Prophylactic Drug Management for Febrile Seizures in Children

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PROPHYLACTIC DRUG MANAGEMENT FOR FEBRILE SEIZURES IN CHILDREN

Offringa Martin, Newton Richard

Offringa Martin, Newton Richard

Cochrane Database of Systematic Reviews, Issue 4, 2013 (Status in this issue: NEW)

Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.DOI: 10.1002/14651858.CD003031.pub4 This review should be cited as: Offringa Martin, Newton Richard. Prophylactic drug management for febrile seizures in

children. Cochrane Database of Systematic Reviews. In: The Cochrane Library, Issue 4, Art. No. CD003031. DOI:10.1002/14651858.CD003031.pub4

A B S T R A C T

Background

Febrile seizures occurring in a child older than one month during an episode of fever affect 2% to 4% of children inGreat Britain and the United States and recur in 30%. Rapid-acting antiepileptics and antipyretics given duringsubsequent fever episodes have been used to avoid the adverse effects of continuous antiepileptic drugs.

Objective

To evaluate the effectiveness and safety of antiepileptic and antipyretic drugs used prophylactically to treat childrenwith febrile seizures.

REVIEW_ABS_OTHER

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011. Issue 3);MEDLINE (1966 to May 2011); EMBASE (1966 to May 2011); Database of Abstracts of Reviews of Effectiveness (DARE)(May 2011). No language restrictions were imposed. We also contacted researchers in the field to identify continuing orunpublished studies.

Selection criteria

Trials using randomised or quasi-randomised patient allocation that compared the use of antiepileptic or antipyreticagents with each other, placebo or no treatment.

Data collection and analysis

Two review authors (RN and MO) independently applied pre-defined criteria to select trials for inclusion and extractedthe pre-defined relevant data, recording methods for randomisation, blinding and exclusions. Outcomes assessed were

seizure recurrence at 6, 12, 18, 24, 36 months and at age 5 to 6 years in the intervention and non-intervention groups,and adverse medication effects. The presence of publication bias was assessed using funnel plots.

Main results

Thirty-six articles describing 26 randomised trials with 2740 randomised participants were included. Thirteeninterventions of continuous or intermittent prophylaxis and their control treatments were analysed. Methodologicalquality was moderate to poor in most studies. We could not do a meta-analysis for eight of the 13 comparisons due toinsufficient numbers of trials. No significant benefit for valproate, pyridoxine, intermittent phenobarbitone or ibuprofenversus placebo or no treatment was found; nor for diclofenac versus placebo followed by ibuprofen, acetominophen orplacebo; nor for intermittent rectal diazepam versus intermittent valproate, nor phenobarbitone versus intermittentrectal diazepam.

Authors' conclusions

No clinically important benefits for children with febrile seizures were found for intermittent oral diazepam, phenytoin,phenobarbitone, intermittent rectal diazepam, valproate, pyridoxine, intermittent phenobarbitone or intermittentibuprofen, nor for diclofenac versus placebo followed by ibuprofen, acetominophen or placebo. Adverse effects werereported in up to 30% of children. Apparent benefit for clobazam treatment in one recent trial needs to be replicated to

be judged reliable. Given the benign nature of recurrent febrile seizures, and the high prevalence of adverse effects of these drugs, parents and families should be supported with adequate contact details of medical services andinformation on recurrence, first aid management and, most importantly, the benign nature of the phenomenon.

P L A I N L A N G U A G E S U M M A R Y

Seizures occurring in association with fever are the most common neurologic disorder in children, affecting two to fourper cent of all children. On average, one out of three children with febrile seizures have recurrent seizures. In thisreview the effects of antiepileptic and antipyretic medications to prevent recurrent seizures was examined. Nosignificant or important benefits of these medications were found for children with febrile seizures. Adverse effects of the medications were common. The benefit found for treatment with clobazam in one 2011 study needs to be repeatedto show that this finding is reliable. Meanwhile, parents and families should be supported with the adequate contactdetails of medical services and information on recurrence, first aid management and, most importantly, the benign

nature of the phenomenon.



B A C K G R O U N D

A febrile seizure is defined as a seizure occurring in a child older than one month during an episode of fever. Whilestudies throughout the world differ in what they accept as an upper age limit, febrile seizures usually occur in childrenbetween the ages of six months and five years ( Nelson 1981 ). Simple febrile seizures are brief (< 15 minutes),generalised, and occur in association with fever and only once during a 24-hour period ( Nelson 1981 ). Children whoseseizures are attributable to a central nervous system infection and those who have had a previous afebrile seizure orcentral nervous system abnormality are not considered to have simple febrile seizures.

Seizure occurring in association with fever is the most common neurologic disorder in paediatrics, and affects 2% to 4%of all children in Great Britain and the United States ( Verity 1985 ). Despite the frequent nature of these seizures,debate continues regarding the optimal management ( Baumann 1999 ). After resolution of the acute episode, thepossibility of recurrent seizures during subsequent febrile illnesses must be addressed. This risk of recurrent seizures inpreviously healthy, untreated children was estimated in a collaborative study that used the individual data from fivefollow-up studies with similar definitions of febrile seizures and risk factors ( Offringa 1994 ). Of a total of 2496 childrenwith 1410 episodes of recurrent seizures in this study, 32% had at least one, 15% had at least two and 7% had threeor more recurrent seizures after a first febrile seizure. The hazard of recurrent seizures was highest between the agesof 12 and 24 months. A history of febrile or unprovoked seizures in a first-degree family member, a relatively lowtemperature at the first seizure, young age at onset (< 12 months), a family history of unprovoked seizures, and apartial initial febrile seizure were all associated with an increased risk of subsequent seizures.

If a child is considered at increased risk of frequent or complicated seizures ( Berg 1990 ), prophylactic medicationmight be considered. However, such treatment may have adverse effects on the child's behaviour and cognitivedevelopment. Thus, the decision to treat requires assessment of the potential risks and benefits to the child. Since1990, at least 300 articles have been published on the drug management of seizures associated with fever ( Gram1984 ). This has been a controversial area for a long time, with a persisting variety of opinions on management. Part of

this controversy reflects the fact that it is uncertain whether prophylactic medication with antiepileptics and antipyreticsis effective and has no important adverse effects. Yet, phenobarbital has adverse effects such as irritability,hyperactivity, and somnolence, and may even lower the cognitive development of the toddlers ( Farwell 1990 ; Herranz1988 ). To avoid the side effects of continuous antiepileptic drugs (AEDs), rapid-acting antiepileptics given only duringfever periods have been used in an attempt to reduce the risk of recurrent febrile seizures. Phenobarbital at times of fever has been proven ineffective, probably because of the delay in achieving appropriate serum and tissue levels. Thusfar, only prophylactic diazepam, given orally or rectally, has been studied in placebo-controlled trials. The efficacy of intermittent antipyretic treatment during febrile episodes in the prevention of seizure recurrence has recently beenstudied.

Newton assessed the efficacy of phenobarbitone and valproate for the prophylactic treatment of febrile seizures bysummarising the results from all eight British placebo-controlled clinical trials that were done before 1988 ( Newton1988). Data were pooled and analysed on an intention-to-treat basis. The overall odds ratio of recurrent febrile seizuresfor phenobarbitone was 0.8 and for valproate 1.42. Neither result was statistically significant. The author thereforeconcluded that neither treatment is to be recommended. A second meta-analysis summarised four published non-British randomised, placebo-controlled trials that had been done up to 1996 using phenobarbital as a preventivetreatment of febrile seizures ( Rantala 1997 ). The risk of recurrences was lower in children receiving continuousphenobarbital therapy than in the placebo group (odds ratio 0.54, 95% confidence interval (CI) 0.33 to 0.90). On

average, eight children would have to be treated with phenobarbital for two years continuously to prevent one febrileseizure (number needed to treat to benefit (NNT Benefit) 8, 95% CI 5 to 27) ( Rantala 1997 ).

We undertook this review to answer the question whether prophylactic treatment with an antiepileptic drug or anantipyretic can, as compared to no therapy, decrease the likelihood of future febrile seizures in children with febrileseizures.

O B J E C T I V E S

To evaluate the effectiveness and safety of antiepileptic and antipyretic drugs used to prophylactically treat childrenwith febrile seizures.

M E T H O D S O F T H E R E V I E W

C R I T E R I A F O R C O N S I D E R I N G S T U D I E S F O R T H I S R E V I E W

Types of studies

All trials using randomised or quasi-randomised patient allocation that compared the use of antiepileptic or antipyreticagents with each other or with placebo or no treatment were included.

Types of participants

Children aged between six months and seven years with a history of febrile seizures and who received treatment withan antiepileptic drug or an antipyretic drug in an attempt to prevent recurrent seizures. A subgroup analysis of neurologically healthy children, children with previous recurrent seizures, and of studies limited to children at aperceived relatively high risk of recurrence was planned.

Types of intervention

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Trials were included if they compared one treatment with another or with placebo (or no treatment) in children withfebrile seizures. Specific drugs included the benzodiazepines (diazepam, lorazepam, clobazam and midazolam),phenytoin, phenobarbitone, valproate, diclofenac, acetaminophen and ibuprofen. A subgroup analysis of intermittentantiepileptic drug (AED) therapies versus continuous AED therapies, and of antipyretics during episodes of fever versusAED therapy during fever was planned.

Types of outcome measures

1) Efficacy: whether febrile or non-febrile seizures recurred at certain time points after treatment onset (6 months, 12months, 24 months, 36 months, and at age five years).2) Safety: the incidence of specific adverse side-effects, irritability, hyperactivity, somnolence, impaired cognitivedevelopment for phenobarbital and intermittent diazepam, gastro-enterologic side effects for valproate and antipyretics,of any administered antiepileptic or antipyretic.

S E A R C H M E T H O D S F O R I D E N T I F I C A T I O N O F S T U D I E S

Search methods for identification of studies

Electronic searches

We searched the following databases. No language restrictions were imposed.

a) Cochrane Epilepsy Group Specialised Register (1 July 2011).

b) Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 3)

c) MEDLINE (Ovid) (1950 to 31 May 2011).

d) EMBASE (1966 to May 2011).

Details of the search strategies used are outlined in Appendix 1 .

Searching other resources

We checked the reference lists of articles identified by the above searches for additional studies. We also contactedresearchers in the field to find any ongoing or published studies.

