Quantifying the response to antiepileptic drugs Side effects of phenobarbital and carbamazepine in childhood epilepsy: randomised controlled trial In utero antiepileptic drug exposure Effect of phenobarbital on seizure frequency and mortality in childhood cerebral malaria: a randomised, controlled intervention study Randomised comparative monotherapy trial of phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed childhood epilepsy Randomised controlled trial to assess acceptability of phenobarbital for childhood epilepsy in rural India Psychologic and behavioral effects of antiepileptic drugs in children: a double-blind comparison between phenobarbital and valproic acid. Antiepileptic drug treatment in a community health care setting in northern Ecuador: a prospective 12-month assessment Late Cognitive Effects of Early Treatment with Phenobarbital Efficacy and safety of intravenous sodium valproate versus phenobarbital in controlling convulsive status epilepticus and acute prolonged convulsive seizures in children: a randomised trial. Outcomes of pregnancy associated with antiepileptic drugs. Comparison of antiepileptic drugs on cognitive function in newly diagnosed epileptic children: a psychometric and neurophysiological study. Enhancing antiepileptic drug adherence: A randomized controlled trial Sudden unexpected death in epilepsy in lamotrigine randomized‐controlled trials Phenobarbital for febrile seizures--effects on intelligence and on seizure recurrence. Effects of Phenobarbital and Levetiracetam on PR and QTc Intervals in Patients with Post-Stroke Seizure AntiEpileptic drug Monitoring in PREgnancy (EMPiRE): a double-blind randomised trial on effectiveness and acceptability of monitoring strategies.
Objective : To quantify the response to treatment with antiepileptic drugs ( AEDs ) as a function of the past treatment history and identify additional prognostic factors for predicting the response to newly administered AED treatments . Methods : A cohort of 478 consecutive patients who received newly administered AED treatments between January 1999 and December 2004 and were followed prospect ively for 1.5 to 7.5 years in a single epilepsy clinic . Results : The response to newly administered AED treatments was highly dependent on the past treatment history . The seizure-free rates decreased from 61.8 % for the first AED to 41.7 % , 16.6 % , and 0 % after one , two to five , and six to seven past AEDs proved inefficient . This response curve corresponded to a mono-exponential function with a maximal response of 61.8 % and half-decay constant of 1.5 AEDs . Likewise the response curve describing a greater than 50 % reduction in seizure frequency corresponded to a mono-exponential function with a maximal response of 85.3 % and half-decay constant of two AEDs . Three additional independent prognostic factors for predicting the response to AEDs were identified : type of epilepsy , duration of epilepsy , and number of seizures in the 3 months prior to AED initiation . Conclusion : Drug resistance is a grade d process that follows a mono-exponential course with a half-decay constant of 1.5 to two antiepileptic drugs ( AEDs ) . Although relative drug-resistant epilepsy can be diagnosed after failure of two past AEDs , absolute drug resistance requires failure of six AEDs , as a significant minority of patients ( 16.6 % ) is rendered seizure-free by addition of newly administered AEDs even after failure of two to five past antiepileptic drugs . GLOSSARY : AED = antiepileptic drug ; CBZ = carbamazepine ; GBP = gabapentin ; LTG = lamotrigine ; TPM = topiramate ; VA = valproic acid Objective To compare the behavioural side effects associated with two commonly used antiepilepsy drugs — phenobarbital and carbamazepine — in children in Bangladesh . Design Prospect i ve r and omised controlled single centre trial . Setting Specialist children 's hospital in Dhaka , Bangladesh . Participants 108 children aged 2 - 15 with generalised tonic-clonic ( n=51 ) or partial and secondary generalised seizures ( n=57 ) . Main outcome measures Seizure control and behavioural side effects . Results 91 children were followed up for 12 months . Six required a change of antiepilepsy drug . Side effects were compared in 85 children . In the last quarter of the 12 month follow-up , 71 children were seizure free after one year 's treatment . Thirty two in the phenobarbital group and 39 in the carbamazepine group had no seizures in 74 and 102 days after r and omisation , respectively . Ten children had increased behavioural problems , which were unacceptable in four ( one in the phenobarbital group and