Side Effects of Phenobarbital in Epilepsy: a Systematic Review

Journal Identiﬁcation = EPD Article Identiﬁcation = 0444 Date: December 22, 2011 Time: 1:52 pm

Review article

Epileptic Disord 2011; 13 (4): 349-65 Side effects of phenobarbital in epilepsy: a systematic review

Ling-Li Zhang 1,2, Li-Nan Zeng 2,3, You-Ping Li 1 1 Chinese Cochrane Centre and Chinese Evidence-Based Medicine Centre, West China Hospital, Sichuan University, West China Medical School 2 Department of Pharmacy, West China Second University Hospital 3 West China School of Pharmacy, Sichuan University, Chengdu 610041, P.R. China

Received December 20, 2009; Accepted May 29, 2011

ABSTRACT – Aim. In recent years, phenobarbital, as an antiepileptic drug, has become less popular based on adverse events, especially cognitive and behavioural side effects. Despite the development of better tolerated new generation AEDs, phenobarbital is still widely used particularly in developing countries because of its low cost. The purpose of this review was to: (i) investigate whether phenobarbital can be safely used as an antiepileptic drug and (ii) determine the questions which need to be addressed in order to comprehensively and adequately evaluate the safety of phenobarbital for the treatment of epilepsy. Methods. The literature was searched using the Cochrane Central Register of randomised controlled trials (1800-2009), Medline (1966-2009), Embase (1966-2009) and three Chinese databases. Results. Twenty studies were finally included in this systematic review. The determination of adverse effects of combined antiepileptic drugs (AEDs) from different studies was complicated by numerous factors including study design, different descriptions of adverse events and a lack of standardised data collection. These factors may also have been responsible for the heterogeneity present in the meta-analysis. The data did not demonstrate any evidence of association between phenobarbital and a higher risk of adverse events. How- ever, phenobarbital appeared to be associated with a higher rate of adverse drug reaction related withdrawal (ADR-related withdraw), compared to carbamazepine, valproic acid and phenytoin. This may have been due to a concern for possible adverse effects of phenobarbital. Conclusions. Phe- nobarbital was associated with a higher rate of drug withdrawal although there was no evidence to suggest that phenobarbital caused more adverse events compared to carbamazepine, valproic acid or phenytoin. However, in the case of pregnant women, it is important for clinicians to evaluate the benefits and risks of phenobarbital administration before making a final recommendation. Furthermore, unified scales for the assessment of cognitive function should be applied for future studies particularly in children. Key words: phenobarbital, side effects, systematic review

Correspondence: Y.P. Li Epilepsy is a chronic disorder of the developing countries have shown Chinese Cochrane Centre and Chinese brain which affects approximately that up to 70% of newly diagnosed Evidence-Based Medicine Centre, 50 million people world-wide, of children and adults with epilepsy West China Hospital, Sichuan University, No.37, Guoxue Road, whom 40 million are estimated to may lead normal lives if properly Cheng du, Si chuan, P.R. China live in developing countries (WHO, treated (WHO, 2009). Unfortunately, doi:10.1684/epd.2011.0444 2004). Studies in both developed and 85% of epilepsy patients living in the

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developing world do not receive any treatment treated with AEDs were included for “major congenital because of the cost of treatment, superstition and the malformation” assessment. unavailability of drugs (Kale, 2002; Muba et al., 2008). – Parallel or cross-over design studies were included Phenobarbital (PB) has been a widely used AED due but the minimum duration of each treatment was eight to its low cost and broad indication. Despite the weeks. development of new AEDs, phenobarbital is recom- – Studies of monotherapy which compared the mended by the World Health Organization (WHO) administration of phenobarbital by oral route with car- as a first-line drug in developing countries (WHO, bamazepine, valproic acid and phenytoin. 1990). Several studies suggested there is little differ- – Studies in which the absolute number of adverse ence in antiepileptic efficacy between phenobarbital effects (AEs) was reported or could be calculated. and other established AEDs (Tudur Smith et al., 2003; Kwan and Brodie, 2004; Mattson et al., 1985). However, concern for adverse effects has resulted in Outcome measures a decline of use for seizure disorders. Phenobarbi- tal is reported to be associated with a higher rate of The classification and definition of AEs were as fol- side effects and was even withdrawn from a trial arm lows, as previously documented (Aronson et al., 2006; in a previous study, as a result of perceived adverse Zaccara et al., 2008): behavioural effects (de Silva et al., 1996). In some other – total withdrawal rate; studies, however, no difference was found between – ADR-related withdrawal; phenobarbital and other AEDs with respect to toler- – nervous system AEs; ance (Pal et al., 1998). Based on the studies reported – psychological and psychiatric AEs; to date, a consensus on the safety of phenobarbi- – major congenital malformation. tal has not been possible. Hence, it is necessary to AEs of the nervous system were divided into three re-evaluate the original controversial issues concern- broad classes: those affecting vigilance, those affecting ing phenobarbital and systematically reassess its safety the brain stem and vestibulo-cerebellar system, and for the treatment of epilepsy. those affecting the motor system (table 1). Psychological and psychiatric AEs included anxiety, depression, dissociation, hallucination, cognitive Methods impairment and behavioural disturbances. Since objective measures for most of these complaints were not used, an analysis of all the psychological Search strategy and psychiatric AEs as a whole could be misleading. We searched the Cochrane Central Register of ran- We, therefore, focused on cognitive dysfunction and domised controlled trials (RCTs) (1800-2009), Medline behavioural disturbances which were frequently rated (1966-2009), Embase (1966-2009) and three Chinese as the most worrisome adverse event of phenobarbital databases; VIP (1989-2009), CNKI (1979-20), CBM (1978- and usually assessed by measuring scales in original 2009), using “epilepsy”, “seizure”, “phenobarbital”, studies. However, since the scales used in different “phenobarbitone”, “anticonvulsant” and “anticonvul- studies varied, data could not be combined and thus sive agent”. We performed an independent search a descriptive analysis was performed to assess the for major congenital malformation using “pregnancy”, cognitive and behavioural effect of phenobarbital. “prenatal exposure delayed effects”, “abnormalities”, “teratogens”, “congenital defect”, “congenital malformation”, “birth defect” and “dysmorph”. Language Table 1. Classification of nervous system adverse was restricted to English and Chinese. The reference events. lists of relevant publications returned by the above searches were examined. Classification Description Affecting vigilance Somnolence

Study selection criteria Affecting brain stem and Dizziness/Vertigo vestibulo-cerebellar Diplopia We selected the trials that met each of the following system Nystagmus criteria: Blurred vision – RCTs, double-blind or open-label, performed in Ataxia patients with partial or generalised epilepsy. There Affecting motor system Chorea and dystonia was no restriction on the age of patients. Prospec- Tremor tive cohort studies performed in women with epilepsy

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Side effects of phenobarbital

Table 2. Outcome of quality assessment of randomized controlled trials.