D A T A C O L L E C T I O N A N D A N A L Y S I S

Data collection and analysis

Two authors (RN and MO) independently assessed trials for inclusion. The same authors extracted the outcome dataspecified above as well as the following data. Any disagreements were resolved by discussion.

Methodological and trial design:a. method of randomisation;b. method of double blinding;c. whether any patients had been excluded from the reported analyses.Where data were missing, attempts were be made to contact original authors for this information.

Patient and demographic information:a. total number of patients allocated to each treatment group or audited in any protocol;b. the proportion of patients in each treatment group with a recurrence at certain time points (6 months, 12 months, 24months, 36 months, 48 months and 72 months, where these data were available);

c. risk factors associated with recurrent seizures, i.e. age at first seizure below 18 months, positive family history of seizures, temperature at index seizure below 40.0 °C.

Data analysis plan

Comparisons were made for studies comparing either different drugs or different treatment approaches, for exampleintermittent AED therapies versus continuous AED therapies, antipyretics during episodes of fever versus AED therapyduring fever, or all versus placebo. The primary analysis was intention to treat and included all randomised patientsanalysed in the treatment group to which they were allocated, irrespective of which treatment they actually received.Meta-analysis was done if sufficient data were available, that is at least two trials looking at the same two treatmentsand the same outcomes. Clinical heterogeneity was assessed by reviewing the differences across trials in thecharacteristics of recruited patients and treatment protocols. Statistical heterogeneity was assessed using a Chi2 testfor heterogeneity. Dichotomous outcomes were expressed as relative risks (RR) with 95% confidence intervals (CIs).The presence of publication bias was assessed using funnel plots.

M E T H O D O L O G I C A L Q U A L I T Y

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R E S U L T S

Results

Description of studies

See: Characteristics of included studies ; Characteristics of excluded studies .

Among 79 articles identified as potentially relevant, only 36 articles met the criteria for this review (see Characteristicsof included studies ). Together, these 36 articles described 26 randomised trials and their (long-term) follow up. Thedetails of the other 43 studies are given in Characteristics of excluded studies .

The interventions compared against placebo included intermittent oral diazepam in four studies ( Autret1990 ;Ramakrishnan 1986 ; Rosman 1993 ; Verrotti 2004 ), continuous oral phenytoin in one study ( Bacon 1981a ),continuous oral phenobarbitone in 10 studies ( Bacon 1981a ; Camfield 1980 ; Farwell 1990 ; Heckmatt 1976 ; Mamelle1984 ; McKinlay 1989 ; Ngwane 1980 ; Ramakrishnan 1986 ; Thilothammal 1993 ; Wolf 1977a ), intermittent rectaldiazepam in four studies ( Knudsen 1985a ; Mosquera 1987 ; Pavlidou 2006 ; Uhari 1995 (where a rectal dose wasfollowed by orals doses for the time of the fever)), continuous oral valproate in five studies ( McKinlay 1989 ; Mamelle1984 ; Mosquera 1987 ; Ngwane 1980 ; Williams 1979 ), continuous oral pyridoxine in one study ( McKiernan 1981 ),intermittent oral phenobarbitone in three studies ( Mackintosh 1970 ; Ramakrishnan 1986 ; Wolf 1977a ), intermittentoral ibuprofen in one study ( van Stuijvenberg 1998 ), intermittent rectal diclofenac versus placebo followed after eighthours by ibuprofen or acetominophen in one study ( Strengell 2009 ), intermittent rectal diazepam and intermittentrectal valproate in one study ( Daugbjerg 1990 ), intermittent oral clobazam in one study ( Bajaj 2005 ), intermittentoral clobazam with intermittent diazepam in one study ( Khosroshahi 2011 ); and a comparison was made betweencontinuous oral phenobarbitone and intermittent rectal diazepam in one study ( Garcia 1984 ).

In total, these studies enrolled 3980 participants with febrile seizures among whom the results of 2740 children wereavailable to include in this review. The number of participants enrolled (and analysed) for each intervention versusplacebo was as follows: intermittent oral diazepam 821 (782) (in 4 studies); phenytoin 207 (138) (in 1 study);phenobarbitone 1535 (1073) (in 10 studies); intermittent rectal diazepam 677 (608) (in 4 studies); valproate 411(303) (in 5 studies); pyridoxine 107 (107) (in 1 study); intermittent phenobarbitone 507 (507) ( in 3 studies);intermittent ibuprofen 230 (230) (in 1 study); intermittent rectal diazepam versus valproate (as opposed to notreatment or placebo) 219 (169) (in 1 study) phenobarbitone versus intermittent rectal diazepam 100 (100) (in 1study); diclofenac versus placebo followed after 8 hours by ibuprofen, acetominophen or placebo 80 (75) (in 1 study);clobazam 60 (60) (in 1 study) and clobazam versus diazepam 80 (72) (in 1 study). It should be noted that a number of these papers included a comparison of outcomes in placebo versus one of two randomised seizure treatments (that is Aversus C; B versus C). As no pooled analyses were done in which the effects of different antiepileptic or antipyreticdrugs were summarised and compared with (placebo) controls, we did not introduce unit-of-analysis errors. Familieswithdrew from these studies for various reasons, including change of residence, withdrawal of consent, and a variety of unacceptable adverse effects detailed in so far as was possible in the additional table 'Unwanted medication effects' ( ).

Study outcomes included a comparison of observed and expected seizure recurrence frequency at time points rangingbetween six and 48 months after randomisation, and in one case ( Ramakrishnan 1986 ) at 60 to 72 months.

A brief description of the 26 original studies reported in the articles included in this review

Autret 1990 was a study of 185 children, aged 8 to 36 months, after their first febrile seizure and with less than tworisk factors for recurrence. Interventions were intermittent oral diazepam (0.5 mg load and 0.2 mg/kg maintenance) orplacebo. Outcomes assessed were recurrent seizures at 12 months after randomisation and adverse medication effectsduring the 12 months of treatment.

Bacon 1981a and Bacon 1981b reported on a single study involving 270 children following a first febrile seizure. Therewere three arms to this study. Children were allocated either to treatment with continuous oral phenytoin 8 mg/kg/day,continuous oral phenobarbitone 5 mg/kg/day, or placebo and followed for assessment of recurrent seizures at 12months after randomisation and adverse medication effects during the 12 months of treatment.

Bajaj 2005 studied 60 children aged 6 months to 5 years presenting with one or more febrile seizures. Children wereallocated to intermittent oral clobazam (0.75 mg/kg body weight twice daily) or placebo during the course of fever andfollowed for assessment of recurrent seizures at 6 months after randomisation and adverse medication effects duringthe 6 months of treatment.

Camfield 1980 was a study of 97 children aged 6 to 36 months following a first febrile seizure. Children were allocatedeither to treatment with continuous oral phenobarbitone 4 to 5 mg/kg/day or placebo (both groups treated withantipyretics) and followed for assessment of recurrent seizures at 12 months after randomisation. In another paper(Camfield 1979 ) the authors assessed the adverse effects of phenobarbitone in toddlers, including behavioural andcognitive aspects, during the 12 months of treatment using the same cohort as in Camfield 1980 .

Daugbjerg 1990 studied 169 children following a first febrile seizure. Children were allocated either to intermittentrectal diazepam (5 mg for those younger than 3 years or 7.5 mg for those 3 years or over) or intermittent valproatesuppositories (150 mg for those weighing less than 10 mg or 300 mg for those weighing 10 kg of more). They werefollowed for assessment of recurrent seizures at 6 and 12 months after randomisation and adverse medication effectsduring 12 months of treatment.

Farwell 1990 was a study of 217 children following a first febrile seizure and who had at least one risk factor forrecurrence. They were allocated either to treatment with continuous oral phenobarbitone 4 to 5 mg/kg/day or placeboand followed for assessment of recurrent seizures at 6, 12, 18, and 24 months after randomisation; and adversemedication effects after 24 months of treatment. Sleep disturbances were reported in Hirtz 1993 and the late cognitiveeffects of phenobarbital for this study were reported in Sulzbacher 1999 .

Garcia 1984 studied 100 children aged 6 to 60 months following a first febrile seizure (simple or complex) with randomallocation either to intermittent rectal diazepam (0.5 mg/kg/dose 8 hourly for the duration of the fever) or continuous





















































































































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oral phenobarbitone (5 mg/kg/day) plus antipyretics for both group. Chi ldren were followed for assessment of recurrentseizures at 18 months after randomisation and adverse medication effects during these 18 months of treatment.

Heckmatt 1976 was a study of 165 children with a mean age of 20 months following a first febrile seizure. They wereallocated either to treatment with continuous oral phenobarbitone 4 to 5 mg/kg/day or no treatment. The children werefollowed for assessment of recurrent seizures at 6 months after randomisation and adverse medication effects duringthe 6 months of treatment.

Knudsen 1985a , Knudsen 1985b reported on a single study of 289 children following their first febrile seizure, allocated

either to intermittent rectal diazepam (5 mg for children less than 3 years or 7.5 mg for those aged over 3 years)compared to no treatment. They were followed for assessment of recurrent seizures at 6, 12, and 18 months afterrandomisation and adverse medication effects during 18 months of treatment.

Khosroshahi 2011 studied 72 children aged 6 months to 5 years who had had a simple febrile seizure. They wereallocated either to intermittent oral diazepam (0.33 mg/kg/ dose every 8 h for 2 days) or intermittent oral clobazam for2 days with the following dosages: 5 mg, daily in children up to 5 kg; 5 mg twice daily (BD) in children 6 to 10 kg; 7.5mg BD in children 11 to 15 kg; and 10 mg BD in children > 15 kg. Children were followed for assessment of recurrentseizures at 12 months after randomisation, and adverse medication effects during these 12 months of treatment.

Mackintosh 1970 was a study of 32 children aged 6 to 16 months who had had a first febrile seizure. They wereallocated either to intermittent oral phenobarbitone at 30 mg with acetyl acetic acid 150 mg or placebo and followed forassessment of recurrent seizures at 6, 12, and 24 months after randomisation; adverse medication effects were notaddressed.