three in the carbamazepine group ) . Independent t tests , however , showed no difference between the two trial drugs . Conclusion There was no excess in behavioural side effects with phenobarbital in children with epilepsy in a country with limited re sources . Trial registration NCT00381537 Background : Pregnancy outcomes following in utero exposure to antiepileptic drugs ( AEDs ) are uncertain , limiting an evidence d-based approach . Objective : To determine if fetal outcomes vary as a function of different in utero AED exposures . Methods : This ongoing prospect i ve observational study across 25 epilepsy centers in the USA and UK enrolled pregnant women with epilepsy from October 1999 to February 2004 to determine if differential long-term cognitive and behavioral neurodevelopmental effects exist across the four most commonly used AEDs . This initial report focuses on the incidence of serious adverse outcomes including major congenital malformations ( which could be attributable to AEDs ) or fetal death .  A total of 333 mother/child pairs were analyzed for monotherapy exposures : carbamazepine ( n = 110 ) , lamotrigine ( n = 98 ) , phenytoin ( n = 56 ) , and valproate ( n = 69 ) . Results : Response frequencies of pregnancies result ing in serious adverse outcomes for each AED were as follows : carbamazepine 8.2 % , lamotrigine 1.0 % , phenytoin 10.7 % , and valproate 20.3 % . Distribution of serious adverse outcomes differed significantly across AEDs and was not explained by factors other than in utero AED exposure . Valproate exhibited a dose-dependent effect . Conclusions : More adverse outcomes were observed in pregnancies with in utero valproate exposure vs the other antiepileptic drugs ( AEDs ) . These results combined with several recent studies provide strong evidence that valproate poses the highest risk to the fetus . For women who fail other AEDs and require valproate , the dose should be limited if possible BACKGROUND Seizures commonly complicate cerebral malaria and are associated with an increased risk of death and neurological sequelae . We undertook a r and omised study to assess the efficacy of intramuscular phenobarbital in preventing seizures in childhood cerebral malaria . METHODS Children with cerebral malaria admitted to one hospital in Kilifi , Kenya , were r and omly assigned a single intramuscular dose of phenobarbital ( 20 mg/kg ) or identical placebo .  Clinical tolerance was assessed at the start of the trial , with particular reference to respiratory depression and hypotension . Seizures were timed and recorded , and treated in a st and ard way . Plasma phenobarbital concentrations were measured . Analyses were by intention to treat . FINDINGS 440 children with cerebral malaria were admitted to the hospital ; 100 were not recruited to the study . Of the remaining 340 , 170 received phenobarbital  and 170 placebo . The drug was adequately absorbed and well tolerated . Seizure frequency was significantly lower in the phenobarbital group than in the placebo group ( 18 [ 11 % ] vs 46 [ 27 % ] children had three or more seizures of any duration ; odds ratio 0.32 [ 95 % CI 0.18 - 0.58 ] ) but mortality was doubled ( 30 [ 18 % ] vs 14 [ 8 % ] deaths ; 2.39 [ 1.28 - 4.64 ] ) . The frequency of respiratory arrest was higher in the phenobarbital group than in the placebo group , and mortality was greatly increased in children who received phenobarbital plus three or more doses of diazepam ( odds ratio 31.7 [ 1.2 - 814 ] ) . INTERPRETATION In children with cerebral malaria , phenobarbital 20 mg/kg provides highly effective seizure prophylaxis but is associated with an unacceptable increase in mortality . Use of this dose can not , therefore , be recommended BACKGROUND The medical treatment of childhood epilepsy is largely influenced by clinical trials in adult patients . We know of only one r and omised comparative trial ( of two drugs ) in newly diagnosed childhood epilepsy . We have undertaken a long-term , prospect i ve , r and omised , unmasked , pragmatic trial of the comparative efficacy and toxicity of four st and ard antiepileptic drugs used as monotherapy in children with newly diagnosed epilepsy . METHODS Between 1981 and 1987 , 167 children aged 3 - 16 years , who had had at least two previously untreated tonic-clonic or partial seizures , with or without secondary generalisation , were r and omly allocated treatment with phenobarbitone , phenytoin , carbamazepine , or sodium valproate . The protocol was design ed to conform to st and ard clinical practice . Efficacy was assessed by time to first seizure after the start of treatment and time to achieving 1-year remission . FINDINGS The overall outcome with all four drugs was good . 