Study ID Sequence Allocation Blinding Incomplete Selective Other potential generation concealment outcome data outcome threats to validity reporting

Mattson et al., 1985 U U Y Y U U

Mitchell and Chavez, UU YNYU 1987

Vining et al., 1987 U U Y Y Y U

Meador et al., 1990 U U Y Y Y U

Feksi et al., 1991 Y U U Y Y Y

Heller et al., 1995 Y Y U Y Y Y

Thilothammal et al., YU YYYY 1996

de Silva et al., 1996 U N N N Y N

Chen et al., 1996 Y U Y Y Y Y

Pal et al., 1998 Y Y Y Y Y Y

Banu et al., 2007 Y Y Y N Y Y

The quality assessment criteria was based the Cochrane collaboration’s “Risk of bias” tool. Y (yes) indicates a low risk of bias, N (no) indicates a high risk of bias and U (unclear) indicates insufﬁcient information to permit judgement of “yes” or “no”.

Major congenital malformations were defined as struc- of AEs, we proceeded as follows: first, we identified tural abnormalities with surgical, medical, or cosmetic all AEs which had been included in our outcome mea- importance (Tomson et al., 2007). Minor malforma- sures from the AE reporting tables of included studies; tions, not included in most published malformation second, for each study, the number of patients com- rate data, were not considered. Major malformation plaining of AEs and the total number of patients were was categorised into nine broad classes according to extracted. We included all studies which were per- organs and systems affected: nervous system, eye, formed with phenobarbital even though some AEs ear, face and neck, circulatory system, respiratory were not observed. Since AEs may not have been con- system, digestive system, genital organs, urinary sys- sidered as such in some trials, there was a potential tem, musculoskeletal system, and other syndromes underestimation of AEs. For cross-over studies, data such as Smith-Lemli-Opitz syndrome and chromoso- was extracted from all periods as a whole, when wash- mal abnormalities. out period was assessed to be long enough.

Data analysis Quality assessment Statistical analysis was undertaken following the guidelines of the Handbook of the Cochrane Col- The quality of RCTs and cross-over studies was laboration 5.0. Related risk for dichotomous data was assessed based on the following aspects: sequence calculated using the random-effects model in Review generation, allocation concealment, blinding, incom- Manager 5.0. Heterogeneity between trials was calcu- plete outcome data, selective outcome data and other lated using the Chi square test and was considered to potential threats to validity (Wells et al., 2008; Higgins be heterogeneous when p≤0.1. I2 values of no more and Green, 2009). The quality of prospective cohort than 25%, 26% to 74% and no less than 75% were studies was judged by the Newcastle-Ottawa quality considered as “low”, “moderate” and “high” hetero- assessment scale. geneity, respectively. We considered associations to be statistically signiﬁcant at p<0.05. A descriptive analysis Data collection was considered for the assessment of congenital and behavioural disturbance, as scales implemented varied Standardised data collection approach among original studies. A sensitivity analysis was per- The characteristics of each study, all participants and formed for the study design in which only randomised interventions used were extracted. For the collection controlled parallel trials were included.

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L.-L. Zhang, et al. tem within the y of study being directly - - - - - Adequacy of follow-up of cohorts . * Was follow-up long enough for outcomes to occur - - Assessment of outcome - - - - - Comparability of cohorts on the basis of design or analysis - -- Demonst- ration that outcome of interest was not present at start of study Outcome of quality assessment of observational studies Ascertain- ment of exposure Table 3. Selection of the non- exposed cohort Representativeness of the exposed cohort - ., et al ., 1991 ., 1992 ., 1994 ., 1997 ., 1999 ., 1999 ., 2001 2006 Study IDvan der Pol Selectionet al Lindhout et al Tanganelli and Regesta, 1992 Waters et al ComparabilitySamrén et al Canger et al OutcomeKaneko et al Holmes et al Burja Total Score The quality assessment criteria was based on the Newcastle-Ottawa Quality Scale for Cohort Studies. A study was awarded a maximum of one star for each i * selection and exposure categories. Aproportional maximum to of the two number stars of was stars. given for comparability. The number of stars represents the quality of study; the qualit

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Results characteristics of included studies are shown in appendix 1 and 2.

Description of studies Quality of included studies The literature search yielded 2,722 and 2,230 cita- Among eleven experimental studies (table 2 ) only tions for congenital malformation and other AEs, six (Feksi et al., 1991; Thilothammal et al., 1996; Chen respectively. After screening, nine prospective cohort et al., 1996; Heller et al., 1995; Pal et al., 1998; Banu et al., studies were included for analysis of congenital 2007) described sequence generation, of which only malformation (van der Pol et al., 1991; Lindhout et al., three (Heller et al., 1995; Pal et al., 1998; Banu et al., 2007) 1992; Waters et al., 1994; Samrén et al., 1997; Tanganelli conducted allocation concealment. Blinding was not and Regesta, 1992; Canger et al., 1999; Kaneko et al., performed in three studies (de Silva et al., 1996; Feksi 1999; Holmes et al., 2001; Burja et al., 2006) and eleven et al., 1991; Heller et al., 1995). In the study of de Silva randomised trials were included for the analysis of et al. (1996), enrolment to the phenobarbital arm was other AEs (Mattson et al., 1985; Mitchell and Chavez, terminated due to drug-related adverse effects, after 1987; Vining et al., 1987; Meador et al., 1990; Feksi randomising only 10 children to this drug.This early ter- et al., 1991; Heller et al., 1995; Thilothammal et al., 1996; mination may be a source of potential threat to validity. de Silva et al., 1996; Chen et al., 1996; Pal et al., 1998; Among the observational studies (table 3), a lack of Banu et al., 2007). comparability between cohorts and no description of Two cross-over trials were included (Vining et al., 1987; subjects lost to follow-up were two factors which lim- Meador et al., 1990). In the trial of Vining et al. (1987), ited the quality of observational studies. The main the wash-out period between two six-month treatment reason was that for all included prospective cohort periods was one month. In the trial of Meador et al. studies, women exposed to AEDs were considered (1990), no exact wash-out period was reported but as part of the “exposed cohort” and women without the authors mentioned that at the beginning of each AED treatment or healthy women were considered as phase, subjects were tapered off their pre-existing part of the “non-exposed cohort”, thus the baseline medication and were started on gradually increasing was compared between two cohorts as a whole and doses of the drug for that treatment phase. Addition- failed to report the comparability between different ally, all cognitive tests in the trial of Meador et al. were AED treatment groups. Likely, lost to follow-up in each performed at the end of each three-month treatment AED treatment group were not reported in most stud- phase. ies although the follow-up of cohorts was reported as a Of the twenty studies, 13 were from developed coun- whole. In addition, although sample size was balanced tries, and seven from developing countries. Most of between experimental and control groups in all RCTs, them were carried out in a single centre (12/20) and had this was not the case for most of the observational stud- limited sample size. Only one prospective cohort study ies (Lindhout et al., 1992; Tanganelli and Regesta, 1992; (Samrén et al., 1997) and one clinical trial (Mattson Samrén et al., 1997; Canger et al., 1999; Kaneko et al., et al., 1985) had a sample size of more than 500. The 1999; Burja et al., 2006).

