Prophylactic drug management for febrile seizures in children (Review)

Authors


Abstract

Background

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

Objectives

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

Search methods

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 We also contacted researchers in the field to identify continuing or unpublished studies.

Selection criteria

Trials using randomised or quasi-randomised patient allocation that compared the use of antiepileptic or antipyretic agents 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 extracted the 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. Thirteen interventions of continuous or intermittent prophylaxis and their control treatments were analysed. Methodological quality was moderate to poor in most studies. We could not do a meta-analysis for eight of the 13 comparisons due to insufficient numbers of trials. No significant benefit for valproate, pyridoxine, intermittent phenobarbitone or ibuprofen versus placebo or no treatment was found; nor for diclofenac versus placebo followed by ibuprofen, acetominophen or placebo; nor for intermittent rectal diazepam versus intermittent valproate, nor phenobarbitone versus intermittent rectal diazepam.

There was a significant reduction of recurrent febrile seizures with intermittent oral diazepam versus placebo with a relative risk (RR) of  0.67 (95% confidence interval (CI) 0.48 to 0.94) at 24 months), RR of 0.61 (95% CI 0.15 to 0.89) at 48 months, with no benefit at 6, 12 or 72 months. Phenobarbitone versus placebo or no treatment reduced seizures at 6, 12 and 24 months but not at 18 or 72 month follow up (RR 0.60, 95% CI 0.42 to 0.84 at 6 months; RR 0.59, 95% CI 0.46 to 0.75 at 12 months; and RR 0.65, 95% CI 0.49 to 0.88 at 24 months). Intermittent rectal diazepam versus no treatment or placebo also reduced seizures (RR 0.60, 95% CI 0.41 to 0.86 at 6 months; RR 0.65, 95% CI 0.49 to 0.87 at 12 months; RR 0.2, 95% CI 0.1 to 0.39 at 18 months; RR 0.36, 95% CI 0.18 to 0.71 at 36 months), with no benefit at 24 months. Intermittent clobazam compared to placebo at 6 months resulted in a RR of 0.09 (95% CI 0.02 to 0.30), an effect found against an extremely high (83.3%) recurrence rate in the controls and which is a result that needs replication.

The recording of adverse effects was variable. Lower comprehension scores in phenobarbitone treated children were found in two studies. In general, adverse effects were recorded in up to some 30% of children in the phenobarbitone treated group and in up to 36% in benzodiazepine treated groups. Evidence of publication bias was found in the meta analyses of comparisons for phenobarbitone versus placebo (8 studies) at 12 months but not at 6 months (6 studies); and valproate versus placebo (4 studies) at 12 months; with too few studies to identify publication bias for the other comparisons.

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 intermittent ibuprofen, nor for diclofenac versus placebo followed by ibuprofen, acetominophen or placebo. Adverse effects were reported 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 and information on recurrence, first aid management and, most importantly, the benign nature of the phenomenon.

Plain Language Summary

Prophylactic drug management for febrile seizures in children

Seizures occurring in association with fever are the most common neurologic disorder in children, affecting two to four per cent of all children. On average, one out of three children with febrile seizures have recurrent seizures. In this review the effects of antiepileptic and antipyretic medications to prevent recurrent seizures was examined. No significant 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 repeated to show that this finding is reliable. Meanwhile, parents and families should be supported with the adequate contact details of medical services and information on recurrence, first aid management and, most importantly, the benign nature of the phenomenon.

Summary of findings for the main comparison [Explanation]

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Background

A febrile seizure is defined as a seizure occurring in a child older than one month during an episode of fever. While studies throughout the world differ in what they accept as an upper age limit, febrile seizures usually occur in children between 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 whose seizures are attributable to a central nervous system infection and those who have had a previous afebrile seizure or central 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, the possibility of recurrent seizures during subsequent febrile illnesses must be addressed. This risk of recurrent seizures in previously healthy, untreated children was estimated in a collaborative study that used the individual data from five follow-up studies with similar definitions of febrile seizures and risk factors (Offringa 1994). Of a total of 2496 children with 1410 episodes of recurrent seizures in this study, 32% had at least one, 15% had at least two and 7% had three or more recurrent seizures after a first febrile seizure. The hazard of recurrent seizures was highest between the ages of 12 and 24 months. A history of febrile or unprovoked seizures in a first-degree family member, a relatively low temperature at the first seizure, young age at onset (< 12 months), a family history of unprovoked seizures, and a partial 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 medication might be considered. However, such treatment may have adverse effects on the child's behaviour and cognitive development. Thus, the decision to treat requires assessment of the potential risks and benefits to the child. Since 1990, at least 300 articles have been published on the drug management of seizures associated with fever (Gram 1984). 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 antipyretics is 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; Herranz 1988). To avoid the side effects of continuous antiepileptic drugs (AEDs), rapid-acting antiepileptics given only during fever 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. Thus far, 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 been studied.

Newton assessed the efficacy of phenobarbitone and valproate for the prophylactic treatment of febrile seizures by summarising the results from all eight British placebo-controlled clinical trials that were done before 1988 (Newton 1988). Data were pooled and analysed on an intention-to-treat basis. The overall odds ratio of recurrent febrile seizures for phenobarbitone was 0.8 and for valproate 1.42. Neither result was statistically significant. The author therefore concluded 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 preventive treatment of febrile seizures (Rantala 1997). The risk of recurrences was lower in children receiving continuous phenobarbital 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 febrile seizure (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 an antipyretic can, as compared to no therapy, decrease the likelihood of future febrile seizures in children with febrile seizures.

Objectives

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

Methods

Criteria for considering studies for this review

Types of studies

All trials using randomised or quasi-randomised patient allocation that compared the use of antiepileptic or antipyretic agents 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 with an 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 a perceived relatively high risk of recurrence was planned.

Types of interventions

Trials were included if they compared one treatment with another or with placebo (or no treatment) in children with febrile seizures. Specific drugs included the benzodiazepines (diazepam, lorazepam, clobazam and midazolam), phenytoin, phenobarbitone, valproate, diclofenac, acetaminophen and ibuprofen. A subgroup analysis of intermittent antiepileptic drug (AED) therapies versus continuous AED therapies, and of antipyretics during episodes of fever versus AED 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, 12 months, 24 months, 36 months, and at age five years). 2) Safety: the incidence of specific adverse side-effects, irritability, hyperactivity, somnolence, impaired cognitive development for phenobarbital and intermittent diazepam, gastro-enterologic side effects for valproate and antipyretics, of any administered antiepileptic or antipyretic.

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 contacted researchers in the field to find any ongoing or published studies.

Data collection and analysis

Two authors (RN and MO) independently assessed trials for inclusion. The same authors extracted the outcome data specified 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, 24 months, 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 example intermittent AED therapies versus continuous AED therapies, antipyretics during episodes of fever versus AED therapy during fever, or all versus placebo. The primary analysis was intention to treat and included all randomised patients analysed 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 treatments and the same outcomes. Clinical heterogeneity was assessed by reviewing the differences across trials in the characteristics of recruited patients and treatment protocols. Statistical heterogeneity was assessed using a Chi2 test for heterogeneity. Dichotomous outcomes were expressed as relative risks (RR) with 95% confidence intervals (CIs). The presence of publication bias was assessed using funnel plots.

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 Characteristics of included studies). Together, these 36 articles described 26 randomised trials and their (long-term) follow up. The details of the other 43 studies are given in Characteristics of excluded studies.

The interventions compared against placebo included intermittent oral diazepam in four studies (Autret 1990; 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; Mamelle 1984; McKinlay 1989; Ngwane 1980; Ramakrishnan 1986; Thilothammal 1993; Wolf 1977a), intermittent rectal diazepam in four studies (Knudsen 1985a; Mosquera 1987; Pavlidou 2006; Uhari 1995 (where a rectal dose was followed by orals doses for the time of the fever)), continuous oral valproate in five studies (McKinlay 1989; Mamelle 1984; 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), intermittent oral ibuprofen in one study (van Stuijvenberg 1998), intermittent rectal diclofenac versus placebo followed after eight hours by ibuprofen or acetominophen in one study (Strengell 2009), intermittent rectal diazepam and intermittent rectal valproate in one study (Daugbjerg 1990), intermittent oral clobazam in one study (Bajaj 2005), intermittent oral clobazam with intermittent diazepam in one study (Khosroshahi 2011); and a comparison was made between continuous 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 were available to include in this review. The number of participants enrolled (and analysed) for each intervention versus placebo 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 no treatment or placebo) 219 (169) (in 1 study) phenobarbitone versus intermittent rectal diazepam 100 (100) (in 1 study); 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 A versus C; B versus C). As no pooled analyses were done in which the effects of different antiepileptic or antipyretic drugs were summarised and compared with (placebo) controls, we did not introduce unit-of-analysis errors. Families withdrew 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' (Table 1.