20 % of children remained free of seizures and 73 % had achieved 1-year remission by 3 years of follow-up . We found no significant differences between the drugs for either measure of efficacy at 1 , 2 , or 3 years of follow-up . The overall frequency of unacceptable side-effects necessitating withdrawal of the r and omised drug was 9 % . This total included six of the first ten children assigned phenobarbitone ; no further children were allocated this drug . Of the other three drugs , phenytoin ( 9 % ) was more likely to be withdrawn than carbamazepine ( 4 % ) or sodium valproate ( 4 % ) . INTERPRETATION Our data will inform choice of drug and outcome with four of the st and ard drugs available for newly diagnosed tonic-clonic or partial seizures with or without secondary generalisation in children BACKGROUND The use of phenobarbital for childhood epilepsy is controversial because of reported behavioural side-effects ; however , whether this research can validly be extrapolated to developing countries is not clear . We undertook a r and omised comparison of phenobarbital and phenytoin to assess the acceptability and efficacy of phenobarbital as monotherapy for childhood epilepsy in rural India . METHODS Between August , 1995 , and February , 1996 , 109 unselected children aged 2 - 18 years with partial and generalised tonic-clonic epilepsy were identified by population screening . 15 families declined to take part . 94 children were r and omly allocated treatment with phenobarbital ( 1.5 mg/kg daily for 2 weeks ; maintenance dose 3.0 mg/kg daily ; n = 47 ) or phenytoin ( 2.5 mg/kg daily then 5.0 mg/kg daily ; n = 47 ) . Children were followed up for 12 months . The primary outcome measure was the frequency of behavioural side-effects ; behaviour was assessed by the Conners parent rating scale for children aged 6 years and older , and by the preschool behaviour screening question naire ( BSQ ) for those aged 2 - 5 years , at 12 months or at withdrawal from treatment . Analysis was by intention to treat . FINDINGS The mean log-transformed scores on the behaviour rating scales did not differ significantly between the phenobarbital and phenytoin groups ( Conners 2.64 [ SD 0.71 ] vs 2.65 [ 0.89 ] , p = 0.97 ; n = 32 in each group : BSQ 2.12 [ 1.31 ] vs 2.18 [ 1.02 ] , p = 0.94 ; n = 4 vs 3 ) . The odds ratio for behavioural problems  ( phenobarbital vs phenytoin ) was 0.51 ( 95 % CI 0.16 - 1.59 ) . There was no excess in parental reports of side-effects for phenobarbital . We found no difference in efficacy between the study drugs ( adjusted hazard ratio for time to first seizure from r and omisation 0.97 [ 0.28 - 3.30 ] ) . INTERPRETATION This evidence supports the acceptability of phenobarbital as a first-line drug for childhood epilepsy in rural setting s in developing countries Traditional clinical monitoring of children with epilepsy does not appear to be sufficiently sensitive to cognitive functioning and behavioral problems . Although subtle , these changes may alter a child 's ability to perform well in school and in society . Physicians must prevent seizures without producing intolerable side effects , and ways of more appropriately assessing these side effects must be developed . In this double-blind , counter-balanced , crossover study of 21 children , the effects of phenobarbital and valproic acid on cognitive functioning and behavior were measured . There was no difference in seizure control between the drugs , and each medication was maintained in the therapeutic range for 6 months ( mean phenobarbital level , 21.2 micrograms/mL ; mean valproic acid level , 94.1 micrograms/mL ) . Children were treated with each drug for 6 months . Differences between the drugs were seen on measurements of cognitive function and behavior . On four tests of neuropsychologic function , children performed significantly less well while receiving phenobarbital ( P less than .01 ) . There was no evidence that the patients were se date d or less able to perform continuous performance tasks while receiving phenobarbital .  