyretic agents were ineffi-
cient in the lowering of the fever in episodes that led to
a seizure and in the prevention of the recurrence of fe-
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B C A B C
Acetaminophen Ibuprofen
16 39 17 16 52
62 177 26 90 213
brile seizures. Rectal administration of the antipyretic
agent did not improve efficacy because the tempera-
tures of children during the first day of a febrile episode
that led to a febrile seizure were, in fact, slightly higher
in the group that received rectal diclofenac. Diclofenac
suppositories were chosen for the initiation of therapy
because they have been shown to produce a rapid and
strong decrease of fever in children.19,20
All the antipyretic agents were, nevertheless, effi-
cient in lowering the temperature during a febrile epi-
sode without a seizure (Figure 4). This, again, supports
previous findings, as ibuprofen and acetaminophen have
been found to be effective in lowering the temperature
of patients with a history of febrile seizures when ad-
ministered during febrile episodes without seizures.21 This
allows us to speculate that the mechanism of fever is dif-
ferent in febrile episodes with vs without a seizure.
In conclusion, we found that antipyretic agents were
ineffective in the prevention of the recurrence of febrile
seizures and in the lowering of the fever during an epi-
sode that leads to a recurrent seizure. Because antipy-
retic agents are effective during a febrile episode that does
not lead to a seizure, their use should not differ between
patients with and without previous febrile seizures. Par-
ents should be informed about the inefficacy of antipy-
retic agents during a febrile episode that leads to a fe-
brile seizure and about the benign nature of febrile seizures
themselves.
Accepted for Publication: February 4, 2009.
Correspondence: Heikki Rantala, MD, PhD, Depart-
ment of Pediatrics, University of Oulu, PO Box 5000, Oulu
90014, Finland (heikki.rantala@oulu.fi).
Author Contributions: Dr Rantala had full access to all
the data in the study and takes responsibility for the in-
tegrity of the data and the accuracy of the data analysis.
WWW.ARCHPEDIATRICS.COM
Study concept and design: Strengell, Uhari, Tarkka, Alen,
and Rantala. Acquisition of data: Uhari, Tarkka, Uusi-
maa, Alen, Lautala, and Rantala. Analysis and interpre-
tation of data: Strengell, Uhari, and Rantala. Drafting of
the manuscript: Strengell, Uhari, Tarkka, Uusimaa, and
Rantala. Critical revision of the manuscript for important
intellectual content: Uhari, Alen, Lautala, and Rantala. Sta-
tistical analysis: Uhari and Rantala. Obtained funding:
Uhari, Tarkka, Alen, and Rantala. Administrative, tech-
nical, or material support: Strengell, Uhari, Uusimaa, Alen,
and Rantala. Study supervision: Uhari and Rantala.
Financial Disclosure: None reported.
Funding/Support: This study was supported by Special
State Grants for Health Research in the Department of
Pediatrics and Adolescence in the Oulu University Hos-
pital.
Role of the Sponsor: The funding source had no role in
the study design; in the collection, analysis, or interpre-
tation of the data; in the writing of the report; or in the
decision to submit the paper for publication.
Additional Contributions: Niilo-Pekka Huttunen, MD,
PhD, recruited patients in the Central Hospital of Cen-
tral Finland; Salli Saulio, RN, gave invaluable help in col-
lecting the follow-up data; and Tytti Pokka, BSc, helped
in preparing the final manuscript.
REFERENCES
1. Nelson KB, Ellenberg JH. Prognosis in children with febrile seizures. Pediatrics.
1978;61(5):720-727.
2. Berg AT, Shinnar S, Hauser WA, Leventhal JM. Predictors of recurrent febrile
seizures: a meta-analytic review. J Pediatr. 1990;116(3):329-337.
3. Offringa M, Hazebroek-Kampschreur AA, Derksen-Lubsen G. Prevalence of fe-
brile seizures in Dutch schoolchildren. Paediatr Perinat Epidemiol. 1991;5(2):
181-188.
