Prophylactic drug management for febrile seizures in children

Martin Offringa; Richard Newton; Martinus A Cozijnsen; Sarah J Nevitt

doi:10.1002/14651858.CD003031.pub3

. 2017 Feb 22;2017(2):CD003031. doi: 10.1002/14651858.CD003031.pub3

Prophylactic drug management for febrile seizures in children

Martin Offringa ^1,^✉, Richard Newton ², Martinus A Cozijnsen ³, Sarah J Nevitt ⁴

Editor: Cochrane Epilepsy Group

PMCID: PMC6464693 PMID: 28225210

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 primarily the effectiveness and safety of antiepileptic and antipyretic drugs used prophylactically to treat children with febrile seizures; but also to evaluate any other drug intervention where there was a sound biological rationale for its use.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2016, Issue 7); MEDLINE (1966 to July 2016); Embase (1966 to July 2016); Database of Abstracts of Reviews of Effectiveness (DARE) (July 2016). We imposed no language restrictions. We also contacted researchers in the field to identify continuing or unpublished studies.

Selection criteria

Trials using randomised or quasi‐randomised participant allocation that compared the use of antiepileptic, antipyretic or other plausible agents with each other, placebo or no treatment.

Data collection and analysis

Two review authors (RN and MO) independently applied predefined criteria to select trials for inclusion and extracted the predefined relevant data, recording methods for randomisation, blinding and exclusions. For the 2016 update a third author (MC) checked all original inclusions, data analyses, and updated the search. Outcomes assessed were seizure recurrence at 6, 12, 18, 24, 36, and 48 months and at age 5 to 6 years in the intervention and non‐intervention groups, and adverse medication effects. We assessed the presence of publication bias using funnel plots.

Main results

We included 40 articles describing 30 randomised trials with 4256 randomised participants. We analysed 13 interventions of continuous or intermittent prophylaxis and their control treatments. Methodological quality was moderate to poor in most studies. We found no significant benefit for intermittent phenobarbitone, phenytoin, valproate, pyridoxine, ibuprofen or zinc sulfate versus placebo or no treatment; nor for diclofenac versus placebo followed by ibuprofen, acetaminophen or placebo; nor for continuous phenobarbitone versus diazepam, intermittent rectal diazepam versus intermittent valproate, or oral diazepam versus clobazam.

There was a significant reduction of recurrent febrile seizures with intermittent diazepam versus placebo or no treatment, with a risk ratio (RR) of 0.64 (95% confidence interval (CI) 0.48 to 0.85 at six months), RR of 0.69 (95% CI 0.56 to 0.84) at 12 months, RR 0.37 (95% CI 0.23 to 0.60) at 18 months, RR 0.73 (95% CI 0.56 to 0.95) at 24 months, RR 0.58 (95% CI 0.40 to 0.85) at 36 months, RR 0.36 (95% CI 0.15 to 0.89) at 48 months, with no benefit at 60 to 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 0.59 (95% CI 0.42 to 0.83) at 6 months; RR 0.54 (95% CI 0.42 to 0.70) at 12 months; and RR 0.69 (95% CI 0.53 to 0.89) at 24 months). Intermittent clobazam compared to placebo at six months resulted in a RR of 0.36 (95% CI 0.20 to 0.64), an effect found against an extremely high (83.3%) recurrence rate in the controls, 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 30% of children in the phenobarbitone‐treated group and in up to 36% in benzodiazepine‐treated groups. We found evidence of publication bias in the meta‐analyses of comparisons for phenobarbitone versus placebo (eight studies) at 12 months but not at six months (six studies); and valproate versus placebo (four studies) at 12 months, with too few studies to identify publication bias for the other comparisons.

Most of the reviewed antiepileptic drug trials are of a methodological quality graded as low or very low. 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 risks of bias. Trials of antipyretics and zinc were of higher quality.

Authors' conclusions

We found reduced recurrence rates for children with febrile seizures for intermittent diazepam and continuous phenobarbitone, with adverse effects in up to 30%. Apparent benefit for clobazam treatment in one 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

Background

Seizures occurring with a fever in children are common and affect about one in thirty under the age of six years. On average, one out of three children who have had a febrile seizure will have at least one more. We reviewed the evidence about the effect of drugs to prevent seizures (antiepileptics), drugs to lower temperature (antipyretics) and zinc on children with febrile seizures.

Objective

We wanted to know in how many children these drugs would prevent a recurrence or bring unwanted effects.

Methods

We included 30 studies with a total of 4256 children in the review. Children who had had at least one febrile seizure were put into groups who either had the study treatment or not. The studies recorded any further seizures at various time intervals between 6 months and up to 6 years of age in each group. Unwanted medication effects were also noted.

Results

The quality of study design and evidence provided by these studies was often low or very low for the antiepileptic drugs. Poor methods known to lead to obvious risks of bias were used. This was to do with the way children were put in each group and how random this allocation was. Other issues included whether the parents and/or doctors knew which group each child was in or perhaps if the study was of treatment compared to no treatment. The quality of trials of antipyretics or zinc was better, with the evidence graded moderate to high.

Zinc therapy gave no benefit. Nor was there benefit in treating children just at the time of the fever with either antipyretic drugs or most antiepileptic drugs.

At times a significant result was noted. In statistics this means there was a less than 1 in 20 chance of this happening by chance. For example, at times between 6 and 48 months follow‐up, intermittent diazepam (an antiepileptic drug) led to a reduction in the number of recurrent seizures by about a third. Continuous phenobarbitone resulted in significantly fewer recurrences at 6, 12 and 24 months, but not at 18 and 60 to 72 months

However, as recurrent seizures are only seen in about a third of children anyway this means that up to 16 children would have to be treated over a year or two to save just one child a further seizure. As febrile seizures are not harmful we viewed these significant findings (in the statistical sense) to be unimportant. This is particularly so as adverse effects of the medications were common. Lower comprehension scores in phenobarbitone‐treated children were found in two studies. In general, adverse effects were recorded in up to about a third of children in both the phenobarbitone and benzodiazepine‐treated groups. The benefit found for treatment with clobazam in one study published in 2011 needs to be repeated to show that this finding is reliable.

Author’s conclusions

Neither continuous nor intermittent treatment with zinc, antiepileptic or antipyretic drugs can be recommended for children with febrile seizures. Febrile seizures can be frightening to witness. 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.

The evidence is current to 21 July 2016.