Parental assessment of behavior indicated significantly worse behavior with the phenobarbital regimen for three items ( P less than .01 ) and children were measurably more " hyperactive " ( P less than .05 ) . Routine clinical assessment of the patients did not reveal differences between the drugs with respect to routine laboratory measurements or side effects as assessed by history or physical examination . Although children may appear to tolerate a medication without clinical ly apparent problems , subtle but significant changes in intellectual function and behavior may be occurring . Additional , more sensitive , methods of monitoring patients while receiving these drugs is necessary The results of a prospect i ve assessment of antiepileptic drug treatment carried out over a 12-month period , in the context of existing community health care in a rural area of a developing country ( a highl and region of northern Ecuador ) , are reported . A house to house survey defined all patients in the area with a history of epileptic seizures , and 192 patients with active epilepsy were recruited into the programme . These patients were r and omised to treatment with carbamazepine or phenobarbital  , and 139 completed the assessment . Treatment was carried out by health visitors and rural doctors , monitored by a team of neurologists , and st and ard treatment regimens were used . Treatment was effective in controlling seizures , 53 % of the patients were rendered entirely seizure free in the second 6 months of therapy , and a further 14 % had a 50 % or more reduction in seizures . These results were similar to those reported in hospital based studies in developed countries . No significant differences were found between the efficacy and safety of phenobarbital or carbamazepine . Antiepileptic drug levels were monitored during the study , and ranges similar to those found in developed countries were recorded . Compliance was good . In view of the successful treatment in this community control programme , we would recommend that community programmes for the control of epilepsy in rural setting s should be given a higher priority in the planning of health care provision than is commonly the case . Finally , the programme afforded the opportunity to study the efficacy of treatment in patients with chronic long-st and ing epilepsy , who had not been previously treated , and the results of this treatment were good We previously reported that IQ , was significantly lowered in a group of toddler-aged children r and omly assigned to receive phenobarbital or placebo  for febrile seizures and there was no difference in the febrile seizure recurrence rate . We retested these children 3 - 5 years later , after they had entered school , to determine whether those effects persisted over the longer term and whether later school performance might be affected . On follow-up testing of 139 ( of the original n=217 ) Western Washington children who had experienced febrile seizures , we found that the phenobarbital group scored significantly lower than the placebo group on the Wide Range Achievement Test ( WRAT-R ) reading achievement st and ard score ( 87.6 vs 95.6 ; p=0.007 ) . There was a nonsignificant mean difference of 3.71 IQ , points on the Stanford-Binet , with the phenobarbital-treated group scoring lower ( 102.2 vs 105.7 ; p=0.09 ) . There were five children in our sample with afebrile seizures during the 5-year period after the end of the medication trial . Two had been assigned to phenobarbital , and three had been in the placebo group . We conclude there may be a long-term adverse cognitive effect of phenobarbital on the developmental skills ( language /verbal ) being acquired during the period of treatment and no beneficial effect on the rate of febrile seizure recurrences or later nonfebrile seizures . Clin Pediatr . 1999;38:387 - Status epilepticus and acute prolonged seizures are the most commonly occurring neurological emergencies in children . Such events have high morbidity and mortality rates along with poor long-term outcomes , depending on their duration and causes . Therefore , such seizures warrant urgent treatment using appropriate doses of anticonvulsants . Benzodiazepines , phenobarbital , and phenytoin are the most commonly used anticonvulsants for controlling status epilepticus and acute prolonged seizures . However , these medications have several well-known adverse effects . Previous studies on both adults and children have shown the efficacy and safety of rapid infusion of valproate in controlling status epilepticus . However , few well- design ed r and omised trials have been carried out in children , and there remains a paucity of data regarding intravenous sodium valproate use in children . Therefore , our aim was to compare the efficacy and safety of rapid loading of valproate with those of intravenous phenobarbital in children with status epilepticus and acute prolonged seizures . Sixty children ( 30 in each group ) with convulsive status epilepticus and acute prolonged seizures were enrolled and r and omly assigned to receive either valproate or