Mamelle 1982 and Mamelle 1984 reported on one study of 69 children aged 6 to 48 months following a first febrileseizure (excluding those with focal seizures or neuropsychiatric disorders). These were allocated either to treatmentwith continuous oral phenobarbitone 3 to 4 mg/kg/day, continuous oral valproate 30 to 40 mg/kg/day, or placebo andfollowed for assessment of recurrent seizures at 18 months after randomisation; adverse medication effects were notaddressed.

McKiernan 1981 studied 107 children aged 6 to 52 months who had had a first or second febrile seizure. Children in theactive treatment arm received continuous oral pyridoxine (in two doses of 20 mg) or placebo. They were followed forassessment of recurrent seizures at 12 months after randomisation; adverse medication effects were not addressed.

McKinlay 1989 was a study of 151 children aged 6 to 72 months who had had at least one previous febrile seizure or acomplicated febrile seizure. There were three arms to this study. Children were allocated either to treatment withcontinuous oral phenobarbitone 5 mg/kg/day, continuous oral valproate 30 mg/kg/day or no treatment and followed forassessment of recurrent seizures at 6, 12, and 24 months after randomisation, and adverse medication effects duringthe 24 months of treatment.

Mosquera 1987 studied 69 children following a first febrile seizure and allocated to intermittent rectal diazepam 0.5mg/kg/dose, continuous oral valproate 30 mg/kg/day or no treatment. Children were followed for assessment of recurrent seizures at 6, 12, and 24 months after randomisation; adverse medication effects were not addressed.

Ngwane 1980 was a study of 64 children aged 6 to 18 months following a first febrile seizure. There were three arms tothis study with allocation either to phenobarbitone 3 to 6 mg/kg/day, valproate 30 to 60 mg/kg/day or no treatment.

Children were followed for a mean of 12 months after randomisation to assess recurrent seizures and adversemedication effects.

Pavlidou 2006 studied 139 children aged 6 to 36 months that were randomly assigned in a prospective controlled trialto receive either intermittent prophylaxis with rectal diazepam or no prophylaxis. The children were followed forassessment of recurrent seizures at 6, 12, and 36 months after randomisation and adverse medication effects during 36months of treatment.

Ramakrishnan 1986 studied 120 children aged 2 to 72 months following a first febrile seizure. These children wereallocated to continuous oral phenobarbitone 3 to 5 mg/kg/day, intermittent oral phenobarbitone in the same dosage,intermittent oral diazepam 0.6 mg/kg/day or no treatment. They were followed for assessment of recurrent seizures at60 to 72 months after randomisation and adverse medication effects during the period of treatment.

Rosman 1993 studied 406 children aged 6 to 60 months who had had at least one febrile seizure. The interventionswere intermittent oral diazepam 1 mg/kg/day or placebo. Outcomes were recurrent seizures at 6 months, 12 months,and 24 months and adverse treatment effects at 24 months.

Strengell 2009 was a study of 231 children aged 4 months to 4 years who had had a first febrile seizure. All febrileepisodes during follow up were treated first with either intermittent rectal diclofenac or placebo. After 8 hours,

treatment was continued with oral ibuprofen 5mg/kg up to four times a day, oral acetaminophen 10mg/kg up to fourtimes a day or placebo. Children were followed for assessment of recurrent seizures at 6, 12, 18, and 24 months afterrandomisation; adverse medication effects were not addressed.

Thilothammal 1993 studied 90 children aged 6 to 72 months following a first febrile seizure and allocated either totreatment with continuous oral phenobarbitone 5 mg/kg/day or placebo. The children were then followed forassessment of recurrent seizures at 6 and 12 months and for adverse medication effects after 12 months of treatment.

Uhari 1995 studied 180 children following a first febrile seizure and allocated to intermittent rectal followed byintermittent oral diazepam 0.6 mg/kg or placebo. Both groups were treated with antipyretics for the duration of thefever. They were followed for assessment of recurrent seizures at 6, 12, and 24 months after randomisation andadverse medication effects during the 24 months of treatment.

van Stuijvenberg 1998 studied 230 children aged 12 to 48 months who had a febrile seizure and at least one risk factorfor recurrence. Children were allocated either to intermittent oral Ibuprofen 5 mg/kg/day or placebo and followed forassessment of recurrent seizures during 24 months after randomisation. We used estimates from the reported KaplanMeier curves to assess recurrent seizures at 12, 18, and 24 months after randomisation; adverse medication effectswere not addressed.

Verrotti 2004 studied 110 children aged 6 months to five years with one simple febrile seizure; 45 children were'randomly' allocated to treatment with intermittent oral diazepam (0.35 mg/kg every 8 h) during each episode of feverhigher than 38 8 °C, continuing until the child had been afebrile for 24 h; and 65 children were allocated to a group




























































with no treatment. They were followed for assessment of recurrent seizures at 48 months after randomisation andadverse medication effects during the 48 months of treatment.

Williams 1979 studied 58 children aged 6 to 72 months after a second simple febrile seizure. Children in the activetreatment group were allocated to continuous oral valproate 40 mg/kg/day and were compared with children on notreatment. They were followed for assessment of recurrent seizures and adverse medication effects at 12 months afterrandomisation.

Wolf 1977a was a study of 355 children aged 6 to 48 months who had had a first febrile seizure. There were three arms

to this study. Children were allocated either to continuous oral phenobarbitone 3 to 4 mg/kg/day, intermittent oralphenobarbitone 5 mg/kg/day or no treatment. They were followed for assessment of recurrent seizures at 6, 12, and24 months after randomisation and adverse medication effects during the 24 months of treatment. In Wolf 1978 behavior disturbances were reported and in Wolf 1981 the long-term effect of phenobarbital on cognitive functionwas reported.

Risk of bias in included studies

Study population sizes varied from 32 to 406. These were associated with numbers in one treatment arm ranging from16 ( Mackintosh 1970 ) up to 204 ( Rosman 1993 ). Clearly smaller studies were very prone to the effect of a treatmentbeing over or under exaggerated.

Satisfactory allocation concealment was noted in seven studies ( Farwell 1990 ; Mackintosh 1970 ; McKiernan1981 ;Ngwane 1980 ; Rosman 1993 ; Uhari 1995 ; van Stuijvenberg 1998 ); no concealment was attempted in eightstudies (Heckmatt 1976 ; Khosroshahi 2011 ; Knudsen 1985a ; Knudsen 1985b ; McKinlay 1989 ; Pavlidou2006 ; Verrotti 2004 ;Wolf 1977a ), which used a method of quasi-randomisation. In the remainder of the studies themethod of allocation concealment, if any, was unclear.

Ten studies were double blinded ( Autret 1990 ; Bajaj 2005 ; Camfield 1979 ; Farwell 1990 ; Mackintosh1970 ;McKiernan 1981 ; Rosman 1993 ; Thilothammal 1993 ; Uhari 1995 ; van Stuijvenberg 1998 ); one study wassingle blinded ( Mamelle 1984 ); and there was no blinding in eight studies ( Bacon 1981a and Bacon1981b ; Daugbjerg 1990 ;Garcia 1984 ; Mosquera 1987 ; Ramakrishnan 1986 ; Strengell 2009 ; Sulzbacher1999 ; Williams 1979 ).

In many studies the analysis did not include all enrolled participants (for example, 69 of 270 enrolled participantsinBacon 1981a and Bacon 1981b ). It must be noted that most of the included studies were undertaken 20 to 30 yearsago, since when the rigour of undertaking and reporting RCTs has improved.

Publication bias

We made three comparisons: phenobarbitone versus placebo to recurrence at 6 and 12 months (comparisons 3.1 and3.2), and valproate versus placebo or no treatment (comparison 5.2). These were the only comparisons to containsufficient numbers of studies to be able to examine a funnel plot. We did not find evidence of publication bias for

comparison 3.1 ( ), but we did find evidence of publication bias for 3.2 ( ) and for comparison 5.2 ( ). There were toofew studies to comment on whether there was publication bias for the other comparisons.

Effects of interventions

See: Summary of findings for the main comparison Intermittent oral diazepam versus placebo for febrile seizures inchildren ; Summary of findings 2 Continuous oral phenytoin versus placebo for febrile seizures ; Summary of findings 3Continuous oral phenobarbitone versus placebo or no treatment for febrile seizures ; Summary of findings 4Intermittent rectal diazepam versus no treatment or placebo for febrile seizures ; Summary of findings 5 Continuousoral valproate versus placebo or no treatment for febrile seizures ; Summary of findings 6 Continuous oral pyridoxineversus placebo for febrile seizures ; Summary of findings 7 Intermittent oral phenobarbitone versus no treatment forfebrile seizures ;Summary of findings 8 Intermittent oral ibuprofen versus placebo for febrile seizures ; Summary of findings 9 Intermittent rectal diazepam versus intermittent rectal valproate for febrile seizures ; Summary of findings10 Continuous oral phenobarbitone versus intermittent rectal diazepam for febrile seizures ; Summary of findings 11Intermittent rectal diclofenac versus placebo followed after 8 hours by oral ibuprofen, acetaminophen or placebo forfebrile seizures ; Summary of findings 12 Intermittent oral clobazam versus placebo for febrile seizures ; Summary of findings 13 Intermittent oral diazepam versus oral clobazam for febrile seizures

Below we have described the results of 13 comparisons, followed by a description of the recurrence risk of febrileseizures in the non-intervention groups and the occurrence of adverse medication effects.

1. Intermittent oral diazepam versus placebo

Autret 1990 had outcome data at 12 months; Rosman 1993 had outcome data at 6, 12 and 24 months;whereas Verrotti 2004 had data from 6, 12, 24, and 48 months; and Ramakrishnan 1986 had data on outcomes at 72months. Autret 1990 studied 185 children aged 8 to 36 months who had had a first febrile seizure and with less thantwo risk factors for recurrence. Rosman 1993 f ollowed 406 children aged 6 to 60 months who had had at least onefebrile seizure. Verrotti 2004 studied 110 children aged 6 months to 5 years who had had a simple febrileseizure. Ramakrishnan 1986 studied 120 children aged 2 to 72 months who had had a first febrile seizure.