Study outcomes included a comparison of observed and expected seizure recurrence frequency at time points ranging between 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

  • 1.Autret 1990 was a study of 185 children, aged 8 to 36 months, after their first febrile seizure and with less than two risk factors for recurrence. Interventions were intermittent oral diazepam (0.5 mg load and 0.2 mg/kg maintenance) or placebo. Outcomes assessed were recurrent seizures at 12 months after randomisation and adverse medication effects during the 12 months of treatment.
  • 2.Bacon 1981a and Bacon 1981b reported on a single study involving 270 children following a first febrile seizure. There were 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 12 months after randomisation and adverse medication effects during the 12 months of treatment.
  • 3.Bajaj 2005 studied 60 children aged 6 months to 5 years presenting with one or more febrile seizures. Children were allocated to intermittent oral clobazam (0.75 mg/kg body weight twice daily) or placebo during the course of fever and followed for assessment of recurrent seizures at 6 months after randomisation and adverse medication effects during the 6 months of treatment.
  • 4.Camfield 1980 was a study of 97 children aged 6 to 36 months following a first febrile seizure. Children were allocated either to treatment with continuous oral phenobarbitone 4 to 5 mg/kg/day or placebo (both groups treated with antipyretics) 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 and cognitive aspects, during the 12 months of treatment using the same cohort as in Camfield 1980.
  • 5.Daugbjerg 1990 studied 169 children following a first febrile seizure. Children were allocated either to intermittent rectal diazepam (5 mg for those younger than 3 years or 7.5 mg for those 3 years or over) or intermittent valproate suppositories (150 mg for those weighing less than 10 mg or 300 mg for those weighing 10 kg of more). They were followed for assessment of recurrent seizures at 6 and 12 months after randomisation and adverse medication effects during 12 months of treatment.
  • 6.Farwell 1990 was a study of 217 children following a first febrile seizure and who had at least one risk factor for recurrence. They were allocated either to treatment with continuous oral phenobarbitone 4 to 5 mg/kg/day or placebo and followed for assessment of recurrent seizures at 6, 12, 18, and 24 months after randomisation; and adverse medication effects after 24 months of treatment. Sleep disturbances were reported in Hirtz 1993 and the late cognitive effects of phenobarbital for this study were reported in Sulzbacher 1999.
  • 7.Garcia 1984 studied 100 children aged 6 to 60 months following a first febrile seizure (simple or complex) with random allocation either to intermittent rectal diazepam (0.5 mg/kg/dose 8 hourly for the duration of the fever) or continuous oral phenobarbitone (5 mg/kg/day) plus antipyretics for both group. Children were followed for assessment of recurrent seizures at 18 months after randomisation and adverse medication effects during these 18 months of treatment.
  • 8.Heckmatt 1976 was a study of 165 children with a mean age of 20 months following a first febrile seizure. They were allocated either to treatment with continuous oral phenobarbitone 4 to 5 mg/kg/day or no treatment. The children were followed for assessment of recurrent seizures at 6 months after randomisation and adverse medication effects during the 6 months of treatment.
  • 9.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 after randomisation and adverse medication effects during 18 months of treatment.
  • 10.Khosroshahi 2011 studied 72 children aged 6 months to 5 years who had had a simple febrile seizure. They were allocated either to intermittent oral diazepam (0.33 mg/kg/ dose every 8 h for 2 days) or intermittent oral clobazam for 2 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; 7.5 mg BD in children 11 to 15 kg; and 10 mg BD in children > 15 kg. Children were followed for assessment of recurrent seizures at 12 months after randomisation, and adverse medication effects during these 12 months of treatment.
  • 11.Mackintosh 1970 was a study of 32 children aged 6 to 16 months who had had a first febrile seizure. They were allocated either to intermittent oral phenobarbitone at 30 mg with acetyl acetic acid 150 mg or placebo and followed for assessment of recurrent seizures at 6, 12, and 24 months after randomisation; adverse medication effects were not addressed.
  • 12.Mamelle 1982 and Mamelle 1984 reported on one study of 69 children aged 6 to 48 months following a first febrile seizure (excluding those with focal seizures or neuropsychiatric disorders). These were allocated either to treatment with continuous oral phenobarbitone 3 to 4 mg/kg/day, continuous oral valproate 30 to 40 mg/kg/day, or placebo and followed for assessment of recurrent seizures at 18 months after randomisation; adverse medication effects were not addressed.
  • 13.McKiernan 1981 studied 107 children aged 6 to 52 months who had had a first or second febrile seizure. Children in the active treatment arm received continuous oral pyridoxine (in two doses of 20 mg) or placebo. They were followed for assessment of recurrent seizures at 12 months after randomisation; adverse medication effects were not addressed.
  • 14.McKinlay 1989 was a study of 151 children aged 6 to 72 months who had had at least one previous febrile seizure or a complicated febrile seizure. There were three arms to this study. Children were allocated either to treatment with continuous oral phenobarbitone 5 mg/kg/day, continuous oral valproate 30 mg/kg/day or no treatment and followed for assessment of recurrent seizures at 6, 12, and 24 months after randomisation, and adverse medication effects during the 24 months of treatment.
  • 15.Mosquera 1987 studied 69 children following a first febrile seizure and allocated to intermittent rectal diazepam 0.5 mg/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.
  • 16.Ngwane 1980 was a study of 64 children aged 6 to 18 months following a first febrile seizure. There were three arms to this 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 adverse medication effects.
  • 17.Pavlidou 2006 studied 139 children aged 6 to 36 months that were randomly assigned in a prospective controlled trial to receive either intermittent prophylaxis with rectal diazepam or no prophylaxis. The children were followed for assessment of recurrent seizures at 6, 12, and 36 months after randomisation and adverse medication effects during 36 months of treatment.
  • 18.Ramakrishnan 1986 studied 120 children aged 2 to 72 months following a first febrile seizure. These children were allocated 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 at 60 to 72 months after randomisation and adverse medication effects during the period of treatment.
  • 19.Rosman 1993 studied 406 children aged 6 to 60 months who had had at least one febrile seizure. The interventions were 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.
  • 20.Strengell 2009 was a study of 231 children aged 4 months to 4 years who had had a first febrile seizure. All febrile episodes 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 four times a day or placebo. Children were followed for assessment of recurrent seizures at 6, 12, 18, and 24 months after randomisation; adverse medication effects were not addressed.
  • 21.Thilothammal 1993 studied 90 children aged 6 to 72 months following a first febrile seizure and allocated either to treatment with continuous oral phenobarbitone 5 mg/kg/day or placebo. The children were then followed for assessment of recurrent seizures at 6 and 12 months and for adverse medication effects after 12 months of treatment.
  • 22.Uhari 1995 studied 180 children following a first febrile seizure and allocated to intermittent rectal followed by intermittent oral diazepam 0.6 mg/kg or placebo. Both groups were treated with antipyretics for the duration of the fever. They were followed for assessment of recurrent seizures at 6, 12, and 24 months after randomisation and adverse medication effects during the 24 months of treatment.
  • 23.van Stuijvenberg 1998 studied 230 children aged 12 to 48 months who had a febrile seizure and at least one risk factor for recurrence. Children were allocated either to intermittent oral Ibuprofen 5 mg/kg/day or placebo and followed for assessment of recurrent seizures during 24 months after randomisation. We used estimates from the reported Kaplan Meier curves to assess recurrent seizures at 12, 18, and 24 months after randomisation; adverse medication effects were not addressed.
  • 24.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 fever higher 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 and adverse medication effects during the 48 months of treatment.
  • 25.Williams 1979 studied 58 children aged 6 to 72 months after a second simple febrile seizure. Children in the active treatment group were allocated to continuous oral valproate 40 mg/kg/day and were compared with children on no treatment. They were followed for assessment of recurrent seizures and adverse medication effects at 12 months after randomisation.
  • 26.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 oral phenobarbitone 5 mg/kg/day or no treatment. They were followed for assessment of recurrent seizures at 6, 12, and 24 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 function was 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 from 16 (Mackintosh 1970) up to 204 (Rosman 1993). Clearly smaller studies were very prone to the effect of a treatment being over or under exaggerated.

Satisfactory allocation concealment was noted in seven studies (Farwell 1990; Mackintosh 1970; McKiernan 1981; Ngwane 1980; Rosman 1993; Uhari 1995; van Stuijvenberg 1998); no concealment was attempted in eight studies (Heckmatt 1976; Khosroshahi 2011; Knudsen 1985a; Knudsen 1985b; McKinlay 1989; Pavlidou 2006; Verrotti 2004; Wolf 1977a), which used a method of quasi-randomisation. In the remainder of the studies the method of allocation concealment, if any, was unclear.

Ten studies were double blinded (Autret 1990; Bajaj 2005; Camfield 1979; Farwell 1990; Mackintosh 1970; McKiernan 1981; Rosman 1993; Thilothammal 1993; Uhari 1995; van Stuijvenberg 1998); one study was single blinded (Mamelle 1984); and there was no blinding in eight studies (Bacon 1981a and Bacon 1981b; Daugbjerg 1990; Garcia 1984; Mosquera 1987; Ramakrishnan 1986; Strengell 2009; Sulzbacher 1999; Williams 1979).

In many studies the analysis did not include all enrolled participants (for example, 69 of 270 enrolled participants in Bacon 1981a and Bacon 1981b). It must be noted that most of the included studies were undertaken 20 to 30 years ago, 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 and 3.2), and valproate versus placebo or no treatment (comparison 5.2). These were the only comparisons to contain sufficient numbers of studies to be able to examine a funnel plot. We did not find evidence of publication bias for comparison 3.1 (Figure 1), but we did find evidence of publication bias for 3.2 (Figure 2) and for comparison 5.2 (Figure 3).Therewere too fewstudies to comment on whether there was publication bias for the other comparisons.

Figure 1.

Funnel plot of comparison 3: continuous oral phenobarbitone versus placebo or no treatment to recurrence at 6 months: no evidence of publication bias.

Figure 2.

Funnel plot of comparison 3: continuous oral phenobarbitone versus placebo or no treatment to recurrence at 12 months: evidence of publication bias.

Figure 3.

Funnel plot of comparison 5: continuous oral valproate versus placebo or no treatment to recurrence at 12 month: evidence of publication bias.

Effects of interventions

See: Summary of findings for the main comparison Intermittent oral diazepam versus placebo for febrile seizures in children; Summary of findings 2 Continuous oral phenytoin versus placebo for febrile seizures; Summary of findings 3 Continuous oral phenobarbitone versus placebo or no treatment for febrile seizures; Summary of findings 4 Intermittent rectal diazepam versus no treatment or placebo for febrile seizures; Summary of findings 5 Continuous oral valproate versus placebo or no treatment for febrile seizures; Summary of findings 6 Continuous oral pyridoxine versus placebo for febrile seizures; Summary of findings 7 Intermittent oral phenobarbitone versus no treatment for febrile 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 findings 10 Continuous oral phenobarbitone versus intermittent rectal diazepam for febrile seizures; Summary of findings 11 Intermittent rectal diclofenac versus placebo followed after 8 hours by oral ibuprofen, acetaminophen or placebo for febrile 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 febrile seizures 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 72 months. Autret 1990 studied 185 children aged 8 to 36 months who had had a first febrile seizure and with less than two risk factors for recurrence. Rosman 1993 followed 406 children aged 6 to 60 months who had had at least one febrile seizure. Verrotti 2004 studied 110 children aged 6 months to 5 years who had had a simple febrile seizure. 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/kg load 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.