Summary of findings

Background

Description of the condition

The International League Against Epilepsy (ILAE) defines a febrile seizure as “a seizure occurring in childhood after one month of age associated with a febrile illness not caused by an infection of the central nervous system, without previous neonatal seizures or a previous unprovoked seizure, and not meeting the criteria for other acute symptomatic seizures” (ILEA 1993). The cumulative incidence of febrile seizures is estimated between 2% and 5% in the US and Western Europe, (Shinnar 2003; Verity 1991) between 6% to 9% in Japan, and 14% in India and Guam (ILEA 1993). Febrile seizures have a peak incidence at 18 months and are most common between the ages of six months and six years. (Berg 1996; Hauser 1994; Offringa 1991)

In 2010 the ILAE proposed that febrile seizures could be organised by typical age at onset (that is, infancy and childhood). Conventionally, febrile seizures have been classified as simple or complex based on duration, recurrence during the same illness episode, and the presence of focal features. Most febrile seizures are generalised tonic‐clonic seizures, and about 30% ‐ 35% of febrile seizures have one or more complex features (focal onset, duration > 10 minutes, or multiple seizures during the illness episode) (Berg 1996). Febrile status epilepticus, a subgroup of complex febrile seizures with seizures lasting more than 30 minutes, occur in about 5% of cases (Berg 1996).

Causation is thought to be multifactorial with environmental factors and increasing evidence for genetic factors contributing to pathogenesis (Audenaert 2006; Offringa 1994). No single susceptibility gene for febrile seizures is known. In contrast, gene identification has been successful in families with genetic epilepsies with febrile seizures plus (GEFS+) where kindreds may well include children with Dravet syndrome (Berg 2010; Kasperaviciute 2013; Tang 2013). In these conditions febrile seizures persist beyond the age of six years; mutations have been found in SCN1A and SCN1B (both sodium channel genes important for neurotransmission) and GABRG2 (related to γ‐aminobutyric acid, an important inhibitory neurotransmitter) (Audenaert 2006; Baulac 2004; Gérard 2002; Hirose 2003; Johnson 1998, Kananura 2002, Nabbout 2002; Nakayama 2006).

Description of the intervention

Despite the frequent nature of these seizures, debate regarding the optimal management arose at an early stage (Baumann 1999) and continues. 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 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 long been a controversial area, with a persistent 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 1988 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. 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 (NNT) 8, 95% CI 5 to 27) (Rantala 1997).

How the intervention might work

The rationale for using prophylactic antiepileptic drugs in children with febrile seizures is to raise seizure threshold in the face of a potentially triggering fever. Antipyretics are used to attenuate the effect of fever as a triggering factor. Previous studies demonstrated blood and cerebrospinal fluid zinc levels to be significantly lower in children with a febrile seizure tendency than in children with afebrile seizures. Zinc level is known to stimulate the excitatory neurotransmitter glutamate and to increase the inhibitory neurotransmitter gamma‐amino‐butyric acid.

Why it is important to do this review

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 primarily the effectiveness and safety of antiepileptic and antipyretic drugs used prophylactically to treat children with febrile seizures; and also to evaluate any other drug intervention where there was a sound biological rationale for its use.

Methods

Criteria for considering studies for this review

Types of studies

We included all trials using randomised or quasi‐randomised participant allocation that compared the use of antiepileptic or antipyretic agents with each other or with placebo or with no treatment.

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. We also planned subgroup analyses of neurologically healthy children, of children with previous recurrent seizures, and of studies limited to children at a perceived relatively high risk of recurrence.

Types of interventions

We included trials 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. We planned a subgroup analysis of intermittent AED therapies versus continuous AED therapies, and of antipyretics during episodes of fever versus AED therapy during fever. A six‐month course of zinc (shown previously to have been significantly lower in children with febrile seizures) was evaluated in one study.

Types of outcome measures

Primary outcomes

Efficacy ‐ proportion of children with recurrence of febrile or non‐febrile seizures at certain time points after treatment onset (6 months, 12 months, 24 months, 36 months, and at age five years).

Secondary outcomes

1) Treatment adherence (as measured in the studies).

2) Safety: the incidence of specific adverse unwanted effects, including irritability, hyperactivity, somnolence, impaired cognitive development for phenobarbital and intermittent diazepam, gastro‐enterologic unwanted effects for valproate and antipyretics, of any administered antiepileptic or antipyretic.

3) As it is of clinical interest, we analysed pooled data at the chosen study time points to estimate the recurrent febrile seizure risk in the placebo and no‐treatment groups. This analysis could provide a useful insight into the natural history of the disorder.

Search methods for identification of studies

Electronic searches

We searched the following databases. We imposed no language restrictions.

a) Cochrane Epilepsy Group Specialised Register (21 July 2016).

b) Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 21 July 2016).

c) MEDLINE (Ovid) (1950 to 21 July 2016).

d) Embase (1966 to 21 July 2016).

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 unpublished studies.

Data collection and analysis

Selection of studies

Two review authors (RN and MO) independently assessed trials for inclusion, resolving any disagreements by discussion. For the 2016 update, a third review author (MC) checked all original inclusions.

Data extraction and management

Two review authors (RN and MO) extracted the outcome data specified above as well as the following data, resolving any disagreements by discussion. For the 2016 update a third review author (MC) checked all data extracted.

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

Participant and demographic information:  a. total number of participants allocated to each treatment group or audited in any protocol;  b. the proportion of participants 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.

Assessment of risk of bias in included studies

Review author MC made an initial assessment of all included studies for risk of bias using the Cochrane 'Risk of bias' tool for RCTs (Higgins 2011). This was compared to an independent assessment by either review author RN or MO, with a third party resolving any disagreements by discussion.

Measures of treatment effect

We treated efficacy (recurrence of febrile or non‐febrile seizures) as dichotomous outcomes and expressed them as risk ratios (RR) with 95% confidence intervals (CIs).

We summarised treatment adherence and incidence of adverse effects narratively according to the definitions reported in the study. We calculated numbers needed to treat (NNTs) as the reciprocal of the absolute risk reduction (McQuay 1998).

Unit of analysis issues

We did not have any unit of analysis issues. Medication dosages were standard. Outcome measures were simply seizure recurrence. No studies were of a repeated measure (longitudinal) nature or of a cross‐over design.

Dealing with missing data

At times recurrence data had to be reconstructed from published survival curves. We were careful to cross‐check this with quoted cumulative incidence rates for in‐study data. We cross‐checked trial details against any additional published report of the trial and contacted original trial authors if we found missing data, errors or inconsistencies (although the response was uniformly poor). No author provided individual patient data (IPD) when requested but we are satisfied with the consistency checks we performed.

Assessment of heterogeneity

We assessed clinical heterogeneity by reviewing the differences across trials in the characteristics of recruited participants and treatment protocols. We assessed statistical heterogeneity using a Chi² test for heterogeneity. We assessed heterogeneity using the Q test (P < 0.10 for significance) and the I² statistic (greater than 50% indicating considerable heterogeneity (Higgins 2003)) and visually by inspecting forest plots.

Assessment of reporting biases

We assessed the presence of publication bias using funnel plots for each meta‐analysis that included results of five or more studies.

Data synthesis

We included 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 participants analysed in the treatment group to which they were allocated, irrespective of which treatment they actually received.

We conducted meta‐analysis if sufficient data were available, that is at least two trials looking at the same two treatments and the same outcomes. All meta‐analyses were conducted using a fixed‐effects model, regardless of the presence of heterogeneity. If we had concerns regarding variability of study design and whether pooling data was appropriate, meta‐analysis would not have been conducted.