The studies had slightly different approaches to therapy. In Autret 1990 diazepam was administered in a 0.5 mg/kgload with a maintenance dose during the febrile period of 0.2 mg/kg/day. Rosman 1993 used a slightly higher dose, of 1 mg/kg/day. Verrotti 2004 used 0.35 mg/kg every 8 h during each episode of fever higher than 38.8 °C, continuing

until the child had been afebrile for 24 h. Ramakrishnan 1986 used oral diazepam 0.2mg/kg/day three times daily (tds)for the duration of the fever.

































































































































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There were significant findings at 24, and 48 months: at 24 months, 42 (21.0%) of 202 treated children had arecurrence compared with 63 (31.00%) of 204 in the placebo group: relative risk (RR) 0.67 (95% CI 0.48 to 0.94);number needed to treat 10. At 48 months, 5 (13.0%) of 45 in the active treatment group had seizures compared to 20(31.0%) of 65 in the control group: RR 0.36 (95% CI 0.15 to 0.89); number needed to treat 5. At 6 months, 25(12.0%) of 202 allocated to the treatment group had a recurrence compared to 31 (15.0%) of 204 allocated to theplacebo group: RR 0.81 (95% CI 0.50 to 1.33). At 72 months, 5 (17.0%) of 30 allocated to the treatment group had arecurrence compared to 6 (20.0%) of 30 allocated to the placebo group: RR 0.83 (95% CI 0.28 to 2.44).

2. Phenytoin versus placebo

This analysis involved Bacon's study ( Bacon 1981a ; Bacon 1981b ) of 138 children following a first febrile seizure.Children were administered phenytoin in a dose of 8 mg/kg/day or placebo, with recurrent seizures at 12 months as theoutcome measure. Of the children allocated to phenytoin treatment 16, (34%) of 47 had a recurrence at 12 monthscompared to 15 (34.8%) of the 43 in the placebo group: RR 0.98 (95% CI 0.55 to 1.73).

3. Phenobarbitone versus placebo or no treatment

Outcome data were available at 6, 12, 18, 24, and 60 to 72 months. At 6 months, the contributing studieswere Camfield 1980 , Farwell 1990 , Heckmatt 1976 , Mackintosh 1970 , McKinlay 1989 and Wolf 1977a . At 6 months,43 (10%) of 411 children had a recurrent seizure compared with 74 (17%) of 420 children on placebo or no treatment:RR 0.60 (95% CI 0.42 to 0.84); number needed to treat 14. Analysis of the 12 month outcome involved Bacon1981a and Bacon 1981b ,Camfield 1980 , Farwell 1990 , McKinlay 1989 , Ngwane 1980 , Thilothammal 1993 and Wolf 1977a . At 12 months, recurrent seizures were seen in 75 (19%) of 394 children allocated to phenobarbitone treatmentcompared with 131 (32.0%) of the 411 in the placebo or no treatment group: RR 0.59 (95% CI 0.46 to 0.75); numberneeded to treat 8. Assessment at 18 months involved analysis of Farwell 1990 and Mamelle 1984 . At 18 months, 44(33.8%) of the 130 in the treatment allocation group had had a seizure recurrence compared to 57 (42.5%) of the 134in the placebo or no treatment group: RR 0.79 (95% CI 0.58 to 1.08).

Recurrent seizures at 24 months: the analysis included the studies of Farwell 1990 , McKinlay 1989 and Wolf 1977a . Inthose allocated to the active treatment group 51(20.0%) of 255 had a recurrence at 24 months compared with 85(31.0%) of 278 in the placebo or no treatment group: RR 0.65 (95% CI 0.49 to 0.88); number needed to treat 9.

Recurrent seizures at 60 to 72 months: analysis involved only one study, that of Ramakrishnan 1986 . Nine of 30(30%) of those allocated to the active treatment group had a recurrent seizure compared with 6 of 30 (20%) in theplacebo or no treatment group: RR 1.5 (95% CI 0.61 to 3.69).

Behavioural changes: Camfield 1979 recorded the incidence of behavioural changes in those allocated to the activephenobarbitone treatment group, comparing them to those in the placebo group, at 12-months follow up. Fifteen of 35(42.8%) allocated to the phenobarbitone reported behavioural change or sleep disturbance compared to 8 of 30(26.3%) allocated to the placebo group: RR 1.61 (95% CI 0.79 to 3.26). More detail of adverse effects in this study isgiven in the summary table under 'adverse effects', see below.

4. Intermittent rectal diazepam versus no treatment or placebo

Outcome data were available at 6,12,18, 24, 36, and 48 to 72 months.

Recurrent seizures at 6 months: analysis involved the studies of Knudsen ( Knudsen 1985a and Knudsen1985b ),Mosquera 1987 , Uhari 1995 and Pavlidou 2006 . At 6 months, 37 of 308 (12.0%) children allocated to theactive treatment group had had a recurrence compared to 61 of 300 (20.0%) allocated to the no treatment group: RR0.60 (95% CI 0.41 to 0.86); number needed to treat 12.

Recurrent seizures at 12 months: analysis involved the studies of Knudsen ( Knudsen 1985a and Knudsen1985b ),Mosquera 1987 , Uhari 1995 and Pavlidou 2006 . At 12 months, 58 of 306 (19.0%) in the active treatmentgroup compared to 86 of 296 (29.0%) in the no treatment group had had a recurrence: RR 0.65 (95% CI 0.49 to0.87); number needed to treat 9.9.

Recurrent seizures at 18 months: only the study by Knudsen ( Knudsen 1985a and Knudsen 1985b ) offered data onthis. In the active treatment group, 16 of 105 (15.2%) compared with 43 (47.5%) of 90 had a recurrence: RR 0.32(95% CI 0.19 to 0.53); number needed to treat 3.07.

Recurrent seizures at 24 months: analysis involved the studies of Mosquera 1987 and Uhari 1995 . At 24 months, 24(22.7%) of 148 children in the active treatment group compared with 22 (19.1%) of 115 children in the no treatmentgroup had had a recurrence: RR 1.13 (95% CI 0.67 to 1.90).

Recurrent seizures at 36 months: only the study by Pavlidou 2006 offered data on this. In the active treatment group,24 of 68 (35.0%) compared with 43 (61.0%) of 71 had a recurrence: RR 0.58 (95% CI 0.40 to 0.85); number neededto treat 4.

5. Valproate versus placebo or no treatment

Recurrent seizures at 6 months: this involved analysis of McKinlay 1989 and Mosquera 1987 . At 6 months, 10 (14%)of 71 children in the active treatment group had had a recurrence compared to 10 (12%) of 85 in the control group: RR1.20 (95% CI 0.55 to 2.62).

Recurrent seizures at 12 months: analysis involved the studies of McKinlay 1989 , Mosquera 1987 , Ngwane1980 andWilliams 1979 . At 12 months, 24 (20%) of 121 children in the active treatment group had had a recurrent

seizure compared to 32 (27.6%) of 134 in the control group: RR 0.82 (95% CI 0.52 to 1.29).

Recurrent seizures at 18 months: this involved the study of Mamelle 1984 . Two (8.7%) of 23 in the active treatmentgroup had a recurrence compared with 8 (32%) of 25 in the control group: RR 0.27 (95% CI 0.06 to 1.15).
































































































































































































Recurrent seizures at 24 months: this involved pooling data from McKinlay 1989 and Mosquera 1987 . At 24 months, 19(26.8%) of 71 in the active treatment group had had a recurrent seizure compared to 18 (21.1%) of 85 in the controlgroup: RR 1.26 (95% CI 0.73 to 2.18).

6. Pyridoxine versus placebo

Recurrent seizures at 6 months: McKiernan 1981 was the only study of pyridoxine versus placebo. At 6 months, 4

(7.3%) of 55 had had a recurrence compared to 8 (15.4%) of 52 in the placebo group: RR 0.47 (95% CI 0.15 to 1.48).Recurrent seizures at 12 months: this again involved only the study of McKiernan 1981 . At 12 months, 7 (12.7%) of 55 children in the active treatment group had had a recurrence compared to 10 (19.2%) of 52 in the placebo group: RR0.66 (95% CI 0.27 to 1.61).

7. Intermittent phenobarbitone versus no treatment

Recurrent seizures at 6 months: data were taken from Mackintosh 1970 and Wolf 1977a . At 6 months, 17 (11%) of 156 in the active treatment group had had a recurrence compared with 10 (8.0%) of 125 in the no treatment group:RR 1.44 (95% CI 0.68 to 3.04).

Recurrent seizures at 12 months: this again involved analysis of data from Mackintosh 1970 and Wolf 1977a . At 12months, 31 (20%) of 156 in the active treatment group had had a recurrence compared with 27 (22.0%) of 125 in thecontrol group: RR 0.93 (95% CI 0.58 to 1.47).

Recurrent seizures at 24 months: data were again from Mackintosh 1970 and Wolf 1977a . Thirty-eight (24%) of 156

children in the active treatment group had had a recurrent seizure compared to 30 (24.0%) of 125 in the no treatmentgroup: RR 1.02 (95% CI 0.67 to 1.55).

Recurrence at 60 to 72 months: this involved the study of Ramakrishnan 1986 . At 72 months, 5 (16.7%) of 30children in the active treatment group had had a recurrent seizure compared with 6 (20%) of 30 in the no treatmentgroup: RR 0.83 (95% CI 0.28 to 2.44).

8. Intermittent ibuprofen versus placebo

The only study was by van Stuijvenberg 1998 , with data as follows.

Recurrent seizures at 6 months: 27 (24.3%) of 111 children allocated to the active treatment group had had arecurrence compared to 25 (21%) of 119 allocated to the placebo group; RR 1.16 (95% CI 0.72 to 1.87).

Recurrent seizures at 12 months: 32 children (28.5%) of 111 children allocated to the active treatment group had hada recurrent seizure compared to 38 (31.9%) of 119 allocated to the placebo group; RR 0.9 (95% CI 0.61 to 1.34).

Recurrent seizures at 24 months: 37 (33.3%) of 111 children allocated to the ibuprofen group had had a recurrent

seizure compared with 45 (37.5%) of 119 children allocated to the placebo group; RR 0.86 (95% CI 0.61 to 1.22).

9. Intermittent rectal diazepam versus intermittent valproate

This comparison involved data from one study, that of Daugbjerg 1990 .

Recurrent seizures at 6 months: 11 (12.3%) of 89 children allocated to intermittent rectal diazepam had had arecurrent seizure compared to 7 (8.8%) of 80 children allocated to the valproate treatment group; RR 1.41 (95% CI0.58 to 3.47).