There were significant findings at 24, and 48 months: at 24 months, 42 (21.0%) of 202 treated children had a recurrence 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 the placebo 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 a recurrence 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 the outcome measure. Of the children allocated to phenytoin treatment 16, (34%) of 47 had a recurrence at 12 months compared 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 studies were 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 Bacon 1981a 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 treatment compared with 131 (32.0%) of the 411 in the placebo or no treatment group: RR 0.59 (95% CI 0.46 to 0.75); number needed 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 134 in 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. In those 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 the placebo 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 active phenobarbitone 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 is given 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 Knudsen 1985b), Mosquera 1987, Uhari 1995 and Pavlidou 2006. At 6 months, 37 of 308 (12.0%) children allocated to the active treatment group had had a recurrence compared to 61 of 300 (20.0%) allocated to the no treatment group: RR 0.60 (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 Knudsen 1985b), Mosquera 1987, Uhari 1995 and Pavlidou 2006. At 12 months, 58 of 306 (19.0%) in the active treatment group compared to 86 of 296 (29.0%) in the no treatment group had had a recurrence: RR 0.65 (95% CI 0.49 to 0.87); number needed to treat 9.9.

Recurrent seizures at 18 months: only the study by Knudsen (Knudsen 1985a and Knudsen 1985b) offered data on this. 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 treatment group 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 needed to 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: RR 1.20 (95% CI 0.55 to 2.62).

Recurrent seizures at 12 months: analysis involved the studies of McKinlay 1989, Mosquera 1987, Ngwane 1980 and Williams 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 treatment group 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 control group: 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: RR 0.66 (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 12 months, 31 (20%) of 156 in the active treatment group had had a recurrence compared with 27 (22.0%) of 125 in the control 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 treatment group: 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 30 children in the active treatment group had had a recurrent seizure compared with 6 (20%) of 30 in the no treatment group: 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 a recurrence 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 had a 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 a recurrent seizure compared to 7 (8.8%) of 80 children allocated to the valproate treatment group; RR 1.41 (95% CI 0.58 to 3.47).

Recurrent seizures at 12 months: 23 (25.8%) of 89 children allocated to the intermittent rectal diazepam group had had a seizure recurrence compared to 14 (17.5%) of 80 children allocated to the valproate group; RR 1.48 (95% CI 0.82 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 seizure recurrence compared to 4 (8%) of 50 children allocated to the intermittent rectal diazepam group; RR 1.25 (95% CI 0.36 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 extrapolated from the Kaplan Meier survival curves. The data presented in the paper did not allow subgroup analysis for each of the subsidiary comparisons of ibuprofen versus placebo or acetaminophen versus placebo. Nonetheless, the authors reported no significant differences at any time point (clearly seen from figure 3). Those who were lost to follow up were included 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 recurrence compared 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 recurrence compared 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 recurrence compared 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 recurrence compared 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 recurrence compared 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 recurrence compared 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 this issue allowed us to weigh the clinical importance of any significant results in the intervention arms of the studies. The data are summarised as follows.

Recurrence risk in placebo or control groups at 6 months: these pooled data included the studies of Bajaj 2005, Camfield 1979, Daugbjerg 1990, Farwell 1990, Heckmatt 1976, Knudsen 1985a, Mackintosh 1970, McKinlay 1989, McKiernan 1981, Mosquera 1987, Pavlidou 2006, Rosman 1993, Strengell 2009, Thilothammal 1993, Uhari 1995, van Stuijvenberg 1998, Wolf 1977a. A total of 253 (20.0%) of 1235 children had had a recurrent febrile seizure within 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, Bacon 1981a, Camfield 1979, Daugbjerg 1990, Farwell 1990, Garcia 1984, Heckmatt 1976, Khosroshahi 2011, Knudsen 1985a, Mackintosh 1970, McKiernan 1981, McKinlay 1989, Mosquera 1987, Ngwane 1980, Pavlidou 2006, Rosman 1993, 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 studies of 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 studies from Farwell 1990, Mackintosh 1970, McKinlay 1989, Mosquera 1987, Rosman 1993, Strengell 2009, Uhari 1995, van Stuijvenberg 1998 and Wolf 1977a; 279 (30.0%) of 938 children had had a documented recurrent febrile seizure at 24 months.

Risk of recurrence of a febrile seizure in the placebo or control group at 48 months: only data from Verrotti 2004 were available; 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 one study (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 for the child to stop medication and, in some instances, to leave the trial. A descriptive summary, detailed in so far as was possible from the articles, is given in 'Unwanted medication effects'.

Additional summary of findings [Explanation]

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Discussion

Most of the reviewed papers date from 20 or more years ago and carry a methodological quality which nowadays would be recognised as needing improvement. Methods of randomisation and allocation concealment often do not meet current standards; and treatment versus no treatment is more commonly seen than treatment versus placebo, leading to obvious sources of bias. Nonetheless, the size of the data pool does allow us to draw some conclusions about the value 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 good irrespective of whether their febrile seizures are successfully prevented or not. As no long-term benefit for treatment has 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 intermittent ibuprofen 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 intermittent valproate, 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 24 months and 48 months. At 24 months the relative risk (RR) on treatment was 0.67 (95% CI 0.48 to 0.94) and at 48 months 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 -0.19 to -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 5.26 to 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 or no treatment intervention group at 6, 12, and 24 months follow up, but not at 18 or 60 to 72 month follow up. It must be noted that only two studies were included at 18 months and one at 60 to 72 months, whereas at 6, 12, and 24 months 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 gauge the 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 to treat 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% CI 5.26 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 no treatment 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 basis as 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 risk differences (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. The extraordinary results at 18 months were seen in the study by Pavlidou, which seem not to have been repeated elsewhere.

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

In summary, where a significant benefit for treatment is noted (for oral diazepam versus placebo, phenobarbitone versus placebo or no treatment, or intermittent rectal diazepam versus placebo or no treatment), the benefits do not seem to be stable over time. The follow-up period in the clobazam versus placebo group was confined to six months so as 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 seizure recurrence (the notable exception being the result for intermittent rectal diazepam versus no treatment or placebo at 18 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 rate compared 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 small numbers), which correlated with length of phenobarbitone treatment (Camfield 1980). The findings were supported by the 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 mild transient 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 to reducing the risk of ultimately developing epilepsy. This leads us to conclude that we cannot advocate any of the interventions included in this review for the management of children with febrile seizures, with attendant risks far outweighing any potential benefit. The mainstay of intervention should be the provision of information for the families involved 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 leads to anxiety and fright in the vast majority of those involved.

Authors' conclusions

Implications for practice

There were some significant results though no clinically important benefits for the management of children with febrile seizures for intermittent oral diazepam, continuous phenobarbitone and intermittent rectal diazepam. No benefit was demonstrated for phenytoin, valproate, pyridoxine, intermittent phenobarbitone or antipyretics in the form of intermittent ibuprofen, acetaminophen or diclofenac in the management of febrile seizures. Intermittent clobazam conferred some benefit at six months follow up but the result may be difficult to replicate. Parents should be supported with the adequate contact details of medical services and information on recurrence, first aid management and, most importantly, 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 and concealment 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 relatively higher rate of reporting of adverse effects to date, unless a significant case of justification can be made it seems difficult to justify further research in this area.

Acknowledgements

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

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Autret 1990

MethodsDouble blind RCT
Participants185, age 8-36 months, first FS, <2 RF
InterventionsIntermittent oral diazepam, 0.5 mg load, 0.2 mg maintenance per kilo, or placebo
OutcomesRS@12months, adverse effects@12months
NotesAttrition: 6 diazepam, 3 placebo; results presented as patient days; significant hyperactivity in diazepam group; one SUDEP in placebo group
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskCentralised allocation

Blinding (performance bias and detection bias)

All outcomes

Low riskActually double blind

Incomplete outcome data (attrition bias)

All outcomes

Low risk9 (6 Dzm 3 Plac) of 185 withdrawn
Selective reporting (reporting bias)Low riskStated outcome objective met
Other biasLow riskNo bias identified

Blinding of participants and personnel (performance bias)

All outcomes

Low riskActually double blind

Blinding of outcome assessment (detection bias)

All outcomes

Low riskActually double blind

Bacon 1981a

Methods

RCT

Participants207, after first FS
InterventionsPhenytoin, 8 mg per kilo, or phenobarbitone 5 mg per kilo, or placebo
OutcomesRS@12months, adverse effects
NotesAttrition 69; outcome rater blinded, doctor not blinded
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskUnstated

Blinding (performance bias and detection bias)

All outcomes

High riskUnstated

Incomplete outcome data (attrition bias)

All outcomes

High risk45 lost: 12 moved; 5 behaviour; 5 Epilepsy; 2 rash = 69 of 207
Selective reporting (reporting bias)Low riskStated outcome objective met
Other biasLow riskNo bias identified

Blinding of participants and personnel (performance bias)

All outcomes

High riskUnstated

Blinding of outcome assessment (detection bias)

All outcomes

High riskUnstated

Bacon 1981b

MethodsSee Bacon 1981a
Participants 
Interventions 
Outcomes 
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear risksee Bacon 1981a

Blinding (performance bias and detection bias)

All outcomes

High riskidem

Incomplete outcome data (attrition bias)

All outcomes

High riskidem
Selective reporting (reporting bias)Low riskidem
Other biasLow riskidem