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Outcomes 1.23 (95% CI: 0.99-1.53), favouring carbamazepine but without statistical significance (p=0.07). Total withdrawal (figure 1) Phenobarbital vs phenytoin. Data comparing the total Phenobarbital vs valproic acid. Total withdrawal infor- withdrawal rate between phenobarbital and phenytoin mation was available for 159 individuals in two trials. was available in three studies, including 404 indivi- The common estimated risk ratio was 1.85 (95% CI: duals. The common estimated risk ratio was 1.20 (95% 0.77-4.41), favouring valproic acid but without statistical CI: 0.94-1.52), favouring phenytoin but without statisti- significance (p=0.17). cal significance (p=0.14). Phenobarbital vs carbamazepine. Four studies, Conclusion. No significant difference was shown including 651 participants, reported total withdrawal between phenobarbital and other AEDs with respect information. The common estimated risk ratio was to total withdrawal rate.

PB Other AED Risk ratio Risk ratio Study or subgroup EventsTotal Events Total Weight M-H. Random, 95% CI M-H. Random, 95% CI 1.1.1 PB vs VPA Thilothammal 1996 8516 52 69.3% 1.36 [0.51 , 3.64] Vining 1987 7282 28 30.7% 3.50 [0.80, 15.40] Subtotal (95% CI) 79 80 100.0% 1.85 [0.77, 4.41] Total events 15 8 Heterogeneity : Tau2=0.04; Chi2=1.10, df=1 (p=0.30); I2=9% Test for overall effect : Z=1.38 (p=0.17)

1.1.2 PB vs CBZ Banu 2007 14 54 9 54 8.8% 1,56 [0.74, 3.29] Feksi 1991 27 150 26 152 20.5% 1.05 [0.65, 1.72] Mattson 1985 56 101 45 101 62.9% 1.24 [0.94, 1.65] Mitchell 1987 10 22 6 17 7.9% 1.29 [0.58, 2.84] Subtotal (95% CI) 327 324 100.0% 1.23 [0.99, 1.53] Total events 107 86 Heterogeneity : Tau2=0.00; Chi2=0.79, df=3 (p=0.85); I2=0% Test for overall effect : Z=1.83 (p=0.07)

1.1.3 PB vs PHT Mattson 1985 56 101 48 110 75.6% 1.27 [0.97, 1.67] Pal 1998 16 47 14 47 16.3% 1.14 [0.63, 2.07] Thilothammal 1996 8 51 10 48 8.1% 0.75 [0.32, 1.75] Subtotal (95% CI) 199 205 100,0% 1.20 [0.94, 1,52] Total events 80 72 Heterogeneity : Tau2=0.00; Chi2=1.41, df=2 (p=0.50); I2=0% Test for overall effect : Z=1.47 (p=0.14)

0.01 0.1 1 10 100 Favours PB Favours other AED

Figure 1. Total withdrawal; PB vs VPA, CBZ, PHT.

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ADR-related withdrawal (ﬁgure 2) Phenobarbital vs phenytoin. ADR-related withdrawal Phenobarbital vs valproic acid. ADR-related with- information was available for 490 individuals in four drawal data was available for 234 individuals in three trials. Phenobarbital was more likely to be withdrawn trials. The common estimated risk ratio was 7.64 (95% because of ADR than phenytoin with an estimated CI: 3.17-18.42), favouring valproic acid (p<0.00001). common risk ratio of 2.75 (95% CI: 0.94-8.09). How- Phenobarbital vs carbamazepine. ADR-related with- ever, there was evidence of quantitative heterogeneity drawal information was available for 832 individuals between trials (chi2=15.68, p=0.001). in six trials. The common estimated risk ratio was Conclusion. Phenobarbital appeared to be associated 1.50 (95% CI: 0.72-3.10), favouring carbamazepine with a higher rate of ADR-related withdrawal com- (p=0.28). However, there was evidence of quan- pared to valproic acid, carbamazepine or phenytoin, titative heterogeneity between trials (chi2=15.72, however, signiﬁcant heterogeneity existed between p=0.008). original trials.

PB Other AED Risk ratio Risk ratio Study or subgroup EventsTotal Events Total Weight M-H. Random, 95% CI M-H. Random, 95% CI 2.1.1 PB vs VPA Heller 1995 13 58 3 61 46.5% 4.56 [1.37, 15.17] Silva 1996 6 10 2 49 38.6% 14.70 [3.45, 62.58] Vining 19875 28 0 28 15.0% 11.00 [0.64, 189.96] Subtotal (95% CI) 96138 100.0% 7.64 [3.17, 18.42] Total events 24 5 Heterogeneity : Tau2=0.00; Chi2=1.59, df=1 (p=0.45); I2=0% Test for overall effect : Z=4.53 (p < 0.00001)

2.1.2 PB vs CBZ Banu 20070 541 54 4.3% 0.33 [0.01, 8.01] Feksi 1991 5 150 8 150 17.5% 0.63 [0.21, 1.87] Heller 1995 13 58 7 61 20.9% 1.95 [0.84, 4.55] Mattson 1985 52 101 42 101 28.2% 1.24 [0.92, 1.67] Mitchell 1987 4 22 4 17 15.7% 0.77 [0.23, 2.65] Silva 1996 610 2 54 13.3% 16.20 [3.80, 69.14] Subtotal (95% CI) 395 437 100.0% 1.50 [0.72, 3.10] Total events 80 64 Heterogeneity : Tau2=0.47; Chi2=15.72, df=5 (p=0.008); I2=68% Test for overall effect : Z=1.08 (p=0.28)

2.1.3 PB vs PHT Heller 1995 13 58 2 63 18.0% 7.06 [1.66, 29.96] Mattson 1985 52 101 42 110 38.1% 1.20 [0.90, 1.61] Pal 1998 447 3 47 18.1% 1.33 [0.32, 5.63] Silva 1996 610 5 54 25.7% 6.48 [2.44, 17.20] Subtotal (95% CI) 216 274 100.0% 2.75 [0.94, 8.09] Total events 75 57 Heterogeneity : Tau2=0.91; Chi2=15.68, df=3 (p=0.001); I2=81% Test for overall effect : Z=1.84 (p=0.07)

0.01 0.1 1 10 100 Favours PB Favours other AED

Figure 2. ADR-related withdrawal; PB vs VPA, CBZ, PHT.