We conducted meta‐analysis only for the primary outcome of efficacy (recurrence of febrile or non‐febrile seizures).

We summarised treatment adherence and incidence of adverse effects narratively according to the definitions reported in the study; we did not pool numerical data for these outcomes, due to variability in definitions and the level of detail reported in the studies.

Subgroup analysis and investigation of heterogeneity

We had no hypotheses needing subgroup analyses.

Sensitivity analysis

We felt no need for any sensitivity analyses as misdiagnosis of febrile seizures or their recurrence is unlikely within the reported study groups.

Summary of Findings and Quality of the Evidence (GRADE)

In a post hoc change from protocol, we present 13 'Summary of findings' tables (Table 1; Table 2; Table 3; Table 4; Table 5; Table 6; Table 7; Table 8; Table 9; Table 10; Table 11; Table 12; Table 13); one for each comparison of the review.

Summary of findings for the main comparison. Intermittent oral or rectal diazepam compared to placebo or no treatment for febrile seizures in children.

Intermittent oral or rectal diazepam compared to placebo or no treatment for febrile seizures in children
Patient or population: Children with febrile seizures  Setting: Outpatients  Intervention: Intermittent oral or rectal diazepam  Comparison: placebo or no treatment
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	№ of participants  (studies)	Quality of the evidence  (GRADE)	Comments
Outcomes	Risk with placebo or no treatment	Risk with Intermittent oral or rectal diazepam	Relative effect  (95% CI)	№ of participants  (studies)	Quality of the evidence  (GRADE)	Comments
Recurrent seizure at 6 months	179 per 1,000	115 per 1,000  (86 to 152)	RR 0.64  (0.48 to 0.85)	1151  (6 RCTs)	⊕⊕⊕⊝  Moderate¹
Recurrent seizure at 12 months	254 per 1,000	175 per 1,000  (142 to 213)	RR 0.69  (0.56 to 0.84)	1416  (8 RCTs)	⊕⊕⊕⊝  Moderate¹
Recurrent seizure at 18 months	336 per 1,000	124 per 1,000  (77 to 201)	RR 0.37  (0.23 to 0.60)	289  (1 RCT)	⊕⊕⊝⊝  Low²
Recurrent seizure at 24 months	273 per 1,000	200 per 1,000  (153 to 260)	RR 0.73  (0.56 to 0.95)	739  (4 RCTs)	⊕⊕⊕⊕  High
Recurrent seizure at 36 months	606 per 1,000	351 per 1,000  (242 to 515)	RR 0.58  (0.40 to 0.85)	139  (1 RCT)	⊕⊕⊝⊝  Low²
Recurrent seizure at 48 months	308 per 1,000	111 per 1,000  (46 to 274)	RR 0.36  (0.15 to 0.89)	110  (1 RCT)	⊕⊕⊕⊝  Moderate³
Recurrent seizure at 60 months or greater	200 per 1,000	16 per 1,000  (0 to 262)	RR 0.08  (0.00 to 1.31)	60  (1 RCT)	⊕⊝⊝⊝  Very low^2,4
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk (the event rate in the control group) and the relative effect of the intervention (and its 95% CI).  CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence   High quality: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Continuous phenobarbitone compared to placebo or no treatment for febrile seizures in children
Patient or population: Children with febrile seizures  Setting: Outpatients  Intervention: Continuous phenobarbitone  Comparison: placebo or no treatment
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	№ of participants  (studies)	Quality of the evidence  (GRADE)	Comments
Outcomes	Risk with placebo or no treatment	Risk with Continuous phenobarbitone	Relative effect  (95% CI)	№ of participants  (studies)	Quality of the evidence  (GRADE)	Comments
Recurrent seizure at 6 months	178 per 1,000	105 per 1,000  (75 to 148)	RR 0.59  (0.42 to 0.83)	833  (6 RCTs)	⊕⊕⊕⊝  Moderate¹
Recurrent seizure at 12 months	308 per 1,000	166 per 1,000  (129 to 216)	RR 0.54  (0.42 to 0.70)	807  (7 RCTs)	⊕⊕⊝⊝  Low^1,2
Recurrent seizure at 18 months	430 per 1,000	331 per 1,000  (241 to 451)	RR 0.77  (0.56 to 1.05)	264  (2 RCTs)	⊕⊕⊕⊝  Moderate¹
Recurrent seizure at 24 months	345 per 1,000	238 per 1,000  (183 to 307)	RR 0.69  (0.53 to 0.89)	533  (3 RCTs)	⊕⊕⊕⊝  Moderate¹
Recurrent seizure at 36 months	Not reported				NA
Recurrent seizure at 48 months	Not reported				NA
Recurrent seizure at 60 months or greater	200 per 1,000	300 per 1,000  (122 to 738)	RR 1.50  (0.61 to 3.69)	60  (1 RCT)	⊕⊝⊝⊝  Very low^3,4
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk (the event rate in the control group) and the relative effect of the intervention (and its 95% CI).  CI: Confidence interval; NA: Not applicable; RR: Risk ratio;
GRADE Working Group grades of evidence   High quality: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Intermittent phenobarbitone compared to placebo or no treatment for febrile seizures in children
Patient or population: Children with febrile seizures  Setting: Outpatients  Intervention: Intermittent phenobarbitone  Comparison: placebo or no treatment
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	№ of participants  (studies)	Quality of the evidence  (GRADE)	Comments
Outcomes	Risk with placebo or no treatment	Risk with Intermittent phenobarbitone	Relative effect  (95% CI)	№ of participants  (studies)	Quality of the evidence  (GRADE)	Comments
Recurrent seizure at 6 months	88 per 1,000	121 per 1,000  (59 to 247)	RR 1.37  (0.67 to 2.81)	281  (2 RCTs)	⊕⊝⊝⊝  Very Low^1,2,3
Recurrent seizure at 12 months	216 per 1,000	218 per 1,000  (140 to 343)	RR 1.01  (0.65 to 1.59)	281  (2 RCTs)	⊕⊕⊕⊝  Moderate¹
Recurrent seizure at 18 months	Not reported				NA
Recurrent seizure at 24 months	294 per 1,000	250 per 1,000  (167 to 376)	RR 0.85  (0.57 to 1.28)	249  (1 RCT)	⊕⊕⊝⊝  Low⁴
Recurrent seizure at 36 months	Not reported				NA
Recurrent seizure at 48 months	Not reported				NA
Recurrent seizure at 60 months or greater	200 per 1,000	166 per 1,000  (56 to 488)	RR 0.83  (0.28 to 2.44)	60  (1 RCT)	⊕⊝⊝⊝  Very low^3,4
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk (the event rate in the control group) and the relative effect of the intervention (and its 95% CI).  CI: Confidence interval; NA: Not applicable; RR: Risk ratio;
GRADE Working Group grades of evidence   High quality: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Continuous oral phenytoin compared to placebo for febrile seizures in children
Patient or population: Children with febrile seizures  Setting: Outpatients  Intervention: Continuous oral phenytoin  Comparison: placebo
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	№ of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Risk with placebo	Risk with Continuous oral phenytoin
Recurrent seizure at 6 months	Not reported				NA
Recurrent seizure at 12 months	349 per 1,000	342 per 1,000  (192 to 603)	RR 0.98  (0.55 to 1.73)	90  (1 RCT)	⊕⊕⊝⊝  Low¹
Recurrent seizure at 18 months	Not reported				NA
Recurrent seizure at 24 months	Not reported				NA
Recurrent seizure at 36 months	Not reported				NA
Recurrent seizure at 48 months	Not reported				NA
Recurrent seizure at 60 months or greater	Not reported				NA
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk (the event rate in the control group) and the relative effect of the intervention (and its 95% CI).  CI: Confidence interval; NA: Not applicable; RR: Risk ratio;
GRADE Working Group grades of evidence   High quality: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Continuous oral valproate compared to placebo or no treatment for febrile seizures in children
Patient or population: Children with febrile seizures  Setting: Outpatients  Intervention: Continuous oral valproate  Comparison: placebo or no treatment
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	№ of participants  (studies)	Quality of the evidence  (GRADE)	Comments
Outcomes	Risk with placebo or no treatment	Risk with Continuous oral valproate	Relative effect  (95% CI)	№ of participants  (studies)	Quality of the evidence  (GRADE)	Comments
Recurrent seizure at 6 months	118 per 1,000	141 per 1,000  (65 to 308)	RR 1.20  (0.55 to 2.62)	156  (2 RCTs)	⊕⊕⊝⊝  Low¹
Recurrent seizure at 12 months	239 per 1,000	196 per 1,000  (124 to 308)	RR 0.82  (0.52 to 1.29)	255  (4 RCTs)	⊕⊕⊝⊝  Low¹
Recurrent seizure at 18 months	346 per 1,000	45 per 1,000  (7 to 332)	RR 0.13  (0.02 to 0.96)	48  (1 RCT)	⊕⊝⊝⊝  Very low^1,2
Recurrent seizure at 24 months	212 per 1,000	267 per 1,000  (155 to 462)	RR 1.26  (0.73 to 2.18)	156  (2 RCTs)	⊕⊕⊝⊝  Low¹
Recurrent seizure at 36 months	Not reported				NA
Recurrent seizure at 48 months	Not reported				NA
Recurrent seizure at 60 months or greater	Not reported				NA
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk (the event rate in the control group) and the relative effect of the intervention (and its 95% CI).  CI: Confidence interval; NA: Not applicable; RR: Risk ratio;
GRADE Working Group grades of evidence   High quality: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Continuous oral pyridoxine compared to placebo for febrile seizures in children
Patient or population: Children with febrile seizures  Setting: Outpatients  Intervention: Continuous oral pyridoxine  Comparison: placebo
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	№ of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Risk with placebo	Risk with Continuous oral pyridoxine
Recurrent seizure at 6 months	154 per 1,000	72 per 1,000  (23 to 228)	RR 0.47  (0.15 to 1.48)	107  (1 RCT)	⊕⊕⊝⊝  Low^1,2
Recurrent seizure at 12 months	192 per 1,000	127 per 1,000  (52 to 310)	RR 0.66  (0.27 to 1.61)	107  (1 RCT)	⊕⊕⊝⊝  Low^1,2
Recurrent seizure at 18 months	Not reported				NA
Recurrent seizure at 24 months	Not reported				NA
Recurrent seizure at 36 months	Not reported				NA
Recurrent seizure at 48 months	Not reported				NA
Recurrent seizure at 60 months or greater	Not reported				NA
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk (the event rate in the control group) and the relative effect of the intervention (and its 95% CI).  CI: Confidence interval; NA: Not applicable; RR: Risk ratio;
GRADE Working Group grades of evidence   High quality: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Intermittent oral ibuprofen compared to placebo for febrile seizures in children
Patient or population: Children with febrile seizures  Setting: Outpatients  Intervention: Intermittent oral ibuprofen  Comparison: placebo