Blinding of participants and personnel (performance bias)

All outcomes

High riskidem

Blinding of outcome assessment (detection bias)

All outcomes

High riskidem

Bajaj 2005

MethodsDouble blind RCT
Participants

60 children aged 6 months to 5 years

Interventions

Clobazam (0.75 mg/kg body weight twice daily) or placebo, during the course of fever

Outcomes

Seizure recurrence at 6 months

Notes

Risk of bias

BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskDouble blind design, not stated how

Blinding (performance bias and detection bias)

All outcomes

Unclear riskNot stated

Incomplete outcome data (attrition bias)

All outcomes

Unclear risk“Sixty patients who completed the study duration of six months were only considered”, unclear out of how many patients originally
Selective reporting (reporting bias)Low riskStated outcome objective met
Other biasLow riskNo bias identified

Blinding of participants and personnel (performance bias)

All outcomes

Unclear riskNot stated

Blinding of outcome assessment (detection bias)

All outcomes

Unclear riskNot stated

Camfield 1979

Methods

Double blind RCT

Participants

97, 6-36 months, first simple FS

Interventions

Phenobarbitone 4-5 mg per kilo, or placebo, both with antipyretics

Outcomes

RS@6 months, RS@12 months, behavioural changes @12 months

Notes

Attrition:2, one in each grp

Risk of bias

BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskNot stated how

Blinding (performance bias and detection bias)

All outcomes

Low riskSpecial placebo manufactured

Incomplete outcome data (attrition bias)

All outcomes

Low risk12 of 79 lost; 4 with side-effects but data collected on 10 of these
Selective reporting (reporting bias)Low riskStated outcome objective met
Other biasLow riskNo bias identified

Blinding of participants and personnel (performance bias)

All outcomes

Low risk 

Blinding of outcome assessment (detection bias)

All outcomes

Low risk 
Methods

See Camfield 1979

Participants 
Interventions 
Outcomes 
Notes 

Risk of bias

BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskidem

Blinding (performance bias and detection bias)

All outcomes

Low riskidem

Incomplete outcome data (attrition bias)

All outcomes

Low riskidem
Selective reporting (reporting bias)Low riskidem
Other biasLow riskidem

Blinding of participants and personnel (performance bias)

All outcomes

Low riskidem

Blinding of outcome assessment (detection bias)

All outcomes

Low riskidem

Daugbjerg 1990

Methods

RCT

Participants

169, first FS

Interventions

Rectal diazepam 5 mg for <3yrs; 7.5 mg for 3 or over; or valproate suppository 150 mg for <10 kg or 300 mg for 10 kg or more

Outcomes

RS@ 6 months, 12 months, adverse effects

Notes

No attrition

Risk of bias

BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)High riskOdd even dates - no concealment

Blinding (performance bias and detection bias)

All outcomes

High riskNo blinding

Incomplete outcome data (attrition bias)

All outcomes

Low risk6 of 169 withdrawn; 4 lost
Selective reporting (reporting bias)Unclear riskStated outcome objective met
Other biasUnclear riskNo bias identified

Blinding of participants and personnel (performance bias)

All outcomes

High riskNo blinding

Blinding of outcome assessment (detection bias)

All outcomes

High riskNo blinding

Farwell 1990

Methods

Double blind RCT

Participants

217, first FS, >1 RF

Interventions

Phenobarbitone 4-5 mg per kilo, or placebo

Outcomes

RS@6 months, RS@12 months, RS@18 months, RS@24 months. IQ after 2 and 3-5 years, sleep disturbances

Notes

attrition 26, 10 PB, 16 placebo

Risk of bias

BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskA - Adequate

Blinding (performance bias and detection bias)

All outcomes

Low riskPlacebo control, blinding maintained with fake phenobarb levels

Incomplete outcome data (attrition bias)

All outcomes

Low risk86% of placebo, 77% phenobarb completed
Selective reporting (reporting bias)Low riskStated outcome objective met
Other biasLow riskNo bias identified

Blinding of participants and personnel (performance bias)

All outcomes

Low riskBlinding maintained with fake phenobarb levels

Blinding of outcome assessment (detection bias)

All outcomes

Low riskBlinding maintained with fake phenobarb levels

Garcia 1984

Methods

RCT

Participants

100. 6-60 months, first FS

Interventions

During fever: either rectal diazepam 0.5 mg/kg/dose x 8 hourly or phenobarbitone 5 mg/kg/day plus antipyretics for both groups

Outcomes

RS@18 months; adverse effects

Notes

No attrition

Risk of bias

BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)High riskNone

Blinding (performance bias and detection bias)

All outcomes

High riskNone

Incomplete outcome data (attrition bias)

All outcomes

Unclear riskNo attrition
Selective reporting (reporting bias)Low riskStated outcome objective met
Other biasLow riskNo bias identified

Blinding of participants and personnel (performance bias)

All outcomes

High riskNone

Blinding of outcome assessment (detection bias)

All outcomes

High riskNone

Heckmatt 1976

Methods

Quasi-RCT

Participants

165, first FS, mean age 20 months

Interventions

Phenobarbitone 4-5 per kilo, or NT

Outcomes

RS@6 months

Notes

attrition 4, 2 per arm, unblinded study

Risk of bias

BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)High riskAlternate day allocation

Blinding (performance bias and detection bias)

All outcomes

High riskNone

Incomplete outcome data (attrition bias)

All outcomes

Low risk4 of 165 lost but 39 of 88 stopped treatment
Selective reporting (reporting bias)Low riskStated outcome objective met
Other biasLow riskNo bias identified

Blinding of participants and personnel (performance bias)

All outcomes

High riskNone

Blinding of outcome assessment (detection bias)

All outcomes

High riskNone

Hirtz 1993

Methods

See Farwell 1990

Participants 
Interventions 
Outcomes 
Notes 

Risk of bias

BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskidem

Blinding (performance bias and detection bias)

All outcomes

Low riskidem

Incomplete outcome data (attrition bias)

All outcomes

Low riskidem
Selective reporting (reporting bias)Low riskidem
Other biasLow riskidem

Blinding of participants and personnel (performance bias)

All outcomes

Low riskidem

Blinding of outcome assessment (detection bias)

All outcomes

Low riskidem

Khosroshahi 2011

Methods

RCT

Participants

80 children, first simple febrile seizure

Interventions

Oral diazepam 0.33 mg/kg/ dose every 8 h for 2 days or oral clobazam for 2 days with the following dosage: 5 mg, daily in children ≤ 5 kg; 5 mg, twice daily (BD) in children 6–10 kg; 7.5 mg, BD in children 11–15 kg; and 10 mg, BD in children >15 kg

Outcomes

Recurrent seizures at 12 months

Notes

Attrition 5 in clobazam group and 3 in diazepam group.

Risk of bias

BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)High riskMethod of allocation not stated.

Blinding (performance bias and detection bias)

All outcomes

High riskNot stated

Incomplete outcome data (attrition bias)

All outcomes

Unclear risk8 (10%) attrition. Clobazam: lost to follow-up (n=5). Poor compliance (n=2). Change drug by other physician (n=2). Repeated seizure without fever (n=1). Diazepam: lost to follow up (n=3). Poor compliance (n=1). Prolonged use of drug (n=1). Inaccessible (n=1)
Selective reporting (reporting bias)Low riskStated outcome objective met
Other biasLow riskNo bias identified

Blinding of participants and personnel (performance bias)

All outcomes

High riskNone

Blinding of outcome assessment (detection bias)

All outcomes

High riskNone

Knudsen 1985a

Methods

Quasi-RCT

Participants

289, first FS

Interventions

Intermittent rectal diazepam 5 for children <3 years, 7.5 for >3 years, or no treatment

Outcomes

RS@6 months, RS@12 months, RS@18 months

Notes

attrition 16, 5 diazepam and 11 no treatment

Risk of bias

BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)High riskOdd/even date allocation

Blinding (performance bias and detection bias)

All outcomes

High riskNone

Incomplete outcome data (attrition bias)

All outcomes

Low risk16 of 289 excluded – parents demanded treatment change
Selective reporting (reporting bias)Low riskStated outcome objective met
Other biasLow riskNo bias identified

Blinding of participants and personnel (performance bias)

All outcomes

High riskNone

Blinding of outcome assessment (detection bias)

All outcomes

High riskNone

Knudsen 1985b

Methods

See Knudsen 1985a

Participants 
Interventions 
Outcomes 
Notes 

Risk of bias

BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)High riskidem

Blinding (performance bias and detection bias)

All outcomes

High riskidem

Incomplete outcome data (attrition bias)

All outcomes

Low riskidem
Selective reporting (reporting bias)Low riskidem
Other biasLow riskidem

Blinding of participants and personnel (performance bias)

All outcomes

High riskidem

Blinding of outcome assessment (detection bias)

All outcomes

High riskidem

Knudsen 1988

Methods

See Knudsen 1985a

Participants 
Interventions 
Outcomes 
Notes 

Risk of bias

BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)High riskidem

Blinding (performance bias and detection bias)

All outcomes

Unclear riskidem

Incomplete outcome data (attrition bias)

All outcomes

Unclear riskidem
Selective reporting (reporting bias)Unclear riskidem
Other biasUnclear riskidem

Blinding of participants and personnel (performance bias)

All outcomes

Unclear riskidem

Blinding of outcome assessment (detection bias)

All outcomes

Unclear riskidem

Knudsen 1996

Methods

See Knudsen 1985a

Participants 
Interventions 
Outcomes 
Notes 

Risk of bias

BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)High riskidem

Blinding (performance bias and detection bias)

All outcomes

Unclear riskidem

Incomplete outcome data (attrition bias)

All outcomes

Unclear riskidem
Selective reporting (reporting bias)Unclear riskidem
Other biasUnclear riskidem

Blinding of participants and personnel (performance bias)

