NIHR Signal Prescribing regular drugs to prevent febrile convulsions risks more harm than benefit

Published on 1 August 2017

The benefits of giving anti-epileptic medication to children aged between six months and seven years who have had a convulsion while feverish, do not outweigh the harms. While diazepam given when a child becomes feverish reduced the chance of a convulsion from about 25% to 18% after a year, one in three children experienced adverse effects. Therefore, the authors suggest benefits do not seem to outweigh the harms.

In the UK 2 to 5% of children less than six years old will have a febrile convulsion, with around a third experiencing another when feverish. Febrile convulsions are usually brief and harmless, though they are disturbing to witness and cause worry for parents and carers. Efforts to reduce the child’s temperature, if they are distressed by a fever are still encouraged.

NICE does not currently recommend preventative medication for febrile convulsions based on the balance of benefits and harms. These systematic review findings support this. Parents and families should be supported with advice and information about how to manage future convulsions and the benign nature of the condition.

Prescribing regular drugs to prevent febrile convulsions risks more harm than benefit

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Why was this study needed?

Febrile convulsions are fits that can occur when a young child (aged six months to six years) has a fever. Around 2 to 4% of children will have a febrile convulsion, with a third of those children going on to have another when feverish in the future. Most convulsions last under five minutes and the child may feel sleepy for a while afterwards.

Simple febrile convulsions, by definition, are harmless and not a sign of serious brain disease, so can be managed with basic first aid such as putting the child in the recovery position and reducing the child’s temperature if they are distressed. However, ensuring that there is not another cause of a convulsion may require a hospital assessment, especially in children under 18 months old. 

For children thought to be at particular risk of recurrence it is tempting to prescribe drugs to try to prevent further fits. However, this approach is unproven and the potential side effects of treatment may outweigh any benefits. This review aimed to gather the evidence on the effectiveness and safety of preventative drugs.

What did this study do?

This systematic review and meta-analysis included 30 randomised or quasi-randomised trials that compared drugs given continuously or intermittently to prevent febrile convulsions with each other, placebo or no treatment in 4,256 children.

The included trials evaluated the anti-epileptic drugs phenobarbitone, phenytoin and valproate; benzodiazepines diazepam and clobazam (sedatives); antipyretics (to reduce fever) paracetamol, ibuprofen and diclofenac; and dietary supplements pyridoxine (vitamin B6) and zinc sulphate.

The majority of included studies were 20 to 30 years old and generally moderate to poor quality. Common sources of bias were lack of blinding; the possibility that patient characteristics influenced group allocation; and incomplete outcome-reporting for all participants. The analysis also suggested some publication bias, meaning studies that found an effect of treatment were more likely to be published than those that didn’t.

What did it find?

  • Intermittent diazepam reduced risk of another febrile convulsion at 12 months (relative risk [RR] 0.69, 95% confidence interval [CI] CI 0.56 to 0.84; eight studies, n=1,416), and 24 months (RR 0.73, 95% CI 0.56 to 0.95; four studies, n=739) compared with placebo or no treatment.
  • By six months 11% of children given diazepam had a recurrent convulsion compared with 18% in the control group, with 16 needing treatment to prevent one convulsion. By 12 months the convulsion rate was 18% vs. 25% with 13 needed to treat.
  • Continuous phenobarbitone reduced the risk of a convulsion at 12 months (RR 0.54, 95% CI 0.42 to 0.70; seven studies; n=807) and 24 months (RR 0.69, 95% CI 0.53 to 0.89; three studies, n=533) compared with placebo or no treatment, but not at 18 or 72 months. The number needed to treat to prevent one convulsion was 14 at six months and eight at 12 months.
  • Intermittent clobazam reduced the risk of another fit at six months (RR 0.36, 95% CI 0.20 to 0.64). However, this single study (n=30) also reported a very high rate of fits in children receiving placebo or no treatment (83%), so it is not clear whether these results are reliable.
  • The following medications had no statistically significant effect on convulsion recurrence compared with placebo or no treatment: intermittent phenobarbitone, phenytoin, valproate, intermittent clobazam, intermittent ibuprofen, pyridoxine (vitamin B6) or zinc sulphate. There were also no significant findings in studies assessing drugs in combination or comparing them with each other.
  • Adverse effects were variably reported across studies, but overall were documented for 30 to 36% of children treated with phenobarbitone or benzodiazepines.