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	№ of participants  (studies)	Quality of the evidence  (GRADE)	Comments
Outcomes	Risk with placebo	Risk with Intermittent oral ibuprofen	Relative effect  (95% CI)	№ of participants  (studies)	Quality of the evidence  (GRADE)	Comments
Recurrent seizure at 6 months	210 per 1,000	233 per 1,000  (145 to 380)	RR 1.11  (0.69 to 1.81)	230  (1 RCT)	⊕⊕⊕⊕  High
Recurrent seizure at 12 months	294 per 1,000	279 per 1,000  (185 to 421)	RR 0.95  (0.63 to 1.43)	230  (1 RCT)	⊕⊕⊕⊕  High
Recurrent seizure at 18 months	Not reported				NA
Recurrent seizure at 24 months	387 per 1,000	325 per 1,000  (228 to 460)	RR 0.84  (0.59 to 1.19)	230  (1 RCT)	⊕⊕⊕⊕  High
Recurrent seizure at 36 months	Not reported				NA
Recurrent seizure at 48 months	Not reported				NA
Recurrent seizure at 60 months or greater	Not reported				NA
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk (the event rate in the control group) and the relative effect of the intervention (and its 95% CI).  CI: Confidence interval; NA: Not applicable; RR: Risk ratio;
GRADE Working Group grades of evidence   High quality: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Intermittent oral clobazam compared to placebo for febrile seizures in children
Patient or population: Children with febrile seizures  Setting: Outpatients  Intervention: Intermittent oral clobazam  Comparison: placebo
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	№ of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Risk with placebo	Risk with Intermittent oral clobazam
Recurrent seizure at 6 months	833 per 1,000	300 per 1,000  (167 to 533)	RR 0.36  (0.20 to 0.64)	60  (1 RCT)	⊕⊕⊝⊝  Low^1,2
Recurrent seizure at 12 months	Not reported				NA
Recurrent seizure at 18 months	Not reported				NA
Recurrent seizure at 24 months	Not reported				NA
Recurrent seizure at 36 months	Not reported				NA
Recurrent seizure at 48 months	Not reported				NA
Recurrent seizure at 60 months or greater	Not reported				NA
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk (the event rate in the control group) and the relative effect of the intervention (and its 95% CI).  CI: Confidence interval; NA: Not applicable; RR: Risk ratio;
GRADE Working Group grades of evidence   High quality: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Continuous zinc sulfate for 6 months compared to placebo for febrile seizures in children
Patient or population: Children with febrile seizures  Setting: Outpatients  Intervention: Continuous zinc sulfate for 6 months  Comparison: placebo
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	№ of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Risk with placebo	Risk with Continuous zinc sulfate for 6 months
Recurrent seizure at 6 months	Not reported				NA
Recurrent seizure at 12 months	380 per 1,000	220 per 1,000  (118 to 414)	RR 0.58  (0.31 to 1.09)	100  (1 RCT)	⊕⊕⊕⊕  High
Recurrent seizure at 18 months	Not reported				NA
Recurrent seizure at 24 months	Not reported				NA
Recurrent seizure at 36 months	Not reported				NA
Recurrent seizure at 48 months	Not reported				NA
Recurrent seizure at 60 months or greater	Not reported				NA
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk (the event rate in the control group) and the relative effect of the intervention (and its 95% CI).  CI: Confidence interval; NA: Not applicable; RR: Risk ratio;
GRADE Working Group grades of evidence   High quality: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Intermittent rectal diclofenac compared to placebo followed after 8 hours by oral ibuprofen, acetaminophen or placebo for febrile seizures in children
Patient or population: Children with febrile seizures  Setting: Outpatients  Intervention: Intermittent rectal diclofenac  Comparison: placebo followed after 8 hours by oral ibuprofen, acetaminophen or placebo
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	№ of participants  (studies)	Quality of the evidence  (GRADE)	Comments
Outcomes	Risk with placebo followed after 8 hours by oral ibuprofen, acetaminophen or placebo	Risk with Intermittent rectal diclofenac	Relative effect  (95% CI)	№ of participants  (studies)	Quality of the evidence  (GRADE)	Comments
Recurrent seizure at 6 months	149 per 1,000	119 per 1,000  (63 to 231)	RR 0.80  (0.42 to 1.55)	231  (1 RCT)	⊕⊕⊕⊕  High
Recurrent seizure at 12 months	237 per 1,000	163 per 1,000  (95 to 275)	RR 0.69  (0.40 to 1.16)	231  (1 RCT)	⊕⊕⊕⊕  High
Recurrent seizure at 18 months	272 per 1,000	196 per 1,000  (122 to 315)	RR 0.72  (0.45 to 1.16)	231  (1 RCT)	⊕⊕⊕⊕  High
Recurrent seizure at 24 months	281 per 1,000	222 per 1,000  (143 to 348)	RR 0.79  (0.51 to 1.24)	231  (1 RCT)	⊕⊕⊕⊕  High
Recurrent seizure at 36 months	Not reported				NA
Recurrent seizure at 48 months	Not reported				NA
Recurrent seizure at 60 months or greater	Not reported				NA
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk (the event rate in the control group) and the relative effect of the intervention (and its 95% CI).  CI: Confidence interval; NA: Not applicable; RR: Risk ratio;
GRADE Working Group grades of evidence   High quality: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Intermittent rectal diazepam compared to intermittent rectal valproate for febrile seizures in children
Patient or population: Children with febrile seizures  Setting: Outpatients  Intervention: Intermittent rectal diazepam  Comparison: intermittent rectal valproate
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	№ of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Risk with intermittent rectal valproate	Risk with Intermittent rectal diazepam
Recurrent seizure at 6 months	88 per 1,000	123 per 1,000  (51 to 304)	RR 1.41  (0.58 to 3.47)	169  (1 RCT)	⊕⊝⊝⊝  Very low^1,2
Recurrent seizure at 12 months	175 per 1,000	259 per 1,000  (144 to 467)	RR 1.48  (0.82 to 2.67)	169  (1 RCT)	⊕⊕⊝⊝  Low¹
Recurrent seizure at 18 months	Not reported				NA
Recurrent seizure at 24 months	Not reported				NA
Recurrent seizure at 36 months	Not reported				NA
Recurrent seizure at 48 months	Not reported				NA
Recurrent seizure at 60 months or greater	Not reported				NA
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk (the event rate in the control group) and the relative effect of the intervention (and its 95% CI).  CI: Confidence interval; NA: Not applicable; RR: Risk ratio;
GRADE Working Group grades of evidence   High quality: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Study	Treatment groups	Assessed	Method	Outcome	Treatment adjusted based on adherence assessment?
Autret 1990	‐DZP (oral) ‐PCB	Yes	Treatment diary	7% (1/15) of the patients with relapses in DZP group were adherent versus 39% (7/18) in PCB group	No
Bacon 1981	‐PT ‐PB (cont.) ‐PCB	Yes	Saliva and plasma	Recurrence was positively related to median drug levels for PB, but not related for PT PB: 0/4 (0%) at < 5 mg/l; 5/19 (26%) at 5 ‐ 8 mg/l; 5/25 (20%) at > 8 mg/l PT: 3/9 (33%) at < 0.5 mg/l, 9/19 (47%) at 0.5 ‐ 1.0 mg/l, 4/19 (21% 0 at > 1.0 mg/l	Yes
Bajaj 2005	‐CBZ ‐PCB	No
Camfield 1980	‐PB (cont.) ‐PCB	Yes	Riboflavin urine check, and serum PB	Urine samples available in 65% (PB) and 56% (PCB), more than 90% of all samples tested positive. PB levels: mean 1.3 ‐ 1.5 mg/dl, 70% ‐ 81% within therapeutic range (≥ 1.0 mg/dl)	Yes
Daugbjerg 1990	‐DZP (rectal) ‐VP	No
Fallah 2015	‐ZNC ‐PCB	No
Farwell 1990	‐PB (cont.) ‐PCB	Yes	Riboflavin urine check, PB blood levels	Riboflavin results not reported 2/3 (66%) of PB blood levels tested were above 645.9 micromole/l or 15 microgram/ml	Yes
Ghazavi 2016	‐CBZ ‐DZP (oral)	No
Garcia 1984	‐DZP (rectal) ‐PB (cont.)	No
Heckmatt 1976	‐PB (cont.) ‐NT	Yes	PB plasma levels	82% (40/49) had a mean PB plasma level above 65 micromole/l. All 4 recurrences in the PB group occurred in children with levels above 65 micromole/l	Yes
Khosroshahi 2011	‐DZP (oral) ‐CBZ	No
Knudsen 1985	‐DZP (rectal) ‐NT	Yes	Historically in case of recurrence	Unclear report: "Parents treated the seizure as prescribed in 56/77 (72%) of the cases." Origin of the denominator is unclear as 21 recurrences occurred in DZP and 77 in NT	No
Mackintosh 1970	‐PB (int.) ‐PCB	No
Mamelle 1984	‐PB (cont.) ‐VP ‐PCB	Yes	Blood levels	Unclear report.	Yes
McKiernan 1981	‐PDX ‐PCB	Yes	Historically and counting of tablets used	Not reported.	Yes
McKinlay 1989	‐PB (cont.) ‐VP ‐NT	Yes	PB and VP serum levels	PB: Level checked 25/41 (61%) of children Therapeutic level at time of recurrence 5/12 (42%) Level in those with non‐recurrence: 9/29 therapeutic, 11/29 subtherapeutic, 9/29 not done VP: Level checked 36/50 (72%) of children Therapeutic level at time of recurrence 12/20 (60%) Level in children with non‐recurrence: 13/30 therapeutic, 6/30 subtherapeutic, 11/30 not done	No
Mosquera 1987	‐DZP (rectal) ‐VP ‐NT	No
Ngwane 1980	‐PB (cont.) ‐VP	Yes	Blood levels (random moments)	35 measure in 28 of 39 included children (72%): 16 in PB of which 4 (25%) below therapeutic range and 19 in VP of which 1 (5%) below therapeutic range	No
Pavlidou 2006	‐DZP (rectal) ‐NT	No
Ramakrishnan 1986	‐PB (cont.) ‐PB (int.) ‐DZP (oral) ‐NT	No
Rosman 1993	‐DZP (oral) ‐PCB	Yes	Riboflavin urine check	1257 DZP samples, 66% of all reported fever days, 96% of samples tested positive 982 PCB samples, 95% of all reported fever days, 95% of samples tested positive	No
Salehiomran 2016	‐DZP (oral) ‐PB (cont.)	No
Strengell 2009	‐DCF ‐PCB	No
Taghdiri 2011	‐DZP (rectal) ‐NT	No
Thilothammal 1993	‐PB (cont.) ‐PCB	Yes	Counting sachets	"Poor compliance" in 2/30 (7%) PB children and in 1/30 (3%) PCB children. All children with "poor compliance" also had a recurrence	No
Uhari 1995	‐DZP ‐PCB	No
Van Stuijvenberg 1998	‐IBU ‐PCB	No
Verrotti 2004	‐DZP (oral) ‐NT	Yes	Unclear, asked at recurrence	All 5 recurrences in DZP group were non‐compliant	No
Williams 1979	‐VP ‐NT	Yes	Random VP plasma samples	Checked in 21/30 (70%) VP children: All showed measurable levels, but 2 below target concentration	No
Wolf 1977	‐PB (cont.) ‐PB (int.) ‐NT	Yes	4‐monthly blood check in the continuous PB group	78 of 106 cont. PB children (74%) had PB concentrations above target in at least 50% of their samples. These include 5 of the 7 children (71%) who had a recurrence in this group.	Yes