Recurrent seizures at 12 months: 23 (25.8%) of 89 children allocated to the intermittent rectal diazepam group hadhad a seizure recurrence compared to 14 (17.5%) of 80 children allocated to the valproate group; RR 1.48 (95% CI0.82 to 2.67).

10. Phenobarbitone versus intermittent rectal diazepam

This analysis involved only one study, that of Garcia 1984 .

Recurrent seizures at 18 months: 5 (10%) of 50 children allocated to the phenobarbitone group had had a seizurerecurrence compared to 4 (8%) of 50 children allocated to the intermittent rectal diazepam group; RR 1.25 (95% CI0.36 to 4.38).

11. Diclofenac versus placebo followed, after 8 hours by ibuprofen, acetaminophen or placebo

This analysis involved only one study, that of Strengell 2009 . For each outcome time point, data were extrapolatedfrom the Kaplan Meier survival curves. The data presented in the paper did not allow subgroup analysis for each of thesubsidiary comparisons of ibuprofen versus placebo or acetaminophen versus placebo. Nonetheless, the authorsreported no significant differences at any time point (clearly seen from figure 3). Those who were lost to follow up wereincluded in the Kaplan Meier analyses; there were no imputations for these dropouts.

Recurrent seizures at 6 months: 12 (10%) of 117 children allocated to the diclofenac group had a seizure recurrencecompared to 17 (15%) of 114 children allocated to the placebo group; RR 0.69 (95% CI 0.34, 1.37).

Recurrent seizures at 12 months: 18 (15%) of 117 children allocated to the diclofenac group had a seizure recurrencecompared to 29 (25%) of 114 children allocated to the placebo group; RR 0.60 (95% CI 0.36 to 1.03).






























































Recurrent seizures at 18 months: 19 (16%) of 117 children allocated to the diclofenac group had a seizure recurrencecompared to 32 (28%) of 114 children allocated to the placebo group; RR 0.63 (0.38 to 1.04).

Recurrent seizures at 24 months: 22 (19%) of 117 children allocated to the diclofenac group had a seizure recurrencecompared to 32 (28%) of 114 children allocated to the placebo group; RR 0.67 (95% CI 0.42 to 1.08).

12. Intermittent clobazam versus placebo

This analysis involved only one study, that of Bajaj 2005 . Outcome data were available at 6 months only.

Recurrent seizures at 6 months: 9 (30%) of 30 children allocated to the clobazam group had a seizure recurrencecompared to 25 (83%) of 30 allocated to the placebo group; RR 0.36 (95% CI 0.20 to 0.64), number needed to treat 2.

13. Intermittent clobazam versus intermittent diazepam

This analysis involved only one study, that of Khosroshahi 2011 . Outcome data were available at 12 months only.

Recurrent seizures at 12 months: 2 (5.71%) of 35 children allocated to the clobazam group had a seizure recurrencecompared to 4 (10.81%) of 37 allocated to the diazepam group; RR 0.53 (95% CI 0.10 to 2.71).

Recurrence risk of febrile seizures in the non-intervention groups

As a number of studies included risk factors known to be associated with a higher recurrence risk, the data on this issue

were skewed towards higher recurrence risk in the placebo or control groups. Nonetheless, viewing pooled data on thisissue allowed us to weigh the clinical importance of any significant results in the intervention arms of the studies. Thedata are summarised as follows.

Recurrence risk in placebo or control groups at 6 months: these pooled data included the studies of Bajaj2005 ,Camfield 1979 , Daugbjerg 1990 , Farwell 1990 , Heckmatt 1976 , Knudsen 1985a , Mackintosh 1970 , McKinlay1989 ,McKiernan 1981 , Mosquera 1987 , Pavlidou 2006 , Rosman 1993 , Strengell 2009 , Thilothammal 1993 , Uhari1995 ,van Stuijvenberg 1998 , Wolf 1977a . A total of 253 (20.0%) of 1235 children had had a recurrent febrile seizurewithin 6 months of study entry.

Recurrence risk of a febrile seizure at 12 months: pooled data at 12 months included the studies of Autret 1990 , Bacon1981a , Camfield 1979 , Daugbjerg 1990 , Farwell 1990 , Garcia 1984 , Heckmatt 1976 , Khosroshahi 2011 , Knudsen1985a , Mackintosh 1970 , McKiernan 1981 , McKinlay 1989 , Mosquera 1987 , Ngwane 1980 , Pavlidou 2006 , Rosman1993 , Strengell 2009 , Thilothammal 1993 , Uhari 1995 , van Stuijvenberg 1998 , Verrotti 2004 , Williams 1979 , Wolf 1977a ; 417 (26.0%) of 1582 children had a recurrent seizure at 12 months.

Recurrent risk of a febrile seizure in the placebo control groups at 18 months: pooled data included the studiesof Farwell 1990 , Garcia 1984 , Knudsen 1985a , Mamelle 1982 and Strengell 2009 . 135 (40.0%) of 338 children in

these studies had had a recurrent seizure at 18 months.Risk of recurrence of a febrile seizure in the placebo/control group at 24 months: pooled data included the studiesfromFarwell 1990 , Mackintosh 1970 , McKinlay 1989 , Mosquera 1987 , Rosman 1993 , Strengell 2009 , Uhari1995 , van Stuijvenberg 1998 and Wolf 1977a ; 279 (30.0%) of 938 children had had a documented recurrent febrileseizure at 24 months.

Risk of recurrence of a febrile seizure in the placebo or control group at 48 months: only data from Verrotti 2004 wereavailable; 20 (30.7%) of 65 children had had a documented recurrent febrile seizure at 48 months.

Recurrent risk of a seizure in the placebo or control group at 60 to 72 months: analysis included data from only onestudy ( Ramakrishnan 1986 ); 6 (20%) of 30 children had had a recurrent seizure at this point in time.

Adverse events and medication effects

A variety of adverse effects were reported in some studies. Some where described as unacceptable or as reasons forthe child to stop medication and, in some instances, to leave the trial. A descriptive summary, detailed in so far as waspossible from the articles, is given in 'Unwanted medication effects'.

D I S C U S S I O N

Discussion

Most of the reviewed papers date from 20 or more years ago and carry a methodological quality which nowadays wouldbe recognised as needing improvement. Methods of randomisation and allocation concealment often do not meetcurrent standards; and treatment versus no treatment is more commonly seen than treatment versus placebo, leadingto obvious sources of bias. Nonetheless, the size of the data pool does allow us to draw some conclusions about thevalue of intervention with medication for this common childhood phenomenon.

Knudsen et al ( Knudsen 1991 ) have indicated that the long-term outcome of children with febrile seizures is goodirrespective of whether their febrile seizures are successfully prevented or not. As no long-term benefit for treatmenthas been identified, the decision to treat must rest on whether quality of life and shorter-term morbidity may be altered

by the use of drugs.

We note no significant benefit for phenytoin, valproate, pyridoxine, intermittent phenobarbitone, and intermittentibuprofen versus placebo or no treatment; or for diclofenac versus placebo followed after 8 hours by ibuprofen,


























































































































































































































































acetaminophen or placebo. Nor was there any significant benefit for intermittent rectal diazepam versus intermittentvalproate, phenobarbitone versus intermittent rectal diazepam, or for intermittent diazepam versus clobazam.

There was a significant reduction of recurrent febrile seizure risk with intermittent oral diazepam versus placebo at 24months and 48 months. At 24 months the relative risk (RR) on treatment was 0.67 (95% CI 0.48 to 0.94) and at 48months the RR was 0.61 (95% CI 0.15 to 0.89). Thus, at 24 months the risk difference (RD) was -0.10 (95% CI -0.19to -0.02) and at 48 months it was -0.20 (95% CI -0.34 to -0.05), with a number needed to treat of 9.91 (95% CI 5.26to 50.0) at 24 months and 5.09 (95% CI 2.94 to 20.0) at 48 months. No benefit was found at 6,12, or 72 months.

A significant reduction in febrile seizure recurrence risk was seen in the continuous phenobarbitone versus placebo orno treatment intervention group at 6, 12, and 24 months follow up, but not at 18 or 60 to 72 month follow up. It mustbe noted that only two studies were included at 18 months and one at 60 to 72 months, whereas at 6, 12, and 24months there were six, seven, and three studies, respectively, with a correspondingly increased number of participants.The relative risks range from 0.65 at 24 month follow up to 0.59 at 12 months. The risk differences (RD) help us gaugethe clinical importance: at 6 months we see an RD of -0.07 (95% CI -0.12 to -0.03); at 12 months the RD is -0.13(95% CI -0.19 to 0.08) and at 24 months the RD is -0.11 (95% CI -0.18 to -0.04). This gives us the number needed totreat to save one child a recurrence of a febrile seizure of 13.97 (95% CI 8.33 to 33.33) at 6 months, 7.99 (95% CI5.26 to 12.50) at 12 months and 9.46 (95% CI 5.56 to 25.0) at 24 months.

A significant reduction in febrile seizure recurrence risk was also seen in the intermittent rectal diazepam versus notreatment or placebo studies at 6, 12, 18, and 36 month follow up. This risk reduction was not seen at 24 months.Reasons for lack of a sustained effect may be related to the families' abilities to adhere to advice on a protracted basisas their perception of risk with the passage of time recedes. The relative risks at 6, 12, 18, and 36 months were 0.60,0.65, 0.32, and 0.58 respectively. Again, the clinical significance of these results can be gauged by assessing the riskdifferences (RD); at 6 months the RD is -0.08 (95% CI -0.14 to 0.03); at 12 months the RD is -0.10 (95% CI -0.17 to -0.04); at 18 months the RD is -0.33 (95% CI -0.45 to -0.20) and at 36 months the RD is -0.25 (95% CI -0.41 to -0.09). The corresponding numbers needed to treat are 12.42 (95% CI 7.14 to 33.33) at 6 months; 9.9 (95% CI 5.88 to

25) at 12 months; 3.07 (95% CI 2.22 to 5.0) at 18 months and 3.96 (95% CI 2.44 to 11.11) at 36 months. Theextraordinary results at 18 months were seen in the study by Pavlidou, which seem not to have been repeatedelsewhere.