4. Rantala H, Uhari M, Hietala J. Factors triggering the first febrile seizure. Acta Paediatr.
1995;84(4):407-410.
5. Shinnar S, Berg AT, Moshe SL, et al. Risk of seizure recurrence following a first
unprovoked seizure in childhood: a prospective study. Pediatrics. 1990;85
(6):1076-1085.
6. Tarkka R, Rantala H, Uhari M, Pokka T. Risk of recurrence and outcome after the
first febrile seizure. Pediatr Neurol. 1998;18(3):218-220.
7. Verity CM, Butler NR, Golding J. Febrile convulsions in a national cohort fol-
lowed up from birth, II: medical history and intellectual ability at 5 years of age.
Br Med J (Clin Res Ed). 1985;290(6478):1311-1315.
8. Verity CM, Ross EM, Golding J. Outcome of childhood status epilepticus and
lengthy febrile convulsions: findings of national cohort study. BMJ. 1993;307
(6898):225-228.
9. Uhari M, Rantala H, Vainionpää L, Kurttila R. Effect of acetaminophen and of low
intermittent doses of diazepam on prevention of recurrences of febrile seizures.
J Pediatr. 1995;126(6):991-995.
10. van Stuijvenberg M, Derksen-Lubsen G, Steyerberg EW, Habbema JD, Moll HA.
Randomized, controlled trial of ibuprofen syrup administered during febrile ill-
nesses to prevent febrile seizure recurrences. Pediatrics. 1998;102(5):E51.
11. Rantala H, Tarkka R, Uhari M. Systematic review of the role of prostaglandins
and their synthetase inhibitors with respect to febrile seizures. Epilepsy Res. 2001;
46(3):251-257.
12. Tamai I, Takei T, Maekawa K, Ohta H. Prostaglandin F2␣ concentrations in the
cerebrospinal fluid of children with febrile convulsions, epilepsy and meningitis.
Brain Dev. 1983;5(4):357-362.
13. Löscher W, Siemes H. Increased concentration of prostaglandin E-2 in cerebro-
spinal fluid of children with febrile convulsions. Epilepsia. 1988;29(3):307-
310.
14. Aronoff DM, Neilson EG. Antipyretics: mechanisms of action and clinical use in
fever suppression. Am J Med. 2001;111(4):304-315.
15. Armitage P, Berry G, Matthews JNS. Analysing means and proportions. In: Sta-
tistical Methods in Medical Research. 4th ed. Oxford, England: Blackwell Sci-
ence; 2002:124-125.
16. Camfield PR, Camfield CS, Shapiro SH, Cummings C. The first febrile seizure:
antipyretic instruction plus either phenobarbital or placebo to prevent recurrence.
J Pediatr. 1980;97(1):16-21.
17. Mitchell JA, Akarasereenont P, Thiemermann C, Flower RJ, Vane JR. Selectivity
of nonsteroidal anti-inflammatory drugs as inhibitors of constitutive and induc-
ible cyclooxygenase. Proc Natl Acad Sci U S A. 1993;90(24):11693-11697.
18. Berg AT. Are febrile seizures provoked by a rapid rise in temperature? Am J Dis
Child. 1993;147(10):1101-1103.
19. Keinänen-Kiukaanniemi S, Similä S, Käpylä H. Antipyretic therapy: evaluation of
diclofenac sodium as an antipyretic agent. Clin Ther. 1980;2:421-426.
20. Polman HA, Huijbers WA, Augusteijn R. The use of diclofenac sodium (Voltaren姞)
suppositories as an antipyretic in children with fever due to acute infections: a
double-blind, between-patient, placebo-controlled study. J Int Med Res. 1981;
9(5):343-348.
21. Van Esch A, Van Steensel-Moll HA, Steyerberg EW, Offringa M, Habbema JDF,
Derksen-Lubsen G. Antipyretic efficacy of ibuprofen and acetaminophen in chil-
dren with febrile seizures. Arch Pediatr Adolesc Med. 1995;149(6):632-637.

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