First author	Number of Children	Adverse medication effects, as reported in article
Autret 1990	177	Hyperactivity (defined as agitation and inability to remain still), significantly (P < 0.003) more frequent in diazepam group (138 vs 34 days). No significant differences noted for normal vigilance or drowsiness; normal staggering or impossible "walking". One sudden unexpected death in placebo group.
Bacon 1981	138, 43 control, 48 phenobarbitone, 48 phenytoin	Rash in 1 child on phenobarbitone, ataxia in 5 on phenytoin. Behavioural items: whinginess; 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 2005	60	Drug 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 1980	79	At 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 subscores 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	169	Diazepam 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%).
Fallah 2015	100	No serious side effects were witnessed in the 2 groups. Gastrointestinal side effects including vomiting in 5 (10%) children, heartburn in 2 (4%) and abdominal pain in 1 (2%) child were seen in 16% of the zinc sulfate group. All of the side effects were well tolerated and disappeared in 2 to 3 wks and supplementation continued. Vomiting occurred in 2 children (4%) in the control group.
Farwell 1990	217	Investigators 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). 6 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 did 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	100	Adverse effects: Diazepam 5 (10%), phenobarbitone 3 (6%). Nature of adverse effects not stated.
Ghazavi 2016	71	Ataxia: Diazepam 4/35 (11%) clobazam 1/36 (3%)
Heckmatt 1976	161	Overall, 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 1985	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 2011	72	The 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 1984		Adverse effects not addressed.
Mackintosh 1970	32	Adverse effects not addressed.
McKiernan 1981	107	Adverse effects not addressed.
McKinlay 1989	151	13 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 1987	69	Adverse effects not addressed.
Ngwane 1980	43	5 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 commonly diarrhoea.
Pavlidou 2006	139	Adverse effects were only reported in the diazepam group. These were described as mild and transient and included somnolence and irritability.
Ramakrishnan 1986	120	Adverse effects not addressed.
Rosman 1993	288	Of 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.
Salehiomran 2016	145	Side effects of phenobarbital like hyperkinesia, irritability, and restlessness were observed in some children but diazepam‐related side effects except sedation were not seen.
Strengell 2009	231	Adverse effects not addressed.
Van Stuijvenberg 1998	230	Adverse effects not addressed.
Thilothammal 1993	90	“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 1995	180 children	Adverse effects not addressed.
Verrotti 2004	110	Adverse 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 hours.
Williams 1979	58	7 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 1977	355	Phenobarbitone 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).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Recurrent seizure @ 6 months	6	1151	Risk Ratio (M‐H, Fixed, 95% CI)	0.64 [0.48, 0.85]
1.1 Intermittent oral diazepam	2	516	Risk Ratio (M‐H, Fixed, 95% CI)	0.70 [0.45, 1.11]
1.2 Intermittent rectal diazepam	4	635	Risk Ratio (M‐H, Fixed, 95% CI)	0.59 [0.41, 0.86]
2 Recurrent seizure @ 12 months	8	1416	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.56, 0.84]
2.1 Intermittent oral diazepam	3	701	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.53, 0.99]
2.2 Intermittent rectal diazepam	5	715	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.50, 0.86]
3 Recurrent seizure @ 18 months	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3.1 Intermittent rectal diazepam	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Recurrent seizure @ 24 months	4	739	Risk Ratio (M‐H, Fixed, 95% CI)	0.73 [0.56, 0.95]
4.1 Intermittent oral diazepam	2	516	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.45, 0.85]
4.2 Intermittent rectal diazepam	2	223	Risk Ratio (M‐H, Fixed, 95% CI)	1.13 [0.67, 1.90]
5 Recurrent seizure @ 36 months	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
5.1 Intermittent rectal diazepam	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6 Recurrent seizure @ 48 months	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
6.1 Intermittent oral diazepam	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
7 Recurrent seizure @ 60‐72 months	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.1 Intermittent oral diazepam	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Recurrent seizure @ 6 months	6	833	Risk Ratio (M‐H, Fixed, 95% CI)	0.59 [0.42, 0.83]
2 Recurent seizure @ 12 months	7	807	Risk Ratio (M‐H, Fixed, 95% CI)	0.54 [0.42, 0.70]
3 Recurent seizure @ 18 months	2	264	Risk Ratio (M‐H, Fixed, 95% CI)	0.77 [0.56, 1.05]
4 Recurent seizure @ 24 months	3	533	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.53, 0.89]
5 Recurrent seizure @ 60‐72 months	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
6 Behavioural changes	1	65	Risk Ratio (M‐H, Fixed, 95% CI)	1.61 [0.79, 3.26]