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Nervous system AEs (figure 3) bamazepine without statistical significance (p=0.64). Phenobarbital vs valproic acid. Data of nervous sys- There was evidence of moderate heterogeneity tem AEs were available for 333 individuals in four trials. between studies for this outcome (chi2=4.07, p=0.13, However, the data from one trial was not considered I2=51%). (Thilothammal et al., 1996) because nervous system Phenobarbital vs phenytoin. Four independent trials AEs occurred in neither the phenobarbital group nor including 472 patients compared nervous system the valproic acid group. The common estimated risk AEs between phenobarbital and phenytoin treatment ratio was 1.41 (95% CI: 0.28-8.53). However, there was groups. However, moderate heterogeneity was shown evidence of quantitative heterogeneity between trials between trials (chi2=7.51, p=0.06). The common esti- (chi2=6.65, p=0.04). mated risk ratio was 0.54 (95% CI: 0.11-2.65), favouring Phenobarbital vs carbamazepine. Three indepen- phenobarbital without statistical significance (p=0.45). dent studies including 385 individuals compared Conclusion. There was no evidence that phenobar- nervous system AEs between phenobarbital and carba- bital was more likely to induce nervous system AEs, mazepine treatment groups. The common estimated compared to valproic acid, carbamazepine or pheny- risk ratio was 1.28 (95% CI: 0.46-3.60), favouring car- toin.

PB Other AED Risk ratio Risk ratio Study or subgroup EventsTotal Events Total Weight M-H. Random, 95% CI M-H. Random, 95% CI 3.1.1 PB vs VPA Heller 1995 6 58 2 61 35.4% 3.16 [0.66, 15.01] Silva 1996 110 1 49 14.8% 4.90 [0.33, 71.97] Thilothammal 1996 004851 Not estimable Vining 1987 3928 28 49.8% 0.33 [0.10, 1.10] Subtotal (95% CI) 147 186 100.0% 1.41 [0.23, 8.53] Total events 10 12 Heterogeneity : Tau2=1.71; Chi2=6.65, df=5 (p=0.04); I2=70% Test for overall effect : Z=0.37 (p=0.71)

3.1.2 PB vs CBZ Heller 1995 658 3 61 27.5% 2.10 [0.55, 8.02] Mattson 1985 24101 33 101 63.1% 0.73 [0.46, 1.14] Silva 1996 110 1 54 9.4% 5.40 [0.37, 79.43] Subtotal (95% CI) 169 216 100.0% 1.28 [0.46, 3.60] Total events 31 37 Heterogeneity : Tau2=0.43; Chi2=4.07, df=2 (p=0.13); I2=51% Test for overall effect : Z=2.47 (p=0.64)

3.1.3 PB vs PHT Mattson 1985 24101 30 110 69.0% 0.87 [0.55, 1.39] Pal 1998 047 1 47 7.7% 0.33 [0.01, 7.98] Silva 1996 110 2 54 13.6% 2.70 [0.27, 27.03] Thilothammal 1996 051 13 52 9.7% 0.04 [0.00, 0.62] Subtotal (95% CI) 209 263 100.0% 0.54 [0.11, 2.65] Total events 25 46 Heterogeneity : Tau2=1.50; Chi2=7.51, df=3 (p=0.06); I2=60% Test for overall effect : Z=0.76 (p=0.45)

0.01 0.1 1 10 100 Favours PB Favours other AED

Figure 3. Nervous system AEs; PB vs VPA, CBZ, PHT.

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Major congenital malformation(ﬁgure 4) (95% CI: 0.32-1.06), favouring phenobarbital but with- Phenobarbital vs valproic acid. Malformation infor- out statistical signiﬁcance (p=0.08). mation was available for 683 offspring in six trials. Phenobarbital vs carbamazepine. Major congenital In one trial, no malformation was reported (Burja et malformation data was available from 10 studies, al., 2006). The common estimated risk ratio was 0.58 accounting for 1148 offspring. The common estimated

PB Other AED Risk ratio Risk ratio Study or subgroup EventsTotal Events Total Weight M-H. Random, 95% CI M-H. Random, 95% CI 4.1.1 PB vs VPA Burja 2006 01 02 Not estimable Canger 1999 4 83 8 44 25.6% 0.27 [0.08, 0.83] Kaneko 1999 4 79 9 81 25.9% 0.46 [0.15, 1.42] Lindhout 1992 1265667.6% 0.51 [0.06, 4.14] Samren 1997 5 48 16 184 36.8% 1.20 [0.46, 3.11] Tanganelli 1992 3630 64.1% 0.77 [0.04, 13.35] Subtotal (95% CI) 300 383 100.0% 0.58 [0.32, 1.06] Total events 17 38 Heterogeneity : Tau2=0.03; Chi2=4.26, df=4 (p=0.37); I2=6% Test for overall effect : Z=1.77 (p=0.08)

4.1.2 PB vs CBZ Burja 2006 01 2193.5% 2.00 [0.14, 28.76] Canger 1999 4 83 12 113 20.5% 0.45 [0.15, 1.36] Holmes 2001 3 64 3 58 10.1% 0.91 [0.19, 4.31] Kaneko 1999 4 79 9 158 18.7% 0.89 [0.28, 2.80] Lindhout 1992 1 26 5 50 5.6% 0.38 [0.05, 3.12] Pol 1991 1 12 1 11 3.5% 0.92 [0.06, 12.95] Samren 1997 5 48 22 280 28.9% 1.33 [0.53, 3.33] Tanganelli 1992 3 63 0 6 3.0% 0.77 [0.04, 13.35] Ven dar Pol 1991 1 12 1 11 3.5% 0.92 [0.06, 12.95] Waters 1994 221033 2.8% 7.73 [0.39, 153.45] Subtotal (95% CI) 409 739 100.0% 0.91 [0.55, 1.49] Total events 24 55 Heterogeneity : Tau2=0.00; Chi2=5.17, df=9 (p=0.82); I2=0% Test for overall effect : Z=0.39 (p=0.69)