All outcomes

Unclear riskidem

Blinding of outcome assessment (detection bias)

All outcomes

Unclear riskidem

Mackintosh 1970

Methods

Double blind RCT

Participants

32, 6-60 months, first simple FS

Interventions

Phenobarbitone 30 with ASA 150, or placebo

Outcomes

RS@6 months, RS@12 months, RS@24 months

Notes

Histogram used in estimations of recurrence risks

Risk of bias

BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskA - Adequate

Blinding (performance bias and detection bias)

All outcomes

Low riskDouble blind

Incomplete outcome data (attrition bias)

All outcomes

Low riskNo losses to follow up
Selective reporting (reporting bias)Low riskStated outcome objective met
Other biasLow riskNo bias identified

Blinding of participants and personnel (performance bias)

All outcomes

Low riskDouble blind

Blinding of outcome assessment (detection bias)

All outcomes

Low riskDouble blind

Mamelle 1982

Methods

See Mamelle 1984

Participants 
Interventions 
Outcomes 
Notes 

Risk of bias

BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)High riskNone

Blinding (performance bias and detection bias)

All outcomes

High riskNone

Incomplete outcome data (attrition bias)

All outcomes

Low risk4 of 69 dropped out
Selective reporting (reporting bias)Low riskStated outcome objective met
Other biasLow riskNo bias identified

Blinding of participants and personnel (performance bias)

All outcomes

High riskUnblinded

Blinding of outcome assessment (detection bias)

All outcomes

High riskUnblinded

Mamelle 1984

Methods

Single blind RCT

Participants

69, 6-48 months, first FS, excluded focal and neuropsychiatric disorders

Interventions

Phenobarbitone 3-4 per kilo, or valproate 30-40 per kilo, or placebo

Outcomes

RS@18 months

Notes

Attrition 4

Risk of bias

BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)High riskNot used

Blinding (performance bias and detection bias)

All outcomes

High riskUnblinded

Incomplete outcome data (attrition bias)

All outcomes

Low risk4 of 69 dropped out
Selective reporting (reporting bias)Low riskStated outcome objective met
Other biasLow riskNo bias identified

Blinding of participants and personnel (performance bias)

All outcomes

High riskUnblinded

Blinding of outcome assessment (detection bias)

All outcomes

High riskUnblinded

McKiernan 1981

Methods

Double blind RCT

Participants

107, 6-52 months, first or second FS

Interventions

Pyridoxine 2 times 20 mg, or placebo

Outcomes

RS@6 months, RS@12 months

Notes

Kaplan Meier used in estimations

Risk of bias

BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskA - Adequate

Blinding (performance bias and detection bias)

All outcomes

Unclear riskOnly for participants

Incomplete outcome data (attrition bias)

All outcomes

High risk80 of 107 completed 6 months
Selective reporting (reporting bias)Low riskStated outcome objective met
Other biasLow riskNo bias identified

Blinding of participants and personnel (performance bias)

All outcomes

Unclear riskOnly for participants

Blinding of outcome assessment (detection bias)

All outcomes

Unclear riskOnly for participants

McKinlay 1989

Methods

Quasi-RCT

Participants

151, 6-72 months, > one previous FS, or complicated FS

Interventions

Phenobarbitone 5 per kilo, or valproate 30 per kilo, or no treatment

Outcomes

RS@6months, RS@12months, RS@24months

Notes 

Risk of bias

BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)High riskAlternate patients allocated

Blinding (performance bias and detection bias)

All outcomes

High riskNone

Incomplete outcome data (attrition bias)

All outcomes

Low risk24 (13%) lost to follow up
Selective reporting (reporting bias)Low riskStated outcome objective met
Other biasLow riskNo bias identified

Blinding of participants and personnel (performance bias)

All outcomes

High riskNone

Blinding of outcome assessment (detection bias)

All outcomes

High riskNone

Mosquera 1987

Methods

RCT

Participants

69, first FS

Interventions

Intermittent rectal diazepam 0.5 per kilo per dose, valproate 30 per kilo, or no treatment

Outcomes

RS@12 months, RS@24 months

Notes

Attrition 5 unaccounted for

Risk of bias

BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskD - Not used

Blinding (performance bias and detection bias)

All outcomes

High riskNot done

Incomplete outcome data (attrition bias)

All outcomes

Low riskSeemingly no attrition
Selective reporting (reporting bias)Low riskStated outcome objective met
Other biasLow riskNo bias identified

Blinding of participants and personnel (performance bias)

All outcomes

High riskNot done

Blinding of outcome assessment (detection bias)

All outcomes

High riskNot done

Ngwane 1980

Methods

Quasi-RCT

Participants

64, 6-18 months, first simple FS

Interventions

Phenobarbitone 3-6 per kilo, or valproate 30-60 per kilo, or no treatment

Outcomes

RS@12 months, adverse effects

Notes

Doctor was blinded to the treatment

Risk of bias

BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskSpecial preparations made pharmacist held key

Blinding (performance bias and detection bias) All outcomes

Low riskSpecial preparations made pharmacist held key

Incomplete outcome data (attrition bias) All outcomes

Low risk4 of 43 in trial withdrew due to side effects
Selective reporting (reporting bias)Low riskStated outcome objective met
Other biasLow riskNo bias identified

Blinding of participants and personnel (performance bias)

All outcomes

Low riskSpecial preparations made pharmacist held key

Blinding of outcome assessment (detection bias)

All outcomes

Low riskSpecial preparations made pharmacist held key

Pavlidou 2006

Methods

RCT

Participants

139 children aged 6 to 36 months; first febrile seizure

Interventions

Rectal diazepam 0.33mg/kg 8 hourly first day and then 12 hourly second day versus no prophylaxis (checked!)

Outcomes

Recurrent seizures 6 months, 12 months and 3 years

Notes

6 children lost to follow up

Risk of bias

BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)High riskD - Quasi-random, alternate day allocation to intervention groups.

Blinding (performance bias and detection bias)

All outcomes

High riskNo blinding

Incomplete outcome data (attrition bias)

All outcomes

Low riskAttrition of only 6 of 145
Selective reporting (reporting bias)Low riskStated outcome objective met
Other biasLow riskNo bias identified

Blinding of participants and personnel (performance bias)

All outcomes

High riskNo blinding

Blinding of outcome assessment (detection bias)

All outcomes

High riskNo blinding

Ramakrishnan 1986

Methods

RCT

Participants

120, 2-72 months, first FS

Interventions

Phenobarbitone 3-5 per kilo, or intermittent phenobarbitone same dose, or intermittent diazepam 0.6 per kilo, or no treatment

Outcomes

RS@60-72 months

Notes

no attrition reported, unblinded study

Risk of bias

BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskD - Not used

Blinding (performance bias and detection bias)

All outcomes

High riskNo blinding

Incomplete outcome data (attrition bias)

All outcomes

Low riskApparently no withdrawal
Selective reporting (reporting bias)Low riskStated outcome objective met
Other biasLow riskNo bias identified

Blinding of participants and personnel (performance bias)

All outcomes

High riskNo blinding

Blinding of outcome assessment (detection bias)

All outcomes

High riskNo blinding

Rosman 1993

Methods

Double blind RCT

Participants

406, 6-60 months, at least one FS

Interventions

Intermittent oral diazepam 1 per kilo per day, or placebo

Outcomes

RS@6 months, RS@12 months, RS@24 months

Notes

Kaplan Meier used in estimations

Risk of bias

BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskAdequate

Blinding (performance bias and detection bias)

All outcomes

Low riskManufactured placebo

Incomplete outcome data (attrition bias)

All outcomes

Low risk29 (12 diazepam. 17 placebo) of 406 withdrew due to side-effects or frequent recurrence
Selective reporting (reporting bias)Low riskStated outcome objective met
Other biasLow riskNo bias identified

Blinding of participants and personnel (performance bias)

All outcomes

Low riskAdequate

Blinding of outcome assessment (detection bias)

All outcomes

Low riskadequate

Strengell 2009

Methods

Randomised, placebo-controlled, double blind trial

Participants

231, 4-48 months, first febrile seizure; 63 of these had had a complicated first seizure

Interventions

Random allocation first into 2 groups (rectal diclofenac [1.5 mg/kg suppository] versus placebo) and then to 3 groups (oral placebo versus acetaminophen [15 mg/kg] versus ibuprofen [10 mg/kg]) - each up to four times per day for as long as temp. > 38oC

Outcomes

Actuarial analysis of seizure recurrence up to 24 months

Notes

Participants included in analyses for as long as they participated because Kaplan Meier used with no imputations for the dropouts

Risk of bias

BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskDouble blind design

Blinding (performance bias and detection bias)

All outcomes

Low riskSpecial preparations made for drugs/placebos by pharmaceutical companies

Incomplete outcome data (attrition bias)

All outcomes

High riskAttrition: 50 of 231: 231 randomised: 34 did not want to continue; 9 lost; 7 others dropped out for a variety of reasons
Selective reporting (reporting bias)Low riskStated outcome objective met
Other biasLow riskNo bias identified

Blinding of participants and personnel (performance bias)

All outcomes

Low riskSpecial preparations made for drugs/placebos by pharmaceutical companies

Blinding of outcome assessment (detection bias)

All outcomes

Low riskSpecial preparations made for drugs/placebos by pharmaceutical companies

Sulzbacher 1999

Methods

See Farwell 1990

Participants 
Interventions 
Outcomes 
Notes 

Risk of bias

BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskidem

Blinding (performance bias and detection bias)

All outcomes

Unclear riskidem

Incomplete outcome data (attrition bias)

All outcomes

Unclear riskidem
Selective reporting (reporting bias)Unclear riskidem
Other biasUnclear riskidem

Blinding of participants and personnel (performance bias)

All outcomes

Unclear riskidem

Blinding of outcome assessment (detection bias)