Intermittent oral diazepam compared to oral clobazam for febrile seizures in children
Patient or population: Children with febrile seizures  Setting: Outpatients  Intervention: Intermittent oral diazepam  Comparison: oral clobazam
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	№ of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Risk with oral clobazam	Risk with Intermittent oral diazepam
Recurrent seizure at 6 months	Not reported				NA
Recurrent seizure at 12 months	42 per 1,000	96 per 1,000  (26 to 356)	RR 2.28  (0.62 to 8.42)	143  (2 RCTs)	⊕⊕⊝⊝  Low^1,2
Recurrent seizure at 18 months	Not reported				NA
Recurrent seizure at 24 months	Not reported				NA
Recurrent seizure at 36 months	Not reported				NA
Recurrent seizure at 48 months	Not reported				NA
Recurrent seizure at 60 months or greater	Not reported				NA
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk (the event rate in the control group) and the relative effect of the intervention (and its 95% CI).  CI: Confidence interval; NA: Not applicable; RR: Risk ratio;
GRADE Working Group grades of evidence   High quality: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Date	Event	Description
21 July 2016	New citation required but conclusions have not changed	Conclusions are unchanged.
21 July 2016	New search has been performed	Searches updated 21 July 2016; four new studies were identified and added as included studies in the review.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Recurrent seizure @ 6 months	2	281	Risk Ratio (M‐H, Fixed, 95% CI)	1.37 [0.67, 2.81]
2 Recurent seizure @ 12 months	2	281	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.65, 1.59]
3 Recurent seizure @ 24 months	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4 Recurrent seizure @ 60‐72 months	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Recurrent seizure @ 6 months	2	156	Risk Ratio (M‐H, Fixed, 95% CI)	1.20 [0.55, 2.62]
2 Recurrent seizure @ 12 months	4	255	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.52, 1.29]
3 Recurrent seizure @ 18 months	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4 Recurrent seizure @ 24 months	2	156	Risk Ratio (M‐H, Fixed, 95% CI)	1.26 [0.73, 2.18]