What does current guidance say on this issue?

NICE guidelines on assessing and managing fever in under-fives (2013) emphasise that regular antipyretic drugs do not prevent febrile convulsions and should not be used for this purpose.  When using paracetamol or ibuprofen in children who are distressed with a fever, NICE suggest continuing if the child appears distressed.

NICE’s Clinical Knowledge Summary gives guidance on the acute management of febrile convulsions, including advice on when a hospital assessment is required to exclude other causes of a convulsion. Drugs to manage or prevent further convulsions should not be prescribed unless advised by a specialist. Antipyretics are suggested, to reduce fever in future illness, but this may not prevent recurrence.

What are the implications?

This systematic review suggests that intermittent diazepam or continuous phenobarbitone may have some effect in preventing further febrile convulsions. However, this benefit was not large enough to outweigh the potential harms associated with these drugs. Other anticonvulsants are ineffective yet still carry potential harms.

Parents and carers may feel concerned about not receiving specific preventive treatment for these worrying, but predominantly harmless, convulsions. Therefore, there may be scope for creating materials for parents and carers about febrile convulsions, what they can do during a convulsion and why drug treatments are of little help.

Citation and Funding

Offringa M, Newton R, Cozijnsen MA, Nevitt SJ. Prophylactic drug management for febrile seizures in children. Cochrane Database Syst Rev. 2017;2:CD003031.

This review was funded by the Department of Pediatric Clinical Epidemiology, Emma Childrens’ Hospital A.M.C. Amsterdam, Netherlands and the Dutch Cochrane Centre, Amsterdam, Netherlands. Cochrane UK and the Epilepsy Cochrane Review Group are supported by NIHR infrastructure funding.

Bibliography

NHS Choices. Febrile seizures. London: Department of Health; 2015.

NICE. Febrile seizure. London: National Institute for Health and Care Excellence; 2013.

NICE. Fever in under 5s: assessment and initial management. CG160. London: National Institute for Health and Care Excellence; 2013.

Why was this study needed?

Febrile convulsions are fits that can occur when a young child (aged six months to six years) has a fever. Around 2 to 4% of children will have a febrile convulsion, with a third of those children going on to have another when feverish in the future. Most convulsions last under five minutes and the child may feel sleepy for a while afterwards.

Simple febrile convulsions, by definition, are harmless and not a sign of serious brain disease, so can be managed with basic first aid such as putting the child in the recovery position and reducing the child’s temperature if they are distressed. However, ensuring that there is not another cause of a convulsion may require a hospital assessment, especially in children under 18 months old. 

For children thought to be at particular risk of recurrence it is tempting to prescribe drugs to try to prevent further fits. However, this approach is unproven and the potential side effects of treatment may outweigh any benefits. This review aimed to gather the evidence on the effectiveness and safety of preventative drugs.

What did this study do?

This systematic review and meta-analysis included 30 randomised or quasi-randomised trials that compared drugs given continuously or intermittently to prevent febrile convulsions with each other, placebo or no treatment in 4,256 children.

The included trials evaluated the anti-epileptic drugs phenobarbitone, phenytoin and valproate; benzodiazepines diazepam and clobazam (sedatives); antipyretics (to reduce fever) paracetamol, ibuprofen and diclofenac; and dietary supplements pyridoxine (vitamin B6) and zinc sulphate.

The majority of included studies were 20 to 30 years old and generally moderate to poor quality. Common sources of bias were lack of blinding; the possibility that patient characteristics influenced group allocation; and incomplete outcome-reporting for all participants. The analysis also suggested some publication bias, meaning studies that found an effect of treatment were more likely to be published than those that didn’t.

What did it find?