phenobarbital . The main outcome variable was termination of all convulsive activity within 20 min of starting anticonvulsant infusion . Intravenous rapid loading of valproate was successful in seizure termination in ( 27/30 , 90 % ) of patients compared to phenobarbital ( 23/30 , 77 % ) ( p = 0.189 ) . Clinical ly significant adverse effects occurred in 74 % patients of the phenobarbital group and 24 % patients of the valproate group ( p < 0.001 ) . In conclusion , rapid loading of valproate is effective and safe in controlling convulsive status epilepticus and acute prolonged convulsive seizures in children . Intravenous valproate should be considered as a suitable choice for terminating status epilepticus and acute prolonged seizures in children OBJECTIVE To determine whether exposure to antiepileptic drugs during pregnancy is associated with poor fetal outcomes ( anomalies and death ) and to assess the relative risks with phenobarbital , phenytoin sodium , and carbamazepine . DESIGN The design was a prospect i ve case-control cohort study of pregnant women with epilepsy and their offspring . Outcomes were compared with those of a control group of 355 healthy women and their offspring . SETTING The obstetrics service at Los Angeles County/University of Southern California Medical Center , Los Angeles , a large , inner-city , teaching hospital . PATIENTS Two hundred eleven subjects who were pregnant during the years 1987 through 1990 , 174 of whom were delivered of infants , were available for analysis . A control group of 355 healthy women and their offspring from the same hospital were r and omly selected from a computerized data base . INTERVENTION None . MAIN OUTCOME MEASURE Anomalies and fetal death were the primary outcome measures . RESULTS Offspring of women with epilepsy who were exposed to antiepileptic drugs had a higher rate of fetal death and anomalies than did the control population ( P = .001 ) . Abnormal outcomes were associated with the three major antiepileptic drugs ( carbamazepine , phenytoin , and phenobarbital ) . In terms of abnormal outcome ( death and anomalies ) , phenobarbital was associated with the highest relative risk , phenytoin with intermediate relative risk , and carbamazepine with the lowest relative risk ( P = .019 ) . Numbers were insufficient for assessment of risk associated with valproic acid . CONCLUSION All three major antiepileptic drugs ( phenobarbital , phenytoin , and carbamazepine ) are associated with an increased risk of fetal death and anomalies . We found phenobarbital to be most associated with poor pregnancy outcome Using a r and omized parallel group study design , we compared the cognit i ve effects of carbamazepine ( CBZ ) , phenobarbital ( PB ) , and valproate ( VPA ) in children with epilepsy . Seventy-three children with newly diagnosed epilepsy were tested with the Wechsler Intelligence Scale for Children-Revised ( WISC-R ) , Bender-Gestalt test , and auditory event-related potentials ( P 300 ) before and 6 and 12 months after antiepileptic drug ( AED ) treatment . There were no significant differences in WISC-R IQs and Bender-Gestalt scores for children in any group at any of the three sessions . P 300 latencies were increased in the children receiving PB but not in children receiving CBZ and VPA . P 300 amplitudes were significantly reduced in treated children in all three groups , but amplitudes were not significantly different among the three groups . These findings suggest that PB may affect cognitive function of epileptic children and that the P 300 may be a sensitive additional procedure that can be used to assess the cognitive effect of AEDs Suboptimal adherence to antiepileptic drug ( AED ) treatment is commonplace , and increases the risk of status epilepticus and sudden unexplained death in epilepsy . This r and omized controlled trial was design ed to demonstrate whether an implementation intention intervention involving the completion of a simple self-administered question naire linking the intention of taking medication with a particular time , place , and other activity can improve AED treatment schedule adherence . Of the 81 patients with epilepsy who were r and omized , 69 completed a 1-month monitoring period with an objective measure of tablet taking ( electronic registration of pill bottle openings , Medication Event Monitoring System [ MEMS ] ) . Intervention participants showed improved adherence relative to controls on all three outcomes : doses taken in total ( 93.4 % vs. 79.1 % ) , days on which correct dose was taken ( 88.7 % vs. 65.3 % ) , and doses taken on schedule ( 78.8 % vs. 55.3 % ) ( P<0.01 ) . The implementation intention intervention may be an easy-to-administer and effective means of promoting AED adherence Purpose : Nonr and omized studies of the relationship of antiepileptic drugs ( AEDs ) with sudden unexpected death in epilepsy ( SUDEP ) may be susceptible to confounding by tonic – clonic seizure frequency , polypharmacy , and other potential risk factors for SUDEP . We evaluated the risk of SUDEP with lamotrigine ( LTG ) compared to active comparators and placebo in r and omized controlled clinical trials conducted by GlaxoSmithKline ( GSK ) between 1984 and 2009 Phenobarbital is widely used in the treatment of children with febrile seizures , although there is concern about possible behavioral and cognitive side effects . In 217 children between 8 and 36 months of age who had had at least one febrile seizure and were at heightened risk of further seizures , we compared the intelligence quotients ( IQs ) of a group r and omly assigned to daily doses of phenobarbital ( 4 to 5 mg per kilogram of body weight per day ) with the IQs of a group r and omly assigned to placebo . After two years , the mean IQ was 7.03 [ corrected ] points lower in the group assigned to phenobarbital than in the placebo group ( 95 percent confidence interval , -11.52 to -2.5 , P = 0.0068 [ corrected ] ) . Six months later , after the medication had been tapered and discontinued , the mean IQ was 5.2 points lower in the group assigned to phenobarbital ( 95 percent confidence interval , -10.5 to 0.04 , P = 0.052 ) . The proportion of children remaining free of subsequent seizures did not differ significantly between the treatment groups . We conclude that phenobarbital depresses cognitive performance in children treated for febrile seizures and that this disadvantage , which may outlast the administration of the drug by several months , is not offset by the benefit of seizure prevention Abstract Background and Objectives Sudden unexplained/unexpected death ( SUDEP ) is related to high mortality in patients with epilepsy . The prolongation of QT interval , involved in cardiac arrhythmia-related SUDEP , may be precipitated by antiepileptic dru gs ( AEDs ) . In this study , we evaluated the effects of phenobarbital and levetiracetam on PR – QTc intervals in patients with post-stroke seizures . Methods We performed an open-label , parallel group , prospect i ve , multicenter study between June 2009 and December 2013 in patients older than 18 years of age with a clinical diagnosis of post-stroke seizure and treated with phenobarbital or levetiracetam .  In order to exclude a role of cerebral post-stroke injury on modulation of PR and QTc intervals , patients with cerebral post-stroke injury and without seizures were also enrolled as controls . Results Interictal electrocardiography analysis revealed no significant difference in PR interval between patients treated with an AED ( n = 49 ) and control patients ( n = 50 ) ( 181.25 ± 12.05 vs. 182.4 ± 10.3 ms ; p > 0.05 ) . In contrast , a significantly longer QTc interval was recorded in patients treated with an AED compared with control patients ( 441.2 ± 56.6 vs. 396.8 ± 49.3 ms ; p < 0.01 ) . Patients treated with phenobarbital showed a significantly longer QTc interval than patients treated with levetiracetam ( 460.0 ± 57.2 vs. 421.5 ± 50.1 ms ; p < 0.05 ) . Conclusions The study reported that in patients with late post-stroke seizures  , phenobarbital  prolonged QTc interval more so than levetiracetam BACKGROUND Pregnant women with epilepsy on antiepileptic drugs ( AEDs ) may experience a reduction in serum AED levels . This has the potential to worsen seizure control . OBJECTIVE To determine if , in pregnant women with epilepsy on AEDs , additional therapeutic drug monitoring reduces seizure deterioration compared with clinical features monitoring after a reduction in serum AED levels . DESIGN A double-blind , r and omised trial nested within a cohort study was conducted and a qualitative study of acceptability of the two strategies was undertaken . Stratified block r and omisation with a 1 : 1 allocation method was carried out . SETTING Fifty obstetric and epilepsy clinics in secondary and tertiary care units in the UK . PARTICIPANTS Pregnant women with epilepsy on one or more of the following AEDs : lamotrigine , carbamazepine , phenytoin or levetiracetam .  