Outcome or subgroup title	No. of studies	Statistical method	Effect size
1 Recurrent seizures @ 6 months	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Recurrent seizures @ 12 months	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3 Recurrent seizures @ 18 months	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4 Recurrent seizures @ 24 months	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Recurrent seizure @ 12 months	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Recurrent seizure @ 18 months	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Methods	Double‐blind RCT
Participants	185, age 8 ‐ 36 months, first FS, < 2 RF
Interventions	Intermittent oral diazepam, 0.5 mg load, 0.2 mg maintenance per kilo, or placebo
Outcomes	RS @ 12 months, adverse effects @ 12 months
Notes	Attrition: 6 diazepam, 3 placebo; results presented as participant days; significant hyperactivity in diazepam group; 1 SUDEP in placebo group
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	Centralised allocation
Blinding (performance bias and detection bias)   All outcomes	Low risk	Double‐blind
Incomplete outcome data (attrition bias)   All outcomes	Low risk	9 (6 Diazepam, 3 Placebo) of 185 withdrawn
Selective reporting (reporting bias)	Low risk	Stated outcome objective met
Other bias	Low risk	No bias identified
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blind
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Double‐blind

Methods	RCT
Participants	207, after first FS
Interventions	Phenytoin, 8 mg per kilo, or phenobarbitone 5 mg per kilo, or placebo
Outcomes	RS @ 12 months, adverse effects
Notes	Attrition 69
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	Allocation methodology and concealment not discussed in publication.
Blinding (performance bias and detection bias)   All outcomes	High risk	Outcome rater blinded, doctor not blinded
Incomplete outcome data (attrition bias)   All outcomes	High risk	45 lost: 12 moved; 5 behaviour; 5 epilepsy; 2 rash = 69 of 207
Selective reporting (reporting bias)	Low risk	Stated outcome objective met
Other bias	Low risk	No bias identified
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Outcome rater blinded, doctor not blinded
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Outcome rater blinded, doctor not blinded

Methods	RCT, open label
Participants	169, first FS
Interventions	Rectal diazepam 5 mg for < 3 yrs; 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	2 withdrawn, 4 lost during follow‐up
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	High risk	Odd/even dates ‐ no concealment
Blinding (performance bias and detection bias)   All outcomes	High risk	No blinding (selection bias)
Incomplete outcome data (attrition bias)   All outcomes	Low risk	6 of 169 withdrawn; 4 lost to follow‐up in each group
Selective reporting (reporting bias)	Low risk	Stated outcome objective met
Other bias	Low risk	No bias identified
Blinding of participants and personnel (performance bias)   All outcomes	High risk	No blinding
Blinding of outcome assessment (detection bias)   All outcomes	High risk	No blinding

Methods	Single‐centre randomised single‐blind clinical study
Participants	Children aged 1½ ‐ 5 years, with first simple FS, with weight and height above the third percentile and with normal serum zinc level
Interventions	Group 1: Daily zinc sulfate 2 mg/kg (maximum 50 mg) for 6 consecutive months  Group 2: Placebo
Outcomes	Seizure recurrence at 12 months, side effects
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	Computer‐generated equal simple randomisation
Blinding (performance bias and detection bias)   All outcomes	Low risk	Single‐blind design
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No loss to follow‐up, no exclusions
Selective reporting (reporting bias)	High risk	Recurrence data at 3, 6 and 9 months not given. Kaplan Meijer method used to report results, no absolute numbers.
Other bias	Low risk	No bias identified
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Randomisation and blinding was done by an investigator with no clinical involvement in the trial. Data collectors, outcome assessors and data analysts were all kept blinded to the allocation
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Randomisation and blinding was done by an investigator with no clinical involvement in the trial. Data collectors, outcome assessors and data analysts were all kept blinded to the allocation

PERMALINK

Prophylactic drug management for febrile seizures in children

Martin Offringa

Richard Newton

Martinus A Cozijnsen

Sarah J Nevitt

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Summary of Findings and Quality of the Evidence (GRADE)

Summary of findings for the main comparison. Intermittent oral or rectal diazepam compared to placebo or no treatment for febrile seizures in children.

Summary of findings 2. Continuous phenobarbitone compared to placebo or no treatment for febrile seizures in children.

Summary of findings 3. Intermittent phenobarbitone compared to placebo or no treatment for febrile seizures in children.

Summary of findings 4. Continuous oral phenytoin compared to placebo for febrile seizures in children.

Summary of findings 5. Continuous oral valproate compared to placebo or no treatment for febrile seizures in children.

Summary of findings 6. Continuous oral pyridoxine compared to placebo for febrile seizures in children.

Summary of findings 7. Intermittent oral ibuprofen compared to placebo for febrile seizures in children.

Summary of findings 8. Intermittent oral clobazam compared to placebo for febrile seizures in children.

Summary of findings 9. Continuous zinc sulfate for 6 months compared to placebo for febrile seizures in children.

Summary of findings 10. Intermittent rectal diclofenac compared to placebo followed after 8 hours by oral ibuprofen, acetaminophen or placebo for febrile seizures in children.

Summary of findings 11. Continuous phenobarbitone compared to intermittent rectal or oral diazepam for febrile seizures in children.

Summary of findings 12. Intermittent rectal diazepam compared to intermittent rectal valproate for febrile seizures in children.

Summary of findings 13. Intermittent oral diazepam compared to oral clobazam for febrile seizures in children.