4.1.3 PB vs PHT Canger 1999 4 83 3 31 16.3% 0.50 [0.12, 2.10] Holmes 2001 3 64 3 87 13.7% 1.36 [0.28, 6.52] Kaneko 1999 4 79 12 132 28.1% 0.56 [0.19, 1.67] Lindhout 1992 1 26 1 17 4.6% 0.65 [0.04, 9.76] Samren 1997 5 48 9 141 31.0% 1.63 [0.58, 4.63] Waters 1994 2 21 1 28 6.2% 2.67 [0.26, 27.49] Subtotal (95% CI) 321 436 100.0% 0.96 [0.54, 1.71] Total events 19 29 Heterogeneity : Tau2=0.00; Chi2=3.75, df=5 (p=0.59); I2=0% Test for overall effect : Z=0.14 (p=0.89)

0.01 0.1 1 10 100 Favours PB Favours other AED

Figure 4. Major congenital malformation; PB vs VPA, CBZ, PHT.

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risk ratio was 0.91 (95% CI: 0.55-1.49), favouring pheno- Table 4. Major congenital malformation reported in barbital but without statistical significance (p=0.69). included prospective cohort studies. Phenobarbital vs phenytoin. Six independent studies including 757 offspring compared major congenital Organs and systems Congenital malformations malformation between phenobarbital and phenytoin treatment groups. The common estimated risk ratio Nervous system Meningomvelocele was 0.96 (95% CI: 0.54-1.71), favouring phenobarbital, Spina bifida but without statistical significance (p=0.89). Hydrocephalus Conclusion. Phenobarbital would appear to be a bet- Vertebral anomalies ter choice of drug compared to valproic acid, in terms Anencelphaly of second generation teratogenicity.No difference was reported between phenobarbital and carbamazepine Eye, ear, face and Facial malformation or phenytoin treatments (table 4). neck Cleft lip and/or palate

Circulatory system Patent ductus arteriosus Cognitive dysfunction and behavioural Ventricular septal defect(VSD) disturbance Heart malformation Hypoplasia of the nitral valve According to our search strategy, six clinical trials were Multiple ventricular septal defects included and are described below in chronological Single ventricle order. Large cavernous hemangioma on 1) Mitchell and Chavez (1987) compared the cog- leg nitive and behavioural function of 33 children with Interatrial defect partial onset seizures randomised to either pheno- Fallot’s tetralogy barbital or carbamazepine. Cognitive tests included the Weschler Intelligence Scale for Children-Revised Respiratory system Lung cyst (WISC-R) and the Raven’s Colored Progressive Matrics for children over the age of six, and the McCarthy Digestive system Oesophageal atresia Scale of Children’s Abilities for children aged three to Pyloric stenosis six years. A behaviour questionnaire was conducted by a psychologist. There were no significant dif- Urinary system Urogenital malformation ferences between phenobarbital and carbamazepine Penile htpospadias with regards to the effect on cognitive or behavioural Hydronephrosis function, either at six-month or 12-month follow-up (p<0.05). Genital organs - 2) Vining et al. (1987) used a randomised, double- blind, cross-over design with 28 subjects over six Musculoskeletal Dysplasia of hips months to investigate the cognitive side effects of system Hip dislocation phenobarbital and valproic acid. Twenty one children Gastroschisis completed the study. The WISC-R and another 11 neu- Inguinal hernia ropsychological function tests were used for cognitive Diaphragmatic hernia function assessment, while behavioural patterns were Umbilical hernias assessed by the Burk’s Behavior Rating Scales. For Omphalocele most measures, there were no differences between the Deformity of the foot two drugs. Statistically significant differences (p<0.01) Club foot were seen for four items, all of which favoured val- Multiple terminal transverse limb proic acid. There was a tendency towards better defects cognitive function in children who received valproic Arthrogryposis acid. Skeletal malformation 3) Meador et al. (1990) investigated the cognitive effect of phenobarbital, phenytoin and carbamazepine Other heterotaxia in a randomised double-blind, triple cross-over trial Smith-Lemli-Opitz syndrome with 21 patients over three months. Separate analyses of covariance using % anticonvulsant blood levels Chromosomal Down syndrome (% ABLs) and seizure frequency were performed for abnormalities each of eight cognitive tests. The only significant