Another significant reduction in febrile seizure recurrence was seen in the intermittent clobazam group compared toplacebo at 6 months follow up. The relative risk was reduced to 0.09; number needed to treat of 1.9. However, with arecurrence rate of 25 (83.3%) out of 30 in the control group we feel the play of chance has most likely led to anunrepeatable apparent beneficial effect for the treatment group. A comparison of the recurrence rate in this study toour pooled 6 month recurrence rate of 253 (20.0%) of 1235 children indicates how potentially misleading this study'sfindings are likely to be.

In summary, where a significant benefit for treatment is noted (for oral diazepam versus placebo, phenobarbitoneversus placebo or no treatment, or intermittent rectal diazepam versus placebo or no treatment), the benefits do notseem to be stable over time. The follow-up period in the clobazam versus placebo group was confined to six months soas yet, ahead of further study, we cannot know if the remarkable result obtained at six months is sustainable over time.Furthermore, it would appear that there is a need to treat about 10 children to save one child a febrile seizurerecurrence (the notable exception being the result for intermittent rectal diazepam versus no treatment or placebo at18 months, where the number needed to treat was only 3; and in the clobazam study where it was 2). We have serious

concerns about the potentially unrepeatable nature of the clobazam study given the 83.3% six-month recurrence ratecompared to the 20.0% we would expect.

As has been indicated, the recording of adverse effects in these studies was very variable and at many times non-existent. Camfield's study documented lower comprehension scores in phenobarbitone treated children (yet with smallnumbers), which correlated with length of phenobarbitone treatment ( Camfield 1980 ). The findings were supported bythe data of Farwell and colleagues ( Farwell 1990 ). In general, adverse effects were recorded in up to some 30% of children in the phenobarbitone treated group, though notably the studies by Bacon ( Bacon 1981b ) and by Camfield(the latter for behavioural change or sleep disturbance) observed no difference with control groups. Knudsen noted mildtransient adverse effects in up to 36% of children in the diazepam treated groups ( Knudsen 1996 ).

In summary, we note a significant prevalence of adverse effects and no long-term benefit conferred in relation toreducing the risk of ultimately developing epilepsy. This leads us to conclude that we cannot advocate any of theinterventions included in this review for the management of children with febrile seizures, with attendant risks faroutweighing any potential benefit. The mainstay of intervention should be the provision of information for the familiesinvolved on recurrence risk, first aid management and the benign nature of the phenomenon; and the provision of contact details for medical services so that they will feel supported in the event of a recurrence, which inevitably leadsto anxiety and fright in the vast majority of those involved.

A U T H O R S ' C O N C L U S I O N S

Implications for practice

There were some significant results though no clinically important benefits for the management of children with febrileseizures for intermittent oral diazepam, continuous phenobarbitone and intermittent rectal diazepam. No benefit wasdemonstrated for phenytoin, valproate, pyridoxine, intermittent phenobarbitone or antipyretics in the form of intermittent ibuprofen, acetaminophen or diclofenac in the management of febrile seizures. Intermittent clobazamconferred some benefit at six months follow up but the result may be difficult to replicate. Parents should be supportedwith the adequate contact details of medical services and information on recurrence, first aid management and, mostimportantly, the benign nature of the phenomenon.

Implications for research

If future studies are to be considered then due attention should be given to the quality of randomisation allocation andconcealment with placebo as a control. Adverse effects should be recorded systematically for both intervention and



















control groups. However, given the long-term benign nature of the phenomenon of febrile seizures and the relativelyhigher rate of reporting of adverse effects to date, unless a significant case of justification can be made it seemsdifficult to justify further research in this area.

A C K N O W L E D G E M E N T S

Acknowledgements

We would like to thank the Cochrane Epilepsy Group for their support and advice throughout the development of thisreview. In particular, we would like to thank Rachael Kelly and Tony Marson. We would also like to thank JenniferPulman for helping us with the Summary of Findings tables.

N O T E S

R E F E R E N C E S

References to studies included in this review

Autret 1990 {published data only}

Autret E, Billard C, Bertrand P, Motte J, Pouplard F, Jonville AP. Double-blind, randomized trial of diazepam versus placebo for prevention of recurrence of febrile seizures. Journal of Pediatrics1990;117:490-4.

Bacon 1981a {published data only}

Bacon CJ, Hierons AM, Mucklow JC, Webb JK, Rawlins MD, Weightman D. Placebo-controlled study of phenobarbitone and phenytoin in the prophylaxis of febrile convulsions. Lancet 1981;2:600-4.

Bacon 1981b {published data only}

Bacon CJ, Cranage JD, Hierons AM, Rawlins MD, Webb JK. Behavioural effects of phenobarbitone andphenytoin in small children. Archives of Disease in Childhood 1981;56:836-40.

Bajaj 2005 {published data only}

Bajaj AS, Bajaj BK, Purib V, Tayal G. Intermittent clobazam in febrile seizures: an Indian experience.Journal of Pediatric Neurology 2005;3:19-23.

Camfield 1979 {published data only}

Camfield CS, Chaplin S, Doyle AB, Shapiro SH, Cummings C, Camfield PR. Side effects of phenobarbitalin toddlers; behavioral and cognitive aspects. Journal of Pediatrics 1979;95:361-5.


Camfield PR, Camfield CS, Shapiro SH, Cummings C. The first febrile seizure--antipyretic instruction pluseither phenobarbital or placebo to prevent recurrence. Journal of Pediatrics 1980;97:16-21.

Daugbjerg 1990 {published data only}

Daugbjerg P, Brems M, Mai J, Ankerhus J, Knudsen FU. Intermittent prophylaxis in febrile convulsions:diazepam or valproic acid?. Acta Neurologica Scandinavica 1990;82:17-20.

Farwell 1990 {published data only}

Farwell JR, Lee YJ, Hirtz DG, Sulzbacher SI, Ellenberg JH, Nelson KB. Phenobarbital for febrile seizures--effects on intelligence and on seizure recurrence [published erratum appears in New England Journal of Medicine 1992 Jan 9;326(2):144] [see comments]. New England Journal of Medicine 1990;322:364-9.

Garcia 1984 {published data only}

Garcia FO, Campos-Castello J, Maldonado JC. Continuous oral fenobarbital or intermitent rectal diazepamto prevent febrile seizures. Anales Espanoles de Pediatria 1984;20:763-9.

Heckmatt 1976 {published data only}

Heckmatt JZ, Houston AB, Clow DJ, Strephenson JB, Dodd KL, Lealman GT. Failure of phenobarbitone toprevent febrile convulsions. BMJ 1976;1:559-61.

Hirtz 1993 {published data only}

Hirtz DG, Chen TC, Nelson KB, Sulzbacher S, Farwell JR, Ellenberg JH. Does phenobarbital used forfebrile seizures cause sleep disturbances?. Pediatric Neurology 1993;9:94-100.

Khosroshahi 2011 {published data only}



Khosroshahi N, Faramarzi F, Salamati P, Haghighi SM, Kamrani K. Diazepam versus clobazam forintermittent prophylaxis of febrile seizures. Indian Journal of Pediatrics 2011;78:38-40.

Knudsen 1985a {published data only}

Knudsen FU. Effective short-term diazepam prophylaxis in febrile convulsions. Journal of Pediatrics1985;106:487-90.

Knudsen 1985b {published data only}

Knudsen FU. Recurrence risk after first febrile seizure and effect of short term diazepam prophylaxis.Archives of Disease in Childhood 1985;60:1045-9.

Knudsen 1988 {published data only}

Knudsen FU. Frequent febrile episodes and recurrent febrile convulsions. Acta Neurologica Scandinavica1988;78:414-7.


Knudsen FU, Paerregaard A, Andersen R, Andresen J. Long term outcome of prophylaxis for febrileconvulsions. Archives of Disease in Childhood 1996;74:13-8.

Mackintosh 1970 {published data only}

Mackintosh TF. Studies on prophylactic treatment of febrile convulsions in children. Is it feasible toinhibit attacks by giving drugs at the first sign of fever or infection?. Clinical Pediatrics 1970;9:283-6.

Mamelle 1982 {published data only}

Mamelle JC, Mamelle N, Plasse JC, Revol M, Gilly R. Efficacy of sodium dipropylacetate compared withphenobarbital and placebo in the prevention of recurrence of febrile convulsions. Pediatrie 1982;37:433-45.

Mamelle 1984 {published data only}

Mamelle N, Mamelle JC, Plasse JC, Revol M, Gilly R. Prevention of recurrent febrile convulsions--arandomized therapeutic assay: sodium valproate, phenobarbital and placebo. Neuropediatrics1984;15:37-42.

McKiernan 1981 {published data only}

McKiernan J, Mellor DH, Court S. A controlled trial of pyridoxine supplementation in children with febrileconvulsions. Clinical Pediatrics 1981;20:208-11.

McKinlay 1989 {published data only}

McKinlay I, Newton R. Intention to treat febrile convulsions with rectal diazepam, valproate orphenobarbitone. Developmental Medicine and Child Neurology 1989;31:617-25.

Mosquera 1987 {published data only}

Mosquera C, Rodriguez J, Cabrero A, Fidalgo I, Fernandez RM. Preventing the recurrence of febrileseizures: intermittent prevention with rectal diazepam compared with continuous treatment with sodiumvalproate. Anales Espanoles de Pediatria 1987;27:379-81.

Ngwane 1980 {published data only}

Ngwane E, Bower B. Continuous sodium valproate or phenobarbitone in the prevention of 'simple' febrileconvulsions. Comparison by a double-blind trial. Archives of Disease in Childhood 1980;55:171-4.

Pavlidou 2006 {published data only}

Pavlidou E, Tzitiridou M, Panteliadis C. Effectiveness of intermittent diazepam prophylaxis in febrile

seizures: long-term prospective controlled study. Journal of Child Neurology 2006;21:1036-40.

Ramakrishnan 1986 {published data only}

Ramakrishnan K, Thomas K. Long term prophylaxis of febrile seizures. Indian Journal of Pediatrics1986;53:397-400.

Rosman 1993 {published data only}

Rosman NP, Colton T, Labazzo J, Gilbert PL, Gardella NB, Kaye EM. A controlled trial of diazepamadministered during febrile illnesses to prevent recurrence of febrile seizures [see comments]. NewEngland Journal of Medicine 1993;329:79-84.