Results

Description of studies

Results of the search

Included studies

1. Treatment adherence.

A brief description of the 30 original studies reported in the articles included in this review:

Excluded studies

Risk of bias in included studies

Allocation

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

1.1. Analysis.

1.2. Analysis.

2.1. Analysis.

2.2. Analysis.

1.

2.

3.

4.

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*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	High risk	None
Blinding (performance bias and detection bias)   All outcomes	High risk	None
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	No attrition
Selective reporting (reporting bias)	Low risk	Stated outcome objective met
Other bias	Low risk	No bias identified
Blinding of participants and personnel (performance bias)   All outcomes	High risk	None
Blinding of outcome assessment (detection bias)   All outcomes	High risk	None

Methods	Single‐centre randomised open‐label trial
Participants	Children 6 ‐ 60 months of age with at least 1 simple FS
Interventions	Oral diazepam 0.33 mg/kg every 8 hours for 2 days or oral clobazam for 2 days dosed by patient's weight (daily 5 mg when weight ≤ 5 kg, twice daily 5 mg when 6 ‐ 10 kg, twice daily 7.5 mg when 11 ‐ 15 kg, and twice daily 10 mg when > 15 kg)
Outcomes	RS @ 12 months and adverse effects
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	High risk	Randomisation methodology not mentioned
Blinding (performance bias and detection bias)   All outcomes	High risk	No blinding
Incomplete outcome data (attrition bias)   All outcomes	High risk	Not discussed
Other bias	Low risk	No bias identified
Blinding of participants and personnel (performance bias)   All outcomes	High risk	No blinding
Blinding of outcome assessment (detection bias)   All outcomes	High risk	No blinding

Methods	Quasi‐RCT
Participants	165, first FS, mean age 20 months
Interventions	Phenobarbitone 4 ‐ 5 per kilo, or no treatment
Outcomes	RS @ 6 months
Notes	Attrition 4, 2 per arm, unblinded study
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	High risk	Alternate day allocation
Blinding (performance bias and detection bias)   All outcomes	High risk	None
Incomplete outcome data (attrition bias)   All outcomes	Low risk	4 of 165 lost but 39 of 88 stopped treatment
Selective reporting (reporting bias)	Low risk	Stated outcome objective met
Other bias	Low risk	No bias identified
Blinding of participants and personnel (performance bias)   All outcomes	High risk	None
Blinding of outcome assessment (detection bias)   All outcomes	High risk	None

Methods	RCT
Participants	80 children, 1 or more simple febrile seizures
Interventions	Oral diazepam 0.33 mg/kg/ dose every 8 hours for 2 days or oral clobazam for 2 days with the following dosage: 5 mg, daily in children ≤ 5 kg; 5 mg twice daily in children 6 – 10 kg; 7.5 mg, twice daily in children 11 – 15 kg; and 10 mg, twice daily in children > 15 kg
Outcomes	Recurrent seizures at 12 months
Notes	Attrition 5 in clobazam group and 3 in diazepam group.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	High risk	Method of allocation not stated.
Blinding (performance bias and detection bias)   All outcomes	High risk	Not stated
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	8 (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 risk	Stated outcome objective met
Other bias	Low risk	No bias identified
Blinding of participants and personnel (performance bias)   All outcomes	High risk	None
Blinding of outcome assessment (detection bias)   All outcomes	High risk	None

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, length of follow‐up differed (mean > 20 months)
Notes	Attrition: 4
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	High risk	Not used
Blinding (performance bias and detection bias)   All outcomes	High risk	Unblinded
Incomplete outcome data (attrition bias)   All outcomes	Low risk	4 of 69 dropped out
Selective reporting (reporting bias)	Low risk	Stated outcome objective met
Other bias	Low risk	No bias identified
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Unblinded
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Unblinded

Methods	RCT
Participants	69, first FS
Interventions	Intermittent rectal diazepam 0.5 mg/kg every 8 hours during fever, valproate 30 per kilo, or no treatment
Outcomes	RS @ 6 months, RS @ 12 months, RS @ 24 months
Notes	Attrition: 4 from the control group unaccounted for
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	High risk	Allocation concealment not discussed in the publication
Blinding (performance bias and detection bias)   All outcomes	High risk	Open label, no blinding
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Seemingly no attrition
Selective reporting (reporting bias)	Low risk	Stated outcome objective met
Other bias	Low risk	No bias identified
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open label, no blinding
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Open label, no blinding

Methods	Quasi‐RCT, included were randomised in the 2 treatment arms, the participants that refused or were otherwise not included but eligible were considered the ‘nothing arm’
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
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	High risk	Although the physicians were blinded to the 2 interventions, no randomisation nor blinding was used for the ‘no treatment’ control group.
Blinding (performance bias and detection bias)   All outcomes	High risk	Although the physicians were blinded to the 2 interventions, no randomisation nor blinding was used for the ‘no treatment’ control group.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	4 of 43 in trial withdrew due to side effects
Selective reporting (reporting bias)	Low risk	Stated outcome objective met
Other bias	Low risk	No bias identified
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Although the physicians were blinded to the 2 interventions, no randomisation nor blinding was used for the ‘no treatment’ control group.
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Although the physicians were blinded to the 2 interventions, no randomisation nor blinding was used for the ‘no treatment’ control group.

Methods	RCT
Participants	139 children aged 6 to 36 months; first febrile seizure
Interventions	Rectal diazepam 0.33 mg/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*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	High risk	Quasi‐random, alternate day allocation to intervention groups.
Blinding (performance bias and detection bias)   All outcomes	High risk	No blinding
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Attrition of 6 of 145
Selective reporting (reporting bias)	Low risk	Stated outcome objective met
Other bias	Low risk	No bias identified
Blinding of participants and personnel (performance bias)   All outcomes	High risk	No blinding
Blinding of outcome assessment (detection bias)   All outcomes	High risk	No blinding

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*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	Not used, “Randomly divided in 4 groups of 30 each”
Blinding (performance bias and detection bias)   All outcomes	High risk	No blinding
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Apparently no withdrawal
Selective reporting (reporting bias)	Low risk	Stated outcome objective met
Other bias	Low risk	No bias identified
Blinding of participants and personnel (performance bias)   All outcomes	High risk	No blinding
Blinding of outcome assessment (detection bias)   All outcomes	High risk	No blinding

Methods	Single‐centre RCT
Participants	Children 6 ‐ 60 months of age with ≥ 3 simple FS or with complex FS
Interventions	Continuous phenobarbitone 3 ‐ 5 mg/kg/day in 2 doses for at least a year, or intermittent oral diazepam 0.33 mg/kg/3 times a day for 2 days
Outcomes	RS @ 12 months, adverse effects
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	High risk	Randomisation methodology not mentioned
Blinding (performance bias and detection bias)   All outcomes	High risk	No blinding
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	9 participants excluded based on exclusion criteria. Loss to follow‐up not discussed
Other bias	Low risk	No bias identified
Blinding of participants and personnel (performance bias)   All outcomes	High risk	No blinding
Blinding of outcome assessment (detection bias)   All outcomes	High risk	No blinding