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effect was for the Digit Symbol test in which perfor- Discussion mance with phenobarbital was worse when covaried ≤ for % ABLs (F[2,27]=3.89; p 0.03) or seizure frequency Difficulties in describing AEs between studies (F[2,27]=3.93; p≤0.03). 4) Chen et al. (1996) investigated cognitive side effects There were many factors that made it difficult to draw of AEDs in children using the WISC-R. Of 76 included comparisons between AED adverse effects among subjects, 25 were allocated to phenobarbital, 26 to car- studies. In particular, the lack of standardised descrip- bamazepine and 25 to valproic acid. There were no tions of adverse events and the fact that objective significant differences in any neuropsychological tests quantifiable measures and severity of most complaints among the three groups at any stage. Although chil- were not considered in reports. Furthermore, the dren in the phenobarbital group showed a slight and variation in methods for data collecting also made the sustained decrease in intelligence quotient (IQ) values comparison of AED adverse effects inaccurate. after six and 12 months of treatment, these values were not statistically significant. Strength of the evidence 5) Pal et al. (1998) undertook a randomised comparison of phenobarbital and phenytoin to assess The duration of follow-up varied between trials, rang- the behavioural effect of the two AEDs. Ninety-four ing from 12 months (Vining et al., 1987, Feksi et al., 1991) children were randomly allocated to treatment with to 91 months (Heller et al., 1995), which might cause phenobarbital (n=47) or phenytoin (n=47). Behavioural detection bias. However, since AED adverse events side effects were assessed by the Conners Parent Rat- usually occur in the first months (Wang et al., 2006; ing Scale for children aged six and older, and by the Nimaga et al., 2002), the difference in follow-up dura- preschool Behaviour Screening Questionnaire (BSQ) tion had limited influence on the results of this review. for those aged two to five years, after 12 months of For the meta-analysis, we included trials performed treatment or treatment withdrawal. The odds ratio for on both children and adults. Age may therefore have behavioural problems (phenobarbital vs. phenytoin) been a cause of heterogeneity. However, when we per- was 0.51 (95% CI: 0.16-1.59). There was no excess in formed a subgroup analysis according to age of study parental reports of side effects for phenobarbital. participants, heterogeneity still existed in most com- 6) Banu et al. (2007) conducted a randomised con- parisons, although the number of trials became limited trolled single centre trial to compare the behavioural especially in the adult group. Thus, we did not present side effects associated with phenobarbital and carba- the results from subgroup analysis. mazepine. Side effects were compared in 85 children. Reports on malformation rates were based on four The Bayley Scale was used for those aged above two prospective observational studies. Women enrolled years and the Richman behavioural assessment ques- in these studies were a diverse group. Three stud- tionnaire for those aged two to three years. Behaviour ies (Lindhout et al., 1992; Tanganelli and Regesta, function was assessed after 12 months of treatment 1992; Kaneko et al., 1999) included pregnant women or at drug withdrawal. The children had increased with epilepsy who received AED treatment, while behavioural problems, which were deemed unaccept- one study (Holmes et al., 2001) enrolled women able in four (one in the phenobarbital group and three who had taken AEDs no matter they were epileptic in the carbamazepine group). The authors concluded or not. However, clinical indications for using AEDs that there was no excess in behavioural side effects include not only epilepsy but also disorders such with phenobarbital in children with epilepsy. as migraine and pain syndromes (Lateef and Nelson, 2007). Thus, epilepsy may become a confounding fac- tor in this review. In addition, most studies failed to account for potential confounders such as socioeco- Sensitivity analysis nomic status and type and severity of the underlying To examine whether the results were sensitive to study condition, which themselves may cause adverse foetal design, we excluded two cross-over trials (Vining et al., outcomes. 1987; Meador et al., 1990) and one randomised parallel trial (de Silva et al., 1996) in which no further Comparison with previous reviews participants were assigned phenobarbital following the ascertainment that six of the first ten participants Some previous reviews have investigated the safety of experienced unacceptable side effects. No difference phenobarbital, but most have focused on only spe- was identified apart from a decline in heterogeneity cific side effects. The review of Taylor et al. (2003) between phenobarbital and carbamazepine in ADR- suggests that phenobarbital was significantly more related withdrawal when the study of de Silva et al. likely to be withdrawn than phenytoin, with an esti- (1996) was excluded (Chi2=3.81, I2=0%). mated common risk ratio of 1.62 (95% CI: 1.22-2.14).

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However, there was evidence of quantitative hetero- effects of AEDs have been studied under a variety of geneity between the trials (chi2=9.34, p=0.009). The scales for the assessment of cognitive impairment. The study of Tudur Smith et al. (2003) indicated that pheno- lack of criteria for scale selection makes it difficult to barbital is less tolerated than carbamazepine (hazard compare or combine data from different trials. A crite- ratio 1.63, 95% CI: 1.23-2.15). Naghme et al. (2004) rion for the selection of scales in assessing cognitive reviewed the adverse effects of phenobarbital on function in epileptic patients is in need. maternal and foetal outcomes in pregnant women with epilepsy. No difference of cognitive function Disclosure. was found between children with uterus exposure This study was funded by the Science and Technology Project of to phenobarbital and the general population. How- Sichuan, China (2010ZR0016). ever, a larger proportion of poor achievers among None of the authors has any conflict of interest to disclose. the phenobarbital-exposed group was found when compared with the carbamazepine-exposed group. Safety of phenobarbital has also been investigated in observational studies, especially in some develop- References ing countries. In an open label trial in rural areas of Mali (Nimaga et al., 2002), an excellent compliance was Aronson JK. Meyler’s side effects of drugs: The international achieved among 80% patients treated with phenobar- encyclopedia of adverse drug reactions and interactions bital. Minor side effects were frequently observed at (15th edition). Vol. 5. Elsevier Inc, 2006: 274-300. the beginning of treatment but they did not continue. Banu SH, Jahan M, Koli UK, Ferdousi S, Khan NZ, Neville B. In a hospital clinic in Nigeria (Sykes, 2002), 344 chil- Side effects of Phenobarbital and randomised controlled trial dren with epilepsy were treated with phenobarbital, carbamazepine in childhood epilepsy, BMJ 2007; 334: 1207-12. of whom only two discontinued because of intolera- Burja S, Rakovec-Felser Z, Treiber M, Hajdinjak D, Gajsek- ble side effects. In a prospective study conducted in Marchetti M. The frequency of neonatal morbidity after rural China (Wang et al., 2006), medication was well exposure to antiepileptic drugs in utero: a retrospec- tolerated and reported adverse events were mild. No tive population-based study. Wien Klin Wochenschr 2006; obvious cognitive or behavioural impact was found. 118: 12-6. Other neurotoxic effects also became less severe as Canger R, Battino D, Canevini MP, et al. Malformations in off- time went on. Overall, previous studies have reported spring of women with epilepsy: a prospective study. Epilepsia similar findings to this review, that is, no evidence sug- 1999; 40: 1231-6. gesting that phenobarbital is associated with a higher Chen YJ, Kang WM, So WC. Comparison of antiepileptic risk of adverse events. drugs on cognitive fun ction in newly diagnosed epileptic children: A psychometric and neurophysiological study. Implications for practice Epilepsia 1996; 37: 81-6. de Silva M, MacArdle B, McGowan M, et al. Randomised com- Although phenobarbital appears to be more comparative monotherapy trial of phenobarbitone, phenytoin, monly associated with a higher withdrawal rate, no carbamazepine, or sodium valproate for newly diagnosed statistically significant difference was found for most childhood epilepsy. Lancet 1996; 347: 709-13. domains of adverse events between phenobarbital and Feksi AT, Kaamugisha J, Sander JW, Gatiti S, Shorvon SD. the other three AEDs. Studies to date suggest there Comprehensive primary health care antiepileptic drug treat- is no difference in major malformation rate between ment programme in rural and semi-urban Kenya. Lancet phenobarbital and the other three AEDs. Hence, we 1991; 337: 406-9. come to the conclusion that phenobarbital should not Heller AJ, Chesterman P, Elwes RD, et al. Phenobarbi- be cited as an AED with a high risk of side effects, tone, phenytoin, carbamazepine or sodium valproate for based on current studies. However, it is important for newly diagnosed adult epilepsy: a randomized comparative clinicians to evaluate the benefits and risks of pheno- monotherapy trial. J Neurol Neurosur Ps 1995; 58: 44-50. barbital administration to child-bearing women before Higgins JPT, Green S. Cochrane Handbook for Systematic making a final recommendation. Reviews of Interventions Version 5.0.1. The Cochrane Collab oration 2009. http://www.cochrane-handbook.org. Implications for research Holmes LB, Harvey EA, Coull BA, et al. The teratogenicity of anticonvulsant drugs. New Engl J Med 2001; 344: 1132-8. One explanation for the higher withdrawal rate in the phenobarbital group is that clinicians were biased Kale R. The treatment gap. Epilepsia 2002; 43: 31-3. towards withdrawing phenobarbital in unblinded Kaneko S, Battino D, Andermann E, et al. Congenital studies. Blinding, therefore, should be performed malformations due to antiepileptic drugs. Epilepsy Res in future pragmatic studies. Furthermore, cognitive 1999; 33: 145-58.