  • Intermittent diazepam reduced risk of another febrile convulsion at 12 months (relative risk [RR] 0.69, 95% confidence interval [CI] CI 0.56 to 0.84; eight studies, n=1,416), and 24 months (RR 0.73, 95% CI 0.56 to 0.95; four studies, n=739) compared with placebo or no treatment.
  • By six months 11% of children given diazepam had a recurrent convulsion compared with 18% in the control group, with 16 needing treatment to prevent one convulsion. By 12 months the convulsion rate was 18% vs. 25% with 13 needed to treat.
  • Continuous phenobarbitone reduced the risk of a convulsion at 12 months (RR 0.54, 95% CI 0.42 to 0.70; seven studies; n=807) and 24 months (RR 0.69, 95% CI 0.53 to 0.89; three studies, n=533) compared with placebo or no treatment, but not at 18 or 72 months. The number needed to treat to prevent one convulsion was 14 at six months and eight at 12 months.
  • Intermittent clobazam reduced the risk of another fit at six months (RR 0.36, 95% CI 0.20 to 0.64). However, this single study (n=30) also reported a very high rate of fits in children receiving placebo or no treatment (83%), so it is not clear whether these results are reliable.
  • The following medications had no statistically significant effect on convulsion recurrence compared with placebo or no treatment: intermittent phenobarbitone, phenytoin, valproate, intermittent clobazam, intermittent ibuprofen, pyridoxine (vitamin B6) or zinc sulphate. There were also no significant findings in studies assessing drugs in combination or comparing them with each other.
  • Adverse effects were variably reported across studies, but overall were documented for 30 to 36% of children treated with phenobarbitone or benzodiazepines.

What does current guidance say on this issue?

NICE guidelines on assessing and managing fever in under-fives (2013) emphasise that regular antipyretic drugs do not prevent febrile convulsions and should not be used for this purpose.  When using paracetamol or ibuprofen in children who are distressed with a fever, NICE suggest continuing if the child appears distressed.

NICE’s Clinical Knowledge Summary gives guidance on the acute management of febrile convulsions, including advice on when a hospital assessment is required to exclude other causes of a convulsion. Drugs to manage or prevent further convulsions should not be prescribed unless advised by a specialist. Antipyretics are suggested, to reduce fever in future illness, but this may not prevent recurrence.

What are the implications?

This systematic review suggests that intermittent diazepam or continuous phenobarbitone may have some effect in preventing further febrile convulsions. However, this benefit was not large enough to outweigh the potential harms associated with these drugs. Other anticonvulsants are ineffective yet still carry potential harms.

Parents and carers may feel concerned about not receiving specific preventive treatment for these worrying, but predominantly harmless, convulsions. Therefore, there may be scope for creating materials for parents and carers about febrile convulsions, what they can do during a convulsion and why drug treatments are of little help.

Citation and Funding

Offringa M, Newton R, Cozijnsen MA, Nevitt SJ. Prophylactic drug management for febrile seizures in children. Cochrane Database Syst Rev. 2017;2:CD003031.

This review was funded by the Department of Pediatric Clinical Epidemiology, Emma Childrens’ Hospital A.M.C. Amsterdam, Netherlands and the Dutch Cochrane Centre, Amsterdam, Netherlands. Cochrane UK and the Epilepsy Cochrane Review Group are supported by NIHR infrastructure funding.

Bibliography

NHS Choices. Febrile seizures. London: Department of Health; 2015.

NICE. Febrile seizure. London: National Institute for Health and Care Excellence; 2013.

NICE. Fever in under 5s: assessment and initial management. CG160. London: National Institute for Health and Care Excellence; 2013.

Prophylactic drug management for febrile seizures in children

Published on 23 February 2017

Offringa, M.,Newton, R.,Cozijnsen, M. A.,Nevitt, S. J.

Cochrane Database Syst Rev Volume 2 , 2017

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.

Expert commentary

Febrile convulsions occur in a substantial proportion of infants and they commonly re-occur. Studies have shown that prophylactic treatment can be effective in preventing the recurrence of convulsions. However, such prophylactic treatment can have unwanted effects in almost a third of the infants, and this is not widely known.

At the same time we know that, although scary when they happen, recurrent febrile convulsions are benign. We should therefore make more effort to explain to families the benign nature of these convulsions and provide information on how to act when a fever or febrile convulsion occurs.

Dr Brigitte Vollmer, Associate Professor of Neonatal and Paediatric Neurology, Honorary Consultant in Paediatric Neurology, University of Southampton