Strengell 2009 {published data only}

Strengell T, Uhari M, Tarkka R, Uusimaa J, Alen R, Lautala P, Rantala H. Antipyretic agents forpreventing recurrences of febrile seizures. Archives of Pediatrics and Adolescent Medicine 2009;163:799-804.

Sulzbacher 1999 {published data only}



Sulzbacher S, Farwell JR, Temkin N, Lu AS, Hirtz DG. Late cognitive effects of early treatment withphenobarbital. Clinical Pediatrics 1999;38:387-94.

Thilothammal 1993 {published data only}

Thilothammal N, Kannan , Krishnamurthy PV, Kamala KG, Ahamed S, Banu K. Role of phenobarbitone inpreventing recurrence of febrile convulsions. Indian Pediatrics 1993;30:637-42.

Uhari 1995 {published data only}

Uhari M, Rantala H, Vainionpaa L, Kurttila R. Effect of acetaminophen and of low intermittent doses of diazepam on prevention of recurrences of febrile seizures. The Journal of Pediatrics 1995;126:991-5.

van Stuijvenberg 1998 {published data only}

Stuijvenberg M, Derksen-Lubsen G, Steyerberg EW, Habbema JD, Moll HA. Randomized, controlled trialof ibuprofen syrup administered during febrile illnesses to prevent febrile seizure recurrences. Pediatrics1998;102:E51-.

Verrotti 2004 {published data only}

Verrottia A, Latinib G, Corciaa G, Giannuzzib R, Salladinia C, Trottaa D, Chiarellia F. Intermittent oraldiazepam prophylaxis in febrile convulsions: its effectiveness for febrile seizure recurrence. EuropeanJournal of Paediatric Neurology 2004;8:131-4.

Williams 1979 {published data only}

Williams AJ, Evans-Jones LG, Kindley AD, Groom PJ. Sodium valproate in the prophylaxis of simplefebrile convulsions. Clinical Pediatrics 1979;18:426-30.

Wolf 1977a {published data only}

Wolf SM, Carr A, Davis DC, Davidson S, Dale EP, Forsythe A. The value of phenobarbital in the child whohas had a single febrile seizure: a controlled prospective study. Pediatrics 1977;59:378-85.

Wolf 1978 {published data only}

Wolf SM, Forsythe A. Behavior disturbance, phenobarbital, and febrile seizures. Pediatrics 1978;61:728-31.

Wolf 1981 {published data only}

Wolf SM, Forsythe A, Stunden AA, Friedman R, Diamond H. Long-term effect of phenobarbital oncognitive function in children with febrile convulsions. Pediatrics 1981;68:820-3.

* indicates the major publication for the study

References to studies excluded from this review

AAP Steering Group 2008 {published data only}

Febrile seizures: Clinical practice guideline for the long-term management of the child with simple febrileseizures. Pediatrics 2008;121:1281-6.

Addy 1977 {published data only}

Addy DP. Tegretol in epilepsy. Proceedings of an International Meeting. Macclesfield: GeigyPharmaceuticals. 1977.

Antony 1983 {published data only}

Antony JH, Hawke SH. Phenobarbital compared with carbamazepine in prevention of recurrent febrileconvulsions. A double-blind study. American Journal of Disease of Children 1983;137:892-5.


Camfield PR, Camfield CS, Tibbles JA. Carbamazepine does not prevent febrile seizures in phenobarbitalfailures. Neurology 1982;32:288-9.


Camfield P, Camfield C, Gordon D. Prevention of recurrent febrile seizures. Journal of Pediatrics1995;126:929-30.

Capocchi 1982 {published data only}

Capocchi G. Girelli L. Prophylaxis of febrile convulsions: resulst of 8 years experience. Bollettino LegaItaliana Contro L'Epilessia 1982;39 (suppl):23-.

Cavazzuti 1975 {published data only}

Cavazzuti GB. Prevention of febrile convulsions with dipropylacetate (Depakine). Epilepsia 1975;16:647-8.

Costa 1996 {published data only}



Costa M, Silva EA, Silva AE, Guerreiro MM. Intermittent prophylaxis in febrile seizures with oraldiazepam: study of 82 cases. Arquivos de Neuro-psiquiatria 1996;54:197-201.

Dalla Bernardina 1988 {published data only}

dalla Bernardina B, Fontana E. Sodium valproate in febrile convulsions. Bollettino Lega Italiana ControL'Epilessia 1988;61:25-7.

De Zan 1982 {published data only}

Zan G, Luchini P, Visentin A, Bruno F. Statistics on 123 children with febrile convulsions from 1976 to1981 with possible advantages of continuous prophylaxis with valproic acid and/or phenobarbital. LaPediatria medica e chirurgica: Medical and Surgical Pediatrics 1982;4:407-12.

Dianese 1979 {published data only}

Dianese G. Prophylactic diazepam in febrile convulsions. Archives of Disease in Childhood 1979;54:244-5.

Domizio 1993 {published data only}

Domizio S, Verrotti A, Ramenghi LA, Sabatino G, Morgese G. Anti-epileptic therapy and behaviourdisturbances in children. Child's Nervous System 1993;9:272-4.

Echenne 1983 {published data only}

Echenne B, Cheminal R, Martin P, Peskine F, Rodiere M, Astruc J. Use of diazepam in the preventive

home treatment of recurrent febrile convulsions. Archives Françaises de Pédiatrie 1983;40:499-501.Faero 1972 {published data only}

Faero O, Kastrup KW, Lykkegaard NE, Melchior JC, Thorn I. Successful prophylaxis of febrile convulsionswith phenobarbital. Epilepsia 1972;13:279-85.

Frehlih 1997 {published data only}

Frelih J, Ravnick IM. Assessing the value of different therapies for the prevention of febrile seizures.Epilepsia 1997;38 Suppl 3:94-.

Galli 1977 {published data only}

Galli V, Gatti G, Massolo F, Nalin A, Rozzi N, Tamborino G. Sodium dipropyl acetate in the prevention of febrile convulsions in children. Acta Neurologica (Napoli) 1977;32:884-91.

Guerreiro 1992 {published data only}

Guerreiro MM, Costa M, Bellomo MA, Sabino SH, Silva EA, Scotoni AE. Intermittent prophylaxis in febrileconvulsions with oral diazepam. Arquivos de Neuro-psiquiatria 1992;50:163-7.

Herranz 1984 {published data only}

Herranz JL, Armijo JA, Arteaga R. Effectiveness and toxicity of phenobarbital, primidone, and sodiumvalproate in the prevention of febrile convulsions, controlled by plasma levels. Epilepsia 1984;25:89-95.


Knudsen FU, Vestermark S. Prophylactic diazepam or phenobarbitone in febrile convulsions: aprospective, controlled study. Archives of Disease in Childhood 1978;53:660-3.

Lahat 2000 {published data only}

Lahat E, Goldman M, Barr J, Bistritzer T, Berkovitch M. Comparison of intranasal midazolam withintravenous diazepam for treating febrile seizures in children: prospective randomised study. BMJ2000;321:83-6.

Lee 1981 {published data only}

Lee K, Melchior JC. Sodium valproate versus phenobarbital in the prophylactic treatment of febrileconvulsions in childhood. European Journal of Pediatrics 1981;137:151-3.

Lee 1986 {published data only}

Lee K, Taudorf K, Hvorslev V. Prophylactic treatment with valproic acid or diazepam in children withfebrile convulsions. Acta Paediatrica Scandinavica 1986;75:593-7.

Manreza 1997 {published data only}

Manreza ML, Gherpelli JL, Machado-Haertel LR, Pedreira CC, Heise CO, Diament A. Treatment of febrileseizures with intermittent clobazam. Arquivos de Neuro-psiquiatria 1997;55:757-61.

Minagawa 1981 {published data only}

Minagawa K, Miura H. Phenobarbital, primidone and sodium valproate in the prophylaxis of febrile

convulsions. Brain and Development 1981;3:385-93.

Parisi 1995 {published data only}



Parasi P, Nasta L, Terenzi S. CBZ does not prevent FS in phenobarbitone failures. Pediatria Oggi Medicae Chirurgia 1995;15:101-3.

Rose 2005 {published data only}

Rose W, Kirubakaran C, Scott JX. Intermittent clobazam therapy in febrile seizures. Indian Journal of Pediatrics 2005;72:31-3.

Rosman 2001 {published data only}

Rosman NP, Douglass LM, Paolini JL. Preventing febrile seizures in children with oral diazepam: can acontrolled trial truly be "double-blind"?. Journal of Pediatrics 2001;138:548-52.

Schnaiderman 1993 {published data only}

Schnaiderman D, Lahat E, Sheefer T, Aladjem M. Antipyretic effectiveness of acetaminophen in febrileseizures: ongoing prophylaxis versus sporadic usage. European Journal of Pediatrics 1993;152:747-9.

Shimazaki 1997 {published data only}

Shimazaki S, Kuremoto K, Oyama S. Efficacy of rectal diazepam suppository in the prophylaxis of febrileseizures: comparison with rectal chloral hydrate suppository. No To Hattatsu 1997;29:278-84.

Shirai 1988 {published data only}

Shirai H, Miura H, Sunaoshi W. A clinical study on the effectiveness of intermittent therapy with rectaldiazepam suppositories for the prevention of recurrent febrile convulsions. Journal of the Japan Epilepsy

Society 1988;6:1-10.Smith 1982 {published data only}

Smith JA, Wallace SJ. Febrile convulsions: intellectual progress in relation to anticonvulsant therapy andto recurrence of fits. Archives of Disease in Childhood 1982;57:104-7.

Sopo 1991 {published data only}

Sopo SM, Pescaresi MA, Celestini E, Stabile A. Short-term prophylaxis of febrile convulsions. ActaPaediatrica Scandinavica 1991;80:248-9.

Steardo 1980 {published data only}

Steardo L, Florio C, Sorge F, Steardo R. DPA and clonazepam activity in febrile convulsions: preliminaryresults. Bollettino- Societa Italiana Biologia Sperimentale (Napoli) 1980;56:1187-91.

Sunami 1990 {published data only}

Sunami K, Hayashi N. Prophylactic effects of acetaminophen suppository on febrile convulsions: anepidemiologic and twin study. Japanese Journal of Psychiatry and Neurology 1990;44:351-3.