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Kwan P, Brodie MJ. Phenobarbital for the treatment of Taylor S, Tudur Smith C, Williamson PR, et al. Phe- epilepsy in the 21st century: a critical review. Epilepsia nobarbitone versus phenytoin monotherapy for partial 2004; 45: 1141-9. onset seizures and generalized onset tonic-clonic seizures, Cochrane Database Syst Rev 2003; Issue 2. Art. No: Lateef TM, Nelson KB. In utero exposure to antiepileptic CD002217.DOI:10.1002/14651858.CD00217. drugs: teratogenicity and neonatal morbidity. Pediatric Neu- rol 2007; 7: 133-8. Thilothammal N, Banu K, Ratnam RS. Comparison of phenobarbitone, phenytoin with sodium valproate: randomized, Lindhout D, Meinardi H, Meijer JW, Nau H. Antiepileptic double-blind study. Indian Pediatr 1996; 3: 549-55. drugs and teratogenesis in two consective cohorts: Changes in prescription policy perelleled by changes in pattern of Tomson T, Battino D, French J, et al. Antiepileptic drug malformations. Neurology 1992; 42: 94-110. exposure and major congenital malformations: the role of pregnancy registries. Epilepsy & Behavior 2007; 11: 277-82. Mattson RH, Cramer JA, Collins JF, et al. Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in Tudur Smith C, Marson AG, Williamson PR. Carbamazepine partial and secondarily generalized tonic-clonic seizures.N versus phenobarbitone monotherapy for epilepsy. Cochrane Engl J Med 1985b; 313: 145-51. Database of Syst Rev 2003; Issue 1. Art. No: CD001904. DOI: 10.1002/14651858 CD001904 Meador KJ, Loring DW, Huh K, Gallagher BB, King DW. Comparative cognitive effects of anticonvulsants. Neurology van der Pol MC, Hadders-Algra M, Huisjes HJ, Touwen BC. 1990; 40: 391-4. Antiepileptic medication in pregnancy: late effects on the children’s central nervous system development. Am J Obstet Mitchell WG, Chavez JM. Carbamazepine versus pheno- Gynecol 1991; 164: 121-8. barbital for partial onset seizures in children. Epilepsia 1987; 28: 56-60. Vining EPG, Mellits ED, Dorsen MM, et al. Psychologic and behavioral effects of anti epileptic drugs in children: a Muba CK, Ngugi AK, Newton CR, Carter JA. The epilepsy treat- double-blind comparison between phenobarbital and val- ment gap in developing countries: A systematic review of proic acid. Pediatrics 1987; 80: 165-74. the magnitude, causes, and intervention strategies. Epilepsia Wang WZ, Wu JZ, Ma GY, et al. Efﬁcacy assessment of phe- 2008; 49: 1491-503. nobarbital in epilepsy: a large community-based intervention Naghme A, Smith T, Vinten C, et al. Common antiepilep- trial in rural China. Lancet Neurol 2006; 5: 46-52. tic drugs in pregnancy in women with epilepsy. Cochrane Waters CH, Belai Y, Gott PS, Shen P, De Giorgio CM. Out- Database of Systematic Rev 2004; Issue 3. Art. No: CD004848. comes of pregnancy associated with antiepileptic drugs. Arch DOI:10.1002/14651858.CD004848. Neurol 1994; 51: 250-3. Nimaga K, Desplats D, Doumbo O, et al. Treatment with phe- Wells GA, Shea B, O’Connell D, et al. The Newcastle-Ottawa nobarbital and monitoring of epileptic patients in rural Mali. Scale (NOS) for assessing the quality of nonrandomised Bull World Health Organ 2002; 80: 532-7. studies in meta-analyses. Ottawa health research institution. Pal DK, Das T, Chaudhury G, Johnson AL, Neville BG. 2008; http://www.ohri.ca/programs/clinical_epidemiology/ Randomised controlled trial to assess acceptability of phe- oxford.htm. nobarbital for childhood epilepsy in rural India. Lancet WHO. Initiative of support to people with epilepsy. WHO, 1998; 351: 19-23. Geneva; 1990. Samrén EB, van Duijn CM, Koch S, et al. Maternal use WHO. Epilepsy in the WHO Africa region, bridging the gap: of antiepileptic drugs and the risk of major congenital the global campaign against epilepsy “out of the shadows.” malformations: a joint European prospective study of human WHO, Geneva; 2004. http: //www.afro.who.int/mentalhealth/ teratogenesis associated with maternal epilepsy. Epilepsia epilepsy_african_brochure_1.pdf. 1997; 38: 981-90. WHO. Fact sheet N◦999. January 2009; ttp://www.who. Sykes RM. Epilepsy in children in Benin City, Nigeria. Ann int/mediacentre/factsheets/fs999/en/index.html. Trop Paediatr 2002; 22: 287-96. Zaccara G, Gangemi PF, Cincotta M. Central nervous system Tanganelli P, Regesta G. Epilepsy, pregnancy, and major birth adverse effects of new antiepileptic drugs. A meta-analysis of anomalies, Neurology 1992; 42: 89-93. placebo-controlled studies. Seizure 2008; 17: 405-21.