Women with a ≥ 25 % decrease in serum AED level from baseline were r and omised to therapeutic drug monitoring or clinical features monitoring strategies . INTERVENTIONS In the therapeutic drug monitoring group , clinicians had access to clinical findings and monthly serum AED levels to guide AED dosage adjustment for seizure control . In the clinical features monitoring group , AED dosage adjustment was based only on clinical features . MAIN OUTCOME MEASURES Primary outcome - seizure deterioration , defined as time to first seizure and to all seizures after r and omisation per woman until 6 weeks post partum . Secondary outcomes - pregnancy complications in mother and offspring , maternal quality of life , seizure rates in cohorts with stable serum AED level , AED dose exposure and adverse events related to AEDs . ANALYSIS Analysis of time to first and to all seizures after r and omisation was performed using a Cox proportional hazards model , and multivariate failure time analysis by the And ersen-Gill model . The effects were reported as hazard ratios ( HRs ) with 95 % confidence intervals ( CIs ) . Secondary outcomes were reported as mean differences ( MDs ) or odds ratios . RESULTS A total of 130 women were r and omised to the therapeutic drug monitoring group and 133 to the clinical features monitoring group ; 294 women did not have a reduction in serum AED level . A total of 127 women in the therapeutic drug monitoring group and 130 women in the clinical features monitoring group ( 98 % of complete data ) were included in the primary analysis . There were no significant differences in the time to first seizure ( HR 0.82 , 95 % CI 0.55 to 1.2 ) or timing of all seizures after r and omisation ( HR 1.3 , 95 % CI 0.7 to 2.5 ) between both trial groups . In comparison with the group with stable serum AED levels , there were no significant increases in seizures in the clinical features monitoring ( odds ratio 0.93 , 95 % CI 0.56 to 1.5 ) or therapeutic drug monitoring group ( odds ratio 0.93 , 95 % CI 0.56 to 1.5 ) associated with a reduction in serum AED levels . Maternal and neonatal outcomes were similar in both groups , except for higher cord blood levels of lamotrigine ( MD 0.55 mg/l , 95 % CI 0.11 to 1 mg/l ) or levetiracetam ( MD 7.8 mg/l , 95 % CI 0.86 to 14.8 mg/l ) in the therapeutic drug monitoring group than in the clinical features monitoring group . There were no differences between the groups on daily AED exposure or quality of life . An increase in exposure to lamotrigine , levetiracetam and carbamazepine significantly increased the cord blood levels of the AEDs , but not maternal or fetal complications . Women with epilepsy perceived the need for weighing up their increased vulnerability to seizures during pregnancy against the side effects of AEDs . LIMITATIONS Fewer women than the original target were recruited . CONCLUSION There is no evidence to suggest that regular monitoring of serum AED levels in pregnancy improves seizure control or affects maternal or fetal outcomes . FUTURE WORK RECOMMENDATIONS Further evaluation of the risks of seizure deterioration for various threshold levels of reduction in AEDs and the long-term neurodevelopment of infants born to mothers in both r and omised groups is needed . An individualised prediction model will help to identify those women who need close monitoring in pregnancy . TRIAL REGISTRATION Current Controlled Trials IS RCT N01253916 . FUNDING This project was funded by the National Institute for Health Research ( NIHR ) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol . 22 , No. 23 . See the NIHR Journals Library website for further project information
There is no evidence for a difference in antiepileptic efficacy between phenobarbital and any other compared AED , yet no evidence for absolute efficacy .
No convincing evidence exists for an excess of behavioural adverse effects , over other AEDs , attributable to phenobarbital .
Masked studies of phenobarbital in childhood epilepsy have shown no significant differences in behavioural or cognitive adverse effects compared to other AEDs .
This is in contrast to the excess of such adverse effects reported in studies open to observer bias .
However , the one finding of reduction in cognitive ability associated with phenobarbital treatment for febrile convulsions remains a concern .
INTRODUCTION : Against a background of concern about the safety of new pharmaceutical products , there has been renewed interest in one of the oldest antiepileptic drugs ( AEDs ) , phenobarbital .
Although still in widespread use in developing countries , its popularity has slipped in Western countries over the past century , partly because of controversy about its adverse effect profile .
This critical review examines the evidence supporting its effectiveness and its associated behavioural adverse effects for febrile convulsions and childhood epilepsy .