All outcomes

Unclear riskidem

Thilothammal 1993

Methods

Double blind RCT

Participants

90, 6-72 months, first simple seizure

Interventions

Phenobarbitone 5 per kilo, or placebo

Outcomes

RS@12 months

Notes

No attrition

Risk of bias

BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskNot stated

Blinding (performance bias and detection bias)

All outcomes

Low riskAdequate placebo

Incomplete outcome data (attrition bias)

All outcomes

Low riskOnly 4 dropouts
Selective reporting (reporting bias)Low riskStated outcome objective met
Other biasLow riskNo bias identified

Blinding of participants and personnel (performance bias)

All outcomes

Low riskAdequate placebo

Blinding of outcome assessment (detection bias)

All outcomes

Low riskAdequate placebo

Uhari 1995

Methods

Double blind RCT

Participants

180, first FS

Interventions

Intermittent rectal followed by oral diazepam, 0.6 per kilo, or placebo, both with antipyretics

Outcomes

RS@6 months, RS@12 months, RS@24 months

Notes

Kaplan Meier used in estimations

Risk of bias

BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskAdequate

Blinding (performance bias and detection bias)

All outcomes

High riskNo obvious blinding

Incomplete outcome data (attrition bias)

All outcomes

Low risk4 0f 161 not followed
Selective reporting (reporting bias)Low riskStated outcome objective met
Other biasLow riskNo bias identified

Blinding of participants and personnel (performance bias)

All outcomes

High riskNo obvious blinding

Blinding of outcome assessment (detection bias)

All outcomes

High riskNo obvious blinding

van Stuijvenberg 1998

Methods

Double blind RCT

Participants

230, 12-48 months, at least one risk factor

Interventions

Intermittent oral ibuprofen 5 per kilo per day, or placebo

Outcomes

RS@6 months, RS@12 months, RS@24 months

Notes

Kaplan Meier used in estimations

Risk of bias

BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskAdequate allocation concealment

Blinding (performance bias and detection bias)

All outcomes

Low riskDouble blinded

Incomplete outcome data (attrition bias)

All outcomes

Low risk23 of 230 without outcome data
Selective reporting (reporting bias)Low riskStated outcome objective met
Other biasLow riskNo bias identified

Blinding of participants and personnel (performance bias)

All outcomes

Low risk 

Blinding of outcome assessment (detection bias)

All outcomes

Low riskDouble blinded

Verrotti 2004

Methods

RCT

Participants

110, 6-60 months, one simple febrile seizure, no risk factors

Interventions

Oral with diazepam, 0.35 mg/kg every 8 h, during each episode of fever higher than 38oC, continuing until child afebrile for 24h or no treatment

Outcomes

RS@6 months, RS@12 months, RS@24 months and RS@48 months

Notes 

Risk of bias

BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskNot stated

Blinding (performance bias and detection bias)

All outcomes

High riskNone

Incomplete outcome data (attrition bias)

All outcomes

Unclear riskData available on 110 of 113 children, yet 45 intervention children are compared to 65 controls
Selective reporting (reporting bias)Low riskStated outcome objective met
Other biasLow riskNo bias identified

Blinding of participants and personnel (performance bias) All outcomes

High riskNone

Blinding of outcome assessment (detection bias) All outcomes

High riskNone

Williams 1979

Methods

RCT

Participants

58, 6-72 months, after second simple FS

Interventions

Valproate 40 per kilo, or no treatment

Outcomes

RS@12 months

Notes 

Risk of bias

BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskD - Not used

Blinding (performance bias and detection bias)

All outcomes

High riskNone

Incomplete outcome data (attrition bias)

All outcomes

Low riskNo attrition
Selective reporting (reporting bias)Low riskStated outcome objective met
Other biasLow riskNo bias identified

Blinding of participants and personnel (performance bias)

All outcomes

High risk 

Blinding of outcome assessment (detection bias)

All outcomes

High riskNone

Wolf 1977a

Methods

Quasi-RCT

Participants

355, 6-48 months, first FS

Interventions

Phenobarbitone 3-4 per kilo, or intermittent phenobarbitone 5 per kilo, or no treatment

Outcomes

RS@6 months, RS@12 months, RS@24 months, late cognition and behaviour, and adverse effect

Notes

Kaplan Meier used in estimations

Risk of bias

BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)High riskNot used

Blinding (performance bias and detection bias)

All outcomes

High riskNone

Incomplete outcome data (attrition bias)

All outcomes

Unclear riskStudy design with actuarial analysis gave little attrition
Selective reporting (reporting bias)Low riskStated outcome objective met
Other biasLow riskNo bias identified

Blinding of participants and personnel (performance bias)

All outcomes

High riskNone

Blinding of outcome assessment (detection bias)

All outcomes

High riskNone

Wolf 1978

Methods

See Wolf 1977a

Participants 
Interventions 
Outcomes 
Notes 

Risk of bias

BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)High riskidem

Blinding (performance bias and detection bias)

All outcomes

Unclear riskidem

Incomplete outcome data (attrition bias)

All outcomes

Unclear riskidem
Selective reporting (reporting bias)Unclear riskidem
Other biasUnclear riskidem

Blinding of participants and personnel (performance bias)

All outcomes

Unclear riskidem

Blinding of outcome assessment (detection bias)

All outcomes

Unclear riskidem

Wolf 1981

Methods

See Wolf 1977a

Participants 
Interventions 
Outcomes 
Notes 

Risk of bias

BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)High riskidem

Blinding (performance bias and detection bias)

All outcomes

Unclear riskidem

Incomplete outcome data (attrition bias)

All outcomes

Unclear riskidem
Selective reporting (reporting bias)Unclear riskidem
Other biasUnclear riskidem

Blinding of participants and personnel (performance bias)

All outcomes

Unclear riskidem

Blinding of outcome assessment (detection bias)

All outcomes

Unclear riskidem

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
AAP Steering Group 2008Practice guideline.
Addy 1977Abstract only.
Antony 1983Seventy-two children randomised, 36 to phenobarbital and 36 to carbamazepine, but 32 not included in final analysis. In 15 there was no follow up, 5 were excluded because of low or no anti-epileptic drug level, 9 excluded because of unacceptable adverse effects, 2 had afebrile seizures and 1 child was incorrectly entered. Unfortunately no follow up detail is given for any of these 32 children (44%!).
Camfield 1982Case series of phenobarbital failures put on carbamazepine, no RCT.
Camfield 1995Editorial.
Capocchi 1982Case series, no RCT, no placebo group.
Cavazzuti 1975No RCT.
Costa 1996Case series, no control group.
Dalla Bernardina 1988No RCT, no placebo group, overview of valproate studies.
De Zan 1982Case series, no RCT.
Dianese 1979No RCT, no placebo group.
Domizio 1993No RCT, no placebo group.
Echenne 1983No RCT, no placebo group.
Faero 1972Case series, no RCT, no placebo group.
Frehlih 1997No data reported to estimate the occurrence of any of the pre-specified outcomes.
Galli 1977Could not get hold of a copy of paper.
Guerreiro 1992No RCT, no control group.
Herranz 1984No RCT, no placebo group.
Knudsen 1978Further exclusions from analysis 16 children in phenobarbitone group due to adverse effects or parents' “dislike to it”. No follow up data given for these 16 (+ 24 lost to follow up) children.
Lahat 2000Not a recurrence study - acute treatment only.
Lee 1981Children "randomised" but method not stated to either phenobarbitone or valproate. 37 children refused prophylactic treatment, 25 traced at the termination of the study to make up control group. Therefore this was not a RCT.
Lee 1986No RCT.
Manreza 1997Case series treated with clobazam, no RCT.
Minagawa 1981Not randomised, unclear allocation, with different numbers of patients per group, the only randomisation was in 15 patients to measure drug levels. Outside scope of this review.
Parisi 1995No RCT, no placebo group.
Rose 2005RCT but with inadequate follow-up range of 0-14 months; dta interpretation at 6 months impossible.
Rosman 2001Research question asking parental experiences.
Schnaiderman 1993Only very short term natural history. No RCT.
Shimazaki 1997Not randomised, unclear allocation, different numbers of patients per group.
Shirai 1988No RCT.
Smith 1982No RCT.
Sopo 1991Acute treatment only, no RCT.
Steardo 1980Not randomised, unclear allocation, different numbers of patients per group.
Sunami 1990No RCT.
Thorn 1975No RCT.
Tondi 1987Letter describing a case series, no RCT.
Van den Berg 1971No RCT.
Van Esch 1995Research question on effect on temperature, not on recurrences.
Vanasse 1984No RCT.
Vining 1987Side effects study not on FC children.
Wallace 1980No RCT, no placebo group.
Winsley 2005No data reported to estimate the occurrence of any of the prespecified outcomes.
Wolf 1977bBiological analysis of perinatal risk factors, no RCT.