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L.-L. Zhang, et al. Geigy Funding calcu- lation Exact p values UYN3 UU Y Y YYNS None N Y N Ciba- NYN1 Intention to treat exact test; Chi square test square test square analysis t tests ; Mann- U tests square test test Statistical method Whitney 196/243 NS Y Y Y None No. patients 1.83-3 127/151 Fischer’s 1 23/39 Chi- 1 249/302 Chi- 7.58 0.75 15/21 NS N N N 2 1 21/28 Paired t (years) Follow-up Analysis Power Examination performed by physician Cognitive tests; Behaviour questionnaire Structured interview NS 0.08- Cognitive tests Examination performed by physician How AEs were recorded g/mL g/mL g/mL g/mL ␮ ␮ g/mL g/mL g/mL g/mL ␮ ␮ ␮ ␮ 10.6 ␮ ␮ 0.9 g/mL ± ␮ ± VPA: 15-50 mg/kg/d PHT: 5-8 mg/kg/d CBZ: 4-7 PB: 30-60 mg/d CBZ: 400-600 mg/d CBZ: 4-11 PHT: 10-20 mg/kg/d VPA: 27 CBZ: 6-12 PHT: 10-20 VPA: 50-100 PB: 15-40 PB: 20-40 mg/kg/d Daily dose/ Serum level 6-65 (mean 21) (mean 39) Mean 29 Age of patients (year) Sample size 1 151 C 4-12 PB:3-5 mg/kg/d 1 28 C 6-14.51 PB: 3.4 21 A 19-62 centres blinded Double- blinded Double- blinded Appendix 1. Characteristics of included randomised controlled trials. Type Blinding Duration over study over study USA RCTUSA Unblinded 10 RCT 622 NS A 18-70 NS 1 39 Self report 1-6 C 2-12 PB:15-24 198/622 Chi- India RCT Double- Georgia Cross- ., ., ., 1987USA Cross- ., 1995 UK RCT Unblinded 2 243 A ., 1991 Kenya RCT Unblinded 1 302 C and A et al et al et al et al et al ., 1996 Study-ID Country Study NoMattson of 1985 Mitchell and Chavez, 1987 Vining Meador Feksi Heller Thilothammal et al 1990

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Side effects of phenobarbital Funding calcu- lation vous system; A: adult; Exact p values YNY6 Intention to treat sample t tests; Mann-Whitney Paired sample t tests Statistical method 15/167 NS Y Y Y None No. patients ) NS 73/76 ANOVA N Y N 4 1 62/94 NS Y Y Y 5 1 17/108 Independent 7.33 (years) Follow-up Analysis Power Cognitive tests Self report; Behaviour questionnaire Behavioural tests NS 0.25- How AEs were recorded Continued g/mL g/mL g/mL ␮ g/mL g/mL ␮ ␮ ␮ ␮ g/mL g/mL ␮ ␮ CBZ: 5-12 VPA: 50-100 mg/kg/d PHT: 2.5-5.0 mg/kg/d CBZ: 16-20 mg/kg/d CBZ: 4-11 PHT: 10-20 VPA: 50-100 Daily dose/ Serum level Appendix 1. ( Age of patients (year) Sample size NS 76 C 7-15 PB: 15-40 1 108 C 2-15 PB: 3-4 mg/kg/d centres blinded blinded RCT Unblinded 1 94 C 2-18 PB: 1.5-3.0 Type Blinding Duration India UK RCT Unblinded 4 167 C 3-16 PB: 20-40 ., ., 1996 Taiwan RCT Single- ., 2007 Bangladesh RCT Double- et al ., 1998 Bengal, et al et al et al National Institute of Neurological CommunicationCiba-Geigy Disorders Corporation; and CIA Stroke. grant fromInternational the Clinical NIH/NIA. Epidemiology Network; BootsNational Pharmaceuticals; Science Reckitt Council and of Colman the ofWellcome Republic India; Trust of Rhone-Poulenc Research China. India. Training Fellowship; InternationalDepartment League for Against International Epilepsy. Development (DFID) administered through the British Council. Study-ID Country Study Node of Silva Chen Pal Banu 1996 1 2 3 4 5 6 RCT: randomised controlled trial; CBZ: carbamazepine; PHT: phenytoin; VPA: valproic acid; Y: yes; N: no; U: unclear; NS: not stated; CNS: central ner C: children.

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L.-L. Zhang, et al. Funding 4 Time of assessment At delivery 3 At delivery; 0.25-5.5 years NS NS 2 How MCMs were recorded by a physician and /or nurse by paediatric neurologist, paediatri- cian or gynaecolo- gist g/mL g/mL ␮ g/mL g/mL ␮ ␮ ␮ PHT: 3.3- 6.1 Daily dose /Serum level 6.4 VPA: 38-63 PB: 13.8- 17.8 Sample size Population setting A: clinical/hospital-based B: community-based 1 A 25 NS NS 6-13 years 1 centres Single- blinded NS 2 ANS 1NS 159 A 1NS CBZ: 4.0- A 5 78 A and B NS 82 NS 653 NS NS NS Examination None Examination Type Blinding cohort study cohort study cohort study cohort study cohort study Appendix 2. Outcome of quality assessment of included experimental studies. Netherlands Prospective Netherlands Prospective Italy Prospective USA Prospective Netherlands Prospective ., 1991 ., 1992 ., 1994 ., 1997 Study ID Country Studyvan der Pol et al Lindhout et al No of Tanganelli and Regesta, 1992 Waters et al Samrén et al

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Side effects of phenobarbital from the 5 Funding None and neurologists. At delivery; First 5 days 1 month Time of assessment At delivery; Day 5 First 5 days None 5 years None a How MCMs were recorded by a paedia- trician by a study physician by midwives, neonatal nurses, doctors Daily dose /Serum level VPA: 100 mg/d CBZ: 100 mg/d PHT: 50 mg/d ) Sample size Continued Population setting A: clinical/hospital-based B: community-based Appendix 2. ( 5 A 209 NS Examination centres NSNS 1 6 ASingle- Ablinded NS 271 1 450 NS A PB: 50 Examination mg/d 22 NS Examination Type Blinding cohort study cohort study Prospective cohort study cohort study Slovenia Prospective Italy Prospective Japan, Italy, Canada USA Prospective ., et al ., 1999 ., 1999 ., 2001 A grant from the Commissie Landelijk Epilepsie OnderzoekINationaal, Epilepsie Fonds and the International League Against Epilepsy through a grant Klingenstein Foundation. A grant from the Praeventiefonds. A grant from Ciba-Geigy, Sanoﬁ, andEducational Chemische grant Industrie from Katwijk. Ciba-Geigy. A grant for Scientiﬁc ResearchA from standardised the checklist Japanese based Ministry on of the Education; report A of grant the from Japanese the Association Japan of Epilepsy Obstetricians Research for Foundation. Maternal Welfare, performed by a team of obstetricians 2006 Study ID Country StudyCanger et al Kaneko et al No of Holmes et al Burja 1 2 3 4 5 a NS: not stated.

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