Thorn 1975 {published data only}

Thorn I. A controlled study of prophylactic long-term treatment of febrile convulsions with phenobarbital.Acta Neurological Scandinavica Supplementum 1975;60:67-73.

Tondi 1987 {published data only}

Tondi M, Carboni F, Deriu A, Manca S, Mastropaolo C. Intermittent therapy with clobazam for simplefebrile convulsions. Developmental Medicine and Child Neurology 1987;29:830-1.

Vanasse 1984 {published data only}

Vanasse M, Masson P, Geoffroy G, Larbrisseau A, David PC. Intermittent treatment of febrile convulsionswith nitrazepam. Canadian Journal of Neurological Sciences 1984;11:377-9.

Van den Berg 1971 {published data only}

Berg BJ, Yerushalmy J. Studies on convulsive disorders in young children. II. Intermittent phenobarbitalprophylaxis and recurrence of febrile convulsions. Journal of Pediatrics 1971;78:1004-12.

Van Esch 1995 {published data only}

Esch A, Steensel-Moll HA, Steyerberg EW, Offringa M, Habbema JD, Derksen-Lubsen G. Antipyreticefficacy of ibuprofen and acetaminophen in children with febrile seizures. Archives of Pediatrics andAdolescent Medicine 1995;149:632-7.

Vining 1987 {published data only}

Vining EP, Mellitis ED, Dorsen MM, Cataldo MF, Quaskey SA, Spielberg SP. Psychologic and behavioraleffects of antiepileptic drugs in children: a double-blind comparison between phenobarbital and valproicacid. Pediatrics 1987;80:165-74.

Wallace 1980 {published data only}

Wallace SJ, Smith JA. Successful prophylaxis against febrile convulsions with valproic acid orphenobarbitone. British Medical Journal 1980;280:353-4.



Winsley 2005 {published data only}

Winsley R, Chellam K, Xavier SJ. Intermittent clobazam therapy in febrile seizures. Indian Journal of Pediatrics 2005;72:31-8.

Wolf 1977b {published data only}

Wolf SM. The effectiveness of phenobarbital in the prevention of recurrent febrile convulsions in childrenwith and without a history of pre-, peri- and postnatal abnormalities. Acta Paediatrica Scandinavica

1977;66:585-7.

Additional references

Baumann 1999

Baumann RJ. Technical report: treatment of the child with simple febrile seizures. Pediatrics1999;103:e86-.

Berg 1990

Berg AT, Shinnar S, Hauser WA, Leventhal JM. Predictors of recurrent febrile seizures: a metaanalyticreview. Journal of Pediatrics 1990;116:329-37.

Gram 1984

Gram L, Bentsen KD. Controlled and comparative trials of valproate performed in Europe and Asia.Epilepsia 1984;25 Suppl 1:S32-S39.

Herranz 1988

Herranz JL, Armijo JA, Arteaga R. Clinical side effects of phenobarbital, primidone, phenytoin,carbamazepine, and valproate during monotherapy in children. Epilepsia 1988;29:794-804.

Knudsen 1991

Knudsen FU. Intermittent diazepam prophylaxis in febrile convulsions. Pros and cons. Acta NeurologicaScandinavica. Supplementum 1991;135:1-24.

Lefebvre 2009

Lefebvre C, Manheimer E, Glanville J. Chapter 6: Searching for studies. In: Higgins JPT, Green S(editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.2 (updatedSeptember 2009). The Cochrane Collaboration, 2009. :-.

Nelson 1981

Nelson KB, Ellenberg JH (editors). In: Febrile Seizures New York: Raven Press, 1981:-.Newton 1988

Newton RW. Randomised controlled trials of phenobarbitone and valproate in febrile convulsions.Archives of Disease in Childhood 1988;63:1189-91.

Offringa 1994

Offringa M, Bossuyt PM, Lubsen J, Ellenberg JH, Nelson KB, Knudsen FU. Risk factors for seizurerecurrence in children with febrile seizures: A pooled analysis of individual patient data from five studies.Journal of Pediatrics 1994;124:574-84.

Rantala 1997

Rantala H. A meta-analytic review of the preventive treatment of recurrences of febrile seizures. Journalof Pediatrics 1997;131:922-5.

Verity 1985

Verity CM, Butler NR, Golding J. Febrile convulsions in a national cohort followed up from birth:Prevalence and recurrence in the first five years of life. British Medical Journal 1985;290:1307-10.

G R A P H S

Graphs and Tables

To view a graph or table, click on the outcome title of the summary table below.

Intermittent oral diazepam versus placebo

Outcome title No. of studiesNo. of

participantsStatistical method Effect size

1 Recurrent seizure @6 months

1 406Risk Ratio (M-H, Fixed,95% CI)

0.81 [0.50,1.33]

http://cochrane.bvsalud.org/cochrane/img_data/CD003031/image_n/nCD003031-CMP-001-01.png









0.74 [0.53,1.03]



0.67 [0.48,0.94]



0.36 [0.15,0.89]

5 Recurrent seizure @60-72 months


0.83 [0.28,2.44]

Continuous oral phenytoin versus placebo

Outcome titleNo. of

studiesNo. of


1 Recurent seizure @12 months

1 90Risk Ratio (M-H,Fixed, 95% CI)

0.98 [0.55, 1.73]

Continuous oral phenobarbitone versus placebo or no treatment



1 Recurrent seizure @ 6months

6 831 Risk Ratio (M-H,Fixed, 95% CI)

0.60 [0.42,0.84]

2 Recurent seizure @ 12months


0.59 [0.46,0.75]



0.79 [0.58,1.08]



0.65 [0.49,0.88]



1.5 [0.61,3.69]

6 Behavioural changes 1 65Risk Ratio (M-H,Fixed, 95% CI)

1.61 [0.79,3.26]

Intermittent rectal diazepam versus no treatment or placebo

Outcome titleNo. of

studiesNo. of




0.60 [0.41, 0.86]



0.65 [0.49, 0.87]



0.32 [0.19, 0.53]



1.13 [0.67, 1.90]



0.58 [0.40, 0.85]

Continuous oral valproate versus placebo or no treatment

Outcome titleNo. of

studiesNo. of




1.20 [0.55,2.62]



0.82 [0.52,1.29]



0.27 [0.06,1.15]



1.26 [0.73,2.18]






























































































Continuous oral pyridoxine versus placebo

Outcome titleNo. of

studiesNo. of




0.47 [0.15,1.48]


1 107 Risk Ratio (M-H, Fixed,95% CI)

0.66 [0.27,1.61]

Intermittent oral phenobarbitone versus no treatment





1.44 [0.68,3.04]



0.93 [0.58,1.47]



1.02 [0.67,1.55]


1 60 Risk Ratio (M-H, Fixed,95% CI)

0.83 [0.28,2.44]

Intermittent oral ibuprofen versus placebo

Outcome titleNo. of

studiesNo. of




1.16 [0.72, 1.87]



0.90 [0.61, 1.34]



0.86 [0.61, 1.22]

Intermittent rectal diazepam versus intermittent rectal valproate

Outcome titleNo. of

studiesNo. of




1.41 [0.58,3.47]



1.48 [0.82,2.67]

Continuous oral phenobarbitone versus intermittent rectal diazepam

Outcome titleNo. of

studiesNo. of


1 Recurrent seizure @ 18

months

1 100Risk Ratio (M-H, Fixed,

95% CI)

1.25 [0.36,

4.38]Intermittent rectal diclofenac versus placebo followed after 8 hours by oral ibuprofen,

acetaminophen or placebo


participantsStatisticalmethod

Effect size

1 Recurrent seizures @ 6months


0.69 [0.34,1.37]



0.60 [0.36,1.03]



0.63 [0.38,1.04]


1 231 Risk Ratio (M-H,Fixed, 95% CI) 0.67 [0.42,1.08]














































































Intermittent oral clobazam versus placebo

Outcome titleNo. of studies

No. of participants

Statisticalmethod

Effect size



0.36 [0.20, 0.64]

Intermittent oral diazepam versus oral clobazam

Outcome titleNo. of

studiesNo. of




0.53 [0.10,2.71]

C O V E R S H E E T

Prophylactic drug management for febrile seizures in children

Reviewer(s) Offringa Martin, Newton Richard

Contribution of Reviewer(s)

Issue protocol first published 2007 issue 2

Issue review first published 2012 issue 4

Date of last minor amendment Information not supplied by reviewer

Date of last substantive amendment Information not supplied by reviewer

Most recent changes

Date new studies sought but none found Information not supplied by reviewer

Date new studies found but not yet included/excluded Information not supplied by reviewer

Date new studies found and included/excluded Information not supplied by reviewer

Date reviewers' conclusions section amended Information not supplied by reviewer

Contact address Offringa555 University AvenueHospital RoadPendleburyTorontoManchesterON

CanadaUK

M5G 1X8M27 4HA













Telephone:Facsimile:E-mail: [email protected]

Cochrane Library number CD003031

Editorial group Cochrane Epilepsy Group

Editorial group code HM-EPILEPSY

S O U R C E S O F S U P P O R T

External sources of support

No sources of support supplied

Internal sources of support

Dept of Pediatric Clinical Epidemiology, Emma Childrens' Hospital A.M.C. Amsterdam, Netherlands.

Dutch Cochrane Centre, Amsterdam, Netherlands.

K E Y W O R D S

Child; Child, Preschool; Humans; Infant; Anticonvulsants [*therapeutic use] ; Antipyretics [*therapeutic use] ;Randomized Controlled Trials as Topic ; Seizures, Febrile [*prevention & control]

H I S T O R Y

History Protocol first published: Issue 2, 2007Review first published: Issue 4, 2012

http://cochrane.bvsalud.org/cochrane/main.php?lib=COC&searchExp=epilepsy%20and%20in%

20and%20childrens&lang=es

mailto:[email protected]



http://cochrane.bvsalud.org/cochrane/show.php?id=_ID_EPILEPSY&lang=es&lib=COC&backto=review

http://cochrane.bvsalud.org/cochrane/main.php?lib=COC&searchExp=epilepsy%20and%20in%20and%20childrens&lang=es





http://cochrane.bvsalud.org/cochrane/show.php?id=_ID_EPILEPSY&lang=es&lib=COC&backto=review


Documents

Prophylactic Drug Management for Febrile Seizures in Children