Data and analyses

Download statistical data

Table Comparison 1. Intermittent oral diazepam versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

1 Recurrent seizure @ 6 months

1406Risk Ratio (M-H, Fixed, 95% CI)0.81 [0.50, 1.33]

2 Recurrent seizure @ 12 months

2582Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.53, 1.03]

3 Recurrent seizure @ 24 months

1406Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.48, 0.94]

4 Recurrent seizure @ 48 months

1110Risk Ratio (M-H, Fixed, 95% CI)0.36 [0.15, 0.89]

5 Recurrent seizure @ 60-72 months

160Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.28, 2.44]
Table Comparison 2. Continuous oral phenytoin versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

1 Recurent seizure @ 12 months

190Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.55, 1.73]
Table Comparison 3. Continuous oral phenobarbitone versus placebo or no treatment
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

1 Recurrent seizure @ 6 months

6831Risk Ratio (M-H, Fixed, 95% CI)0.60 [0.42, 0.84]

2 Recurent seizure @ 12 months

7805Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.46, 0.75]

3 Recurent seizure @ 18 months

2264Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.58, 1.08]

4 Recurent seizure @ 24 months

3533Risk Ratio (M-H, Fixed, 95% CI)0.65 [0.49, 0.88]

5 Recurrent seizure @ 60-72 months

160Risk Ratio (M-H, Fixed, 95% CI)1.5 [0.61, 3.69]

6 Behavioural changes

165Risk Ratio (M-H, Fixed, 95% CI)1.61 [0.79, 3.26]
Table Comparison 4. Intermittent rectal diazepam versus no treatment or placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

1 Recurrent seizure @ 6 months

4608Risk Ratio (M-H, Fixed, 95% CI)0.60 [0.41, 0.86]

2 Recurrent seizure @ 12 months

4602Risk Ratio (M-H, Fixed, 95% CI)0.65 [0.49, 0.87]

3 Recurrent seizure @ 18 months

1195Risk Ratio (M-H, Fixed, 95% CI)0.32 [0.19, 0.53]

4 Recurrent seizure @ 24 months

2223Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.67, 1.90]

5 Recurrent seizure @ 36 months

1139Risk Ratio (M-H, Fixed, 95% CI)0.58 [0.40, 0.85]
Table Comparison 5. Continuous oral valproate versus placebo or no treatment
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

1 Recurrent seizure @ 6 months

2156Risk Ratio (M-H, Fixed, 95% CI)1.20 [0.55, 2.62]

2 Recurrent seizure @ 12 months

4255Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.52, 1.29]

3 Recurrent seizure @ 18 months

148Risk Ratio (M-H, Fixed, 95% CI)0.27 [0.06, 1.15]

4 Recurrent seizure @ 24 months

2156Risk Ratio (M-H, Fixed, 95% CI)1.26 [0.73, 2.18]
Table Comparison 6. Continuous oral pyridoxine versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

1 Recurrent seizure @ 6 months

1107Risk Ratio (M-H, Fixed, 95% CI)0.47 [0.15, 1.48]

2 Recurrent seizure @ 12 months

1107Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.27, 1.61]
Table Comparison 7. Intermittent oral phenobarbitone versus no treatment
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

1 Recurrent seizure @ 6 months

2281Risk Ratio (M-H, Fixed, 95% CI)1.44 [0.68, 3.04]

2 Recurrent seizure @ 12 months

2281Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.58, 1.47]

3 Recurrent seizure @ 24 months

2281Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.67, 1.55]

4 Recurrent seizure @ 60-72 months

160Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.28, 2.44]
Table Comparison 8. Intermittent oral ibuprofen versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

1 Recurrent seizure @ 6 months

1230Risk Ratio (M-H, Fixed, 95% CI)1.16 [0.72, 1.87]

2 Recurrent seizure @ 12 months

1230Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.61, 1.34]

3 Recurrent seizure @ 24 months

1230Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.61, 1.22]
Table Comparison 9. Intermittent rectal diazepam versus intermittent rectal valproate
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

1 Recurrent seizure @ 6 months

1169Risk Ratio (M-H, Fixed, 95% CI)1.41 [0.58, 3.47]

2 Recurrent seizure @ 12 months

1169Risk Ratio (M-H, Fixed, 95% CI)1.48 [0.82, 2.67]
Table Comparison 10. Continuous oral phenobarbitone versus intermittent rectal diazepam
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

1 Recurrent seizure @ 18 months

1100Risk Ratio (M-H, Fixed, 95% CI)1.25 [0.36, 4.38]
Table Comparison 11. Intermittent rectal diclofenac versus placebo followed after 8 hours by oral ibuprofen, acetaminophen or placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

1 Recurrent seizures @ 6 months

1231Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.34, 1.37]

2 Recurrent seizures @ 12 months

1231Risk Ratio (M-H, Fixed, 95% CI)0.60 [0.36, 1.03]

3 Recurrent seizures @ 18 months

1231Risk Ratio (M-H, Fixed, 95% CI)0.63 [0.38, 1.04]

4 Recurrent seizures @ 24 months

1231Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.42, 1.08]
Table Comparison 12. Intermittent oral clobazam versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

1 Recurrent seizure @ 6 months

160Risk Ratio (M-H, Fixed, 95% CI)0.36 [0.20, 0.64]
Table Comparison 13. Intermittent oral diazepam versus oral clobazam
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

1 Recurrent seizure @ 12 months

172Risk Ratio (M-H, Fixed, 95% CI)0.53 [0.10, 2.71]
Figure Analysis 1.1.

Comparison 1 Intermittent oral diazepam versus placebo, Outcome 1 Recurrent seizure @ 6 months.

Figure Analysis 1.2.

Comparison 1 Intermittent oral diazepam versus placebo, Outcome 2 Recurrent seizure @ 12 months.

Figure Analysis 1.3.

Comparison 1 Intermittent oral diazepam versus placebo, Outcome 3 Recurrent seizure @ 24 months.

Figure Analysis 1.4.

Comparison 1 Intermittent oral diazepam versus placebo, Outcome 4 Recurrent seizure @ 48 months.

Figure Analysis 1.5.

Comparison 1 Intermittent oral diazepam versus placebo, Outcome 5 Recurrent seizure @ 60-72 months.

Figure Analysis 2.1.

Comparison 2 Continuous oral phenytoin versus placebo, Outcome 1 Recurent seizure @ 12 months.

Figure Analysis 3.1.

Comparison 3 Continuous oral phenobarbitone versus placebo or no treatment, Outcome 1 Recurrent seizure @ 6 months.

Figure Analysis 3.2.

Comparison 3 Continuous oral phenobarbitone versus placebo or no treatment, Outcome 2 Recurent seizure @ 12 months.

Figure Analysis 3.3.

Comparison 3 Continuous oral phenobarbitone versus placebo or no treatment, Outcome 3 Recurent seizure @ 18 months.

Figure Analysis 3.4.

Comparison 3 Continuous oral phenobarbitone versus placebo or no treatment, Outcome 4 Recurent seizure @ 24 months.

Figure Analysis 3.5.

Comparison 3 Continuous oral phenobarbitone versus placebo or no treatment, Outcome 5 Recurrent seizure @ 60-72 months.

Figure Analysis 3.6.

Comparison 3 Continuous oral phenobarbitone versus placebo or no treatment, Outcome 6 Behavioural changes.

Figure Analysis 4.1.

Comparison 4 Intermittent rectal diazepam versus no treatment or placebo, Outcome 1 Recurrent seizure @ 6 months.

Figure Analysis 4.2.

Comparison 4 Intermittent rectal diazepam versus no treatment or placebo, Outcome 2 Recurrent seizure @ 12 months.

Figure Analysis 4.3.

Comparison 4 Intermittent rectal diazepam versus no treatment or placebo, Outcome 3 Recurrent seizure @ 18 months.

Figure Analysis 4.4.

Comparison 4 Intermittent rectal diazepam versus no treatment or placebo, Outcome 4 Recurrent seizure @ 24 months.

Figure Analysis 4.5.

Comparison 4 Intermittent rectal diazepam versus no treatment or placebo, Outcome 5 Recurrent seizure @ 36 months.

Figure Analysis 5.1.

Comparison 5 Continuous oral valproate versus placebo or no treatment, Outcome 1 Recurrent seizure @ 6 months.

Figure Analysis 5.2.

Comparison 5 Continuous oral valproate versus placebo or no treatment, Outcome 2 Recurrent seizure @ 12 months.

Figure Analysis 5.3.

Comparison 5 Continuous oral valproate versus placebo or no treatment, Outcome 3 Recurrent seizure @ 18 months.

Figure Analysis 5.4.

Comparison 5 Continuous oral valproate versus placebo or no treatment, Outcome 4 Recurrent seizure @ 24 months.

Figure Analysis 6.1.

Comparison 6 Continuous oral pyridoxine versus placebo, Outcome 1 Recurrent seizure @ 6 months.

Figure Analysis 6.2.

Comparison 6 Continuous oral pyridoxine versus placebo, Outcome 2 Recurrent seizure @ 12 months.

Figure Analysis 7.1.

Comparison 7 Intermittent oral phenobarbitone versus no treatment, Outcome 1 Recurrent seizure @ 6 months.

Figure Analysis 7.2.

Comparison 7 Intermittent oral phenobarbitone versus no treatment, Outcome 2 Recurrent seizure @ 12 months.

Figure Analysis 7.3.

Comparison 7 Intermittent oral phenobarbitone versus no treatment, Outcome 3 Recurrent seizure @ 24 months.

Figure Analysis 7.4.

Comparison 7 Intermittent oral phenobarbitone versus no treatment, Outcome 4 Recurrent seizure @ 60-72 months.

Figure Analysis 8.1.

Comparison 8 Intermittent oral ibuprofen versus placebo, Outcome 1 Recurrent seizure @ 6 months.

Figure Analysis 8.2.

Comparison 8 Intermittent oral ibuprofen versus placebo, Outcome 2 Recurrent seizure @ 12 months.

Figure Analysis 8.3.

Comparison 8 Intermittent oral ibuprofen versus placebo, Outcome 3 Recurrent seizure @ 24 months.

Figure Analysis 9.1.

Comparison 9 Intermittent rectal diazepam versus intermittent rectal valproate, Outcome 1 Recurrent seizure @ 6 months.

Figure Analysis 9.2.

Comparison 9 Intermittent rectal diazepam versus intermittent rectal valproate, Outcome 2 Recurrent seizure @ 12 months.

Figure Analysis 10.1.

Comparison 10 Continuous oral phenobarbitone versus intermittent rectal diazepam, Outcome 1 Recurrent seizure @ 18 months.

Figure Analysis 11.1.

Comparison 11 Intermittent rectal diclofenac versus placebo followed after 8 hours by oral ibuprofen, acetaminophen or placebo, Outcome 1 Recurrent seizures @ 6 months.

Figure Analysis 11.2.

Comparison 11 Intermittent rectal diclofenac versus placebo followed after 8 hours by oral ibuprofen, acetaminophen or placebo, Outcome 2 Recurrent seizures @ 12 months.

Figure Analysis 11.3.

Comparison 11 Intermittent rectal diclofenac versus placebo followed after 8 hours by oral ibuprofen, acetaminophen or placebo, Outcome 3 Recurrent seizures @ 18 months.

Figure Analysis 11.4.

Comparison 11 Intermittent rectal diclofenac versus placebo followed after 8 hours by oral ibuprofen, acetaminophen or placebo, Outcome 4 Recurrent seizures @ 24 months.

Figure Analysis 12.1.

Comparison 12 Intermittent oral clobazam versus placebo, Outcome 1 Recurrent seizure @ 6 months.

Figure Analysis 13.1.

Comparison 13 Intermittent oral diazepam versus oral clobazam, Outcome 1 Recurrent seizure @ 12 months.

Additional Tables

Table 1. Unwanted medication effects
First authorNumber of ChildrenAdverse medication effects, as reported in article
Autret 1990177Hyperactivity (defined as agitation and inability to remain still), significantly [P < 0.003] more frequent in diazepam group (138 v 34 days. No significant differences noted for normal vigilance or drowsiness; normal staggering or impossible “walking”. One sudden unexpected death in placebo group.

Bacon 1981a;

Bacon 1981b

138, 43 control, 48 phenobarbitone, 48 phenytoinRash in one child on phenobarbitone, ataxia in 5 on phenytoin. Behavioural items: whingeness; crying a lot, bad temper, tantrums, dislike of being left, unsteadiness, desire for cuddling, difficulty feeding, noisiness, thumb sucking. No significant difference for any of these items between phenobarbitone/phenytoin or placebo group. Any behavioural change attributed to hospitalisation.
Bajaj 200560Drug reactions Group A (clobazam) Group B (placebo); n (%) n (%): Weakness 1 (3.3) 11 (33.3); Irritability 4 (13.3) 1 (3.3); Sedation 5 (16.7) 5 (16.7); Anorexia 2 (6.6) 5 (16.7); Nausea and vomiting 0 - 2 (6.6); Abdominal pain 0 - 1 (3.3); Diarrhoea 1 (3.3) 3 (10); Headache 1 (3.3) 5 (16.7)
Camfield 198079At 12 months no difference between phenobarbitone and placebo groups for behavioural change or sleep disturbance. Placebo group, transient adverse effects in 7 of 30. Phenobarbitone group, transient adverse effects 15 of 35. Significant negative correlation between phenobarbitone serum level and memory concentration sub scores on Binet scores. Lower comprehension scores showed significant correlation with length of phenobarbitone treatment (but n = 7 at 8 months and 9 at 12 months, therefore small numbers).

Daugbjerg 1990

169Diazepam seen in 42 (47%) as follows: sedation 33 (37%), ataxia 42 (47%), hyperkinesia 21 (24%), diarrhoea, urge to defecate 1 (1%), depression 1 (1%). Valproic acid: sedation 9 (11%), ataxia 3 (4%), hyperkinesia 6 (7%), diarrhoea, urge to defecate 14 (18%). Vomiting 1 (1%), bleeding per rectum 1 (1%), abdominal pain 3 (4%), aggressiveness 3 (4%).
Farwell 1990217Investigators compared intelligence quotients (IQs) of a group randomly assigned to phenobarbitone to a group randomly assigned to placebo. After 2 years mean IQ 8.4 points lower in phenobarbitone group (95% CI ?13.3 to -3.5, P + 0.006). Six months later after discontinuing medication IQ 5.2 points lower in phenobarbitone group (95% CI -10.5 to 0.04, P = 0.052). Proportion remaining seizure free not differ significantly between treatment groups. 14 total sleep time, night awakenings and lengthy awakenings compared in phenobarbitone and placebo groups. No difference noted between groups except subset of predisposed children did experience an increase in night awakenings, (that is those already recorded to have frequent sleep disturbances at study entry). 35: Retesting of group after school entry. Phenobarbitone treated group had Wide Range Achievement Test (WRAT-R) reading achievement score significantly lower than placebo group: 87.6 v 95.6; P = 0.007. No significant difference for IQ on Stamford Binet.
Garcia 1984 Adverse effects: Diazepam 5 (10%), phenobarbitone 3 (6%). Nature of adverse effects not stated.
Heckmatt 1976161Overall, 39 of 88 stopped taking phenobarbital:16 behaviour (over-activity, unpleasant behaviour, temper, not sleeping) 12 improved; 23 for a variety of reasons e.g. drowsy/unsteady. 3 in control group reported behaviour problems.

Knudsen 1985a;

Knudsen 1985b;

Knudsen 1988

152

No severe adverse effects. Mild transient: 36% sedation, 15% euphoria, 8% ataxia, 2% aggression. adverse effects not addressed in report on follow up.

 

Khosroshahi 201172The adverse effects of clobazam were noted to be lower than with diazepam. Sedation was noted more often with diazepam compared to clobazam (P<0.0001) - further details are not given.

Mamelle 1982

Mamelle 1984

 Adverse effects not addressed.
Mackintosh 197032Adverse effects not addressed. 
McKiernan 1981107Adverse effects not addressed. 
McKinlay 198915113 of 41 on phenobarbitone had disturbed behaviour and/or drowsiness; 1 vomiting; 2 rash; 1 unacceptable taste. 8 stopped treatment; 3 within 3 months. 5 of 50 on Valproate; drowsy initially; 2 behavioural problems; 1 vomited; 1 diarrhoea. 2 stopped taking drug. 16 control group adverse effects not addressed.
Mosquera 198769adverse effects not addressed. 
Ngwane 1980435 of 23 on phenobarbitone had adverse effects within 72 hours; 2 of these drug withdrawn (details not given). 4 of 20 on Valproate, adverse effects - most common diarrhoea.
Pavlidou 2006139Adverse effects were only reported in the diazepam group. These were described as mild and transient and included somnolence and irritability.
Ramakrishnan 1986120Adverse effects not addressed. 
Rosman 1993288Of 135 children on placebo: 1 “moderate” maculopapular rash.153 on diazepam with 59 (39%) at least moderate adverse effects: ataxia 30%, lethargy 29%, irritability 24%. Moderate adverse effects: unclear speech 6%; hyperactivity 6%, insomnia 5%, hallucinations 0.7%. (Percentages of those 59 (39%) overall who had adverse effects).Mild adverse effects paralleled moderate numbers.
Strengell 2009231Adverse effects not addressed.
van Stuijvenberg 1998230Adverse effects not addressed. 
Thilothammal 199390“Intolerable” side effects presented in 2 of 30 children with simple febrile seizures on phenobarbitone and 1 of 30 children with atypical febrile seizures. Recorded adverse effects were “mainly hyperkinetic behaviour, extreme irritability, fussiness and aggressiveness”. Details of percentages are not given.
Uhari 1995180 childrenAdverse effects not addressed.
Verrotti 2004110Adverse effects were only reported from the treatment group, including ataxia, lethargy and irritability: 14 children (31.1%) had ataxia, 13 (28.8%) presented lethargy and 11 children (24.4%) had irritability. These adverse effects lasted no more than 36 h.
Williams 197958Seven of 30 children taking Valproate (23%) had adverse effects: 4 diarrhoea or vomiting; 1 increased appetite; 1 increased daytime activity, night terrors and confusion; 1 anorexia, withdrawn and crying. adverse effects in control group not detailed.

Wolf 1977a;

Wolf 1981

355Phenobarbitone 34 of 109 (32%) discontinued continuous phenobarbitone, reasons as follows:16% hyperactivity; 1% irritability; 3% rash; 2% lethargy; 10% parental non-compliance. Long term effect of phenobarbitone on cognitive function: Group of 50 matched for age, sex, rash and socio-economic status for difference cognitive function to median age of 57.5 months (phenobarbitone treated children) and 59.6 months (children not receiving phenobarbitone).

Appendices

Appendix 1. Search strategies

CENTRAL search strategy

#1         (febrile seizure*) or (febrile convulsion*)

#2         MeSH descriptor Seizures, Febrile explode all trees

#3         (anticonvulsant*) OR (antiepilep*)

#4         MeSH descriptor Anticonvulsants explode all trees

#5         (acetaminophen OR paracetamol OR aspirin)

#6         MeSH descriptor Ibuprofen explode all trees

#7         MeSH descriptor Acetaminophen explode all trees

#8         (#1 OR #2)

#9         (#3 OR #4 OR #5 OR #6 OR #7)

#10       (#8 AND #9)

MEDLINE search strategy

This strategy is based on the Cochrane Highly Sensitive Search Strategy for identifying randomised trials (Lefebvre 2009).

1. randomised controlled trial.pt.

2. controlled clinical trial.pt.

3. randomised.ab

4. placebo.ab.

5. clinical trials as topic.sh.

6. randomly.ab.

7. trial.ti.

8. 1 or 2 or 3 or 4 or 5 or 6 or 7

9. exp animals/ not humans.sh.

10. 8 not 9

11. febrile seizure$.tw.

12. febrile convulsion$.tw.

13. exp Seizures, Febrile/

14. 11 or 12 or 13

15. exp Anticonvulsants/

16. anticonvulsant$.tw.

17. antiepilep$.tw.

18. exp Acetaminophen/

19. (acetaminophen or paracetamol).tw.

20. exp Ibuprofen/

21. ibuprofen.tw.

22. 15 or 16 or 17 or 18 or 19 or 20 or 21

23. 10 and 14 and 22

History

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

Contributions of authors

Martin Offringa is the guarantor for this review. Martin Offringa and Richard Newton were involved at all stages of the review, from conception to completion. They independently assessed trials for inclusion, appraised papers, and extracted data. They jointly prepared the report.

Declarations of interest

None

Sources of support

Internal sources

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

  • Dutch Cochrane Centre, Amsterdam, Netherlands.

External sources

  • No sources of support supplied

Differences between protocol and review

None

Notes

None

Ancillary