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1.
Comparison of the relapse rates in seizure-free patients in whom antiepileptic therapy was discontinued and those in whom the therapy was continued: A meta-analysis.
Wang, J, Huang, P, Song, Z
Epilepsy & behavior : E&B. 2019;(Pt A):106577
Abstract
About 70% of patients with epilepsy can be seizure-free with an appropriate treatment. When the seizures are under control, discontinuation of the antiepileptic drugs (AEDs) can help avoid their side effects; however, it may increase the risk of relapse. Some studies have compared the relapse rates between patients in whom AEDs have been continued and those in whom AEDs have been discontinued. However, it is not clear whether AED discontinuation causes a higher seizure recurrence rate. This meta-analysis aimed mainly to determine whether the seizure recurrence rate was different between seizure-free patients in whom AEDs were continued and those in whom AEDs were discontinued. The I2 value was used for assessing the heterogeneity; the Mantel-Haenszel test was used to calculate the odds ratios (ORs) with 95% confidence intervals (CIs). Seven cohort studies and randomized controlled trials (RCTs) met the inclusion criteria. The study quality evaluation was performed respectively using the Newcastle-Ottawa Scale and the Jadad scale. A total of 1253 patients were included. The relapse rate was higher in patients in whom AEDs were discontinued than in those in whom the AED treatment was continued. Furthermore, we also compared the epilepsy recurrence rates after AED discontinuation between seizure-free patients who were on monotherapy with different AEDs (carbamazepine, phenytoin, sodium valproate, and phenobarbitone/primidone). Four studies and 625 patients were included in this analysis. The epilepsy recurrence rates did not significantly differ between the patients on different AED treatment.
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2.
Valproate decreases vitamin D levels in pediatric patients with epilepsy.
Xu, Z, Jing, X, Li, G, Sun, J, Guo, H, Hu, Y, Sun, F, Wen, X, Chen, F, Wang, T, et al
Seizure. 2019;:60-65
Abstract
PURPOSE To compare Vitamin D (Vit D) levels in children with epilepsy on valproate monotherapy with healthy controls. METHODS A meta-analysis performed on articles identified from PubMed and Web of Science online databases evaluated using National Institute of Health National Heart, Lung, and Blood Institute Study Quality Assessment Tools. Subgroup analyses and publication bias assessments were also performed. RESULTS Eleven publications were eligible based on inclusion/exclusion criteria for the meta-analysis. Results noted a decrease in the mean Vit D level in children with epilepsy on valproate monotherapy compared with healthy children with a Standard Mean Difference = -0.313 [-0.457, -0.169]. Cumulative meta-analysis showed progressive negative effect of valproate therapy on Vit D levels across time. Other antiepileptic medications caused a similar effect on Vit D status. There was no evidence of publication bias in the analyses. Type of study design and country of origin introduced heterogeneities into the meta-analyses. CONCLUSION This meta-analysis provides evidence that long-term therapy with valproate causes a decrease in Vit D levels in children. Therefore, in children with a seizure disorder on long-term valproate therapy, 25-OH-Vit D levels should be monitored and appropriate supplementation implemented if levels are deficient.
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3.
Effects of Second-Generation Antiepileptic Drugs Compared to First-Generation Antiepileptic Drugs on Bone Metabolism in Patients with Epilepsy: A Meta-Analysis.
Fu, J, Peng, L, Li, J, Tao, T, Chen, Y
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2019;(8):511-521
Abstract
We conducted this meta-analysis to evaluate effects of second-generation anti-epileptic drugs (AEDs; levetiracetam, lamotrigine) compared to first-generation AEDs (valproic acid, carbamazepine) on bone metabolism in epilepsy patients. PubMed, Web of Science, Clinical trials.gov, Wanfang, and China national knowledge infrastructure databases were searched. Ten trials were included. Results showed: (1) The overall SMD for changes of serum calcium, phosphorus, ALP, and PTH levels from baseline of LEV versus first-generation AEDs were 1.00 (95% CI=0.23-1.77, Z=2.56, p=0.01), 0.98 (95% CI=- 0.05 to 2.01, Z=1.86, p=0.06), - 1.17 (95% CI=- 2.08 to - 0.25, Z=2.50, p=0.01), 0.07 (95% CI=- 0.14 to 0.27, Z=0.63, p=0.53), respectively. (2) The overall SMD for changes of serum calcium, phosphorus, ALP, and PTH levels from baseline of LTG versus first-generation AEDs were -0.16 (95% CI=- 0.47 to 0.16, Z=0.99, p=0.32), -0.05 (95% CI=- 0.55 to 0.44, Z=0.22, p=0.83), 0.10 (95% CI=- 0.53 to 0.73, Z=0.31, p=0.75), -0.05 (95% CI=- 0.52 to 0.42, Z=0.22, p=0.83), respectively. Overall, our results indicate that compared to first-generation AEDs, LEV has less adverse effects on blood bone metabolism markers in epilepsy patients, while LTG does not. However, due to small number of included studies, our results warrant additional research.
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4.
Short-term and long-term efficacy of classical ketogenic diet and modified Atkins diet in children and adolescents with epilepsy: A systematic review and meta-analysis.
Rezaei, S, Abdurahman, AA, Saghazadeh, A, Badv, RS, Mahmoudi, M
Nutritional neuroscience. 2019;(5):317-334
Abstract
OBJECTIVES Classical ketogenic diet (KD) and modified Atkins diet (MAD) are two types of KD commonly used for the treatment of intractable epilepsy throughout the world. Studies have shown the efficacy of these diets. However, no systematic review and meta-analysis study has to date compared the efficacy of KD and MAD in a time trend. Therefore, the objectives of the present study were to compare the short-term and long-term efficacy of classical KD and MAD in children and adolescents with epilepsy and to determine the efficacy of classical KD and MAD at multiple time points and in a time trend. METHODS Main electronic literature databases, including MEDLINE/PubMed, Web of Science, Scopus, and EMBASE, were searched in November 2016. Rate difference and random effects model were used to compare the efficacy of the classical KD and MAD. RESULTS Overall, 70 studies were eligible for inclusion. Meta-analysis revealed a non-significant trend toward a higher efficacy of MAD at month-3 and month-6 (P > 0.05). In the classical KD group, the percentage of responder patients achieving ≥50% seizure reduction was 62, 60, 52, 42, and 46% at month-1, 3, 6, 12 and 24 and for the MAD group was 55, 47, 42, and 29% at month-1, 3, 6, and 12, respectively. DISCUSSION Classical KD does not differ substantially from MAD in ≥50% and ≥90% reduction of seizure frequency at month-3 and month-6. Overall, the number of patients achieving seizure freedom increases over time.
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5.
SCN1A rs3812718 polymorphism is associated with epilepsy: An updated meta-analysis.
Zhi, H, Wu, C, Yang, Z
Epilepsy research. 2018;:81-87
Abstract
To clarify the association between SCN1A rs3812718 polymorphism and epilepsy, we performed an updated meta-analysis. PubMed, Science Direct, Embase, Springer, Google Scholar, and Cochrane databases were searched before January 20, 2018. Odds ratios and 95% confidence intervals were used to assess the strength of associations. Finally, simply eight studies were included in this meta-analysis and all together recruited 7184 individuals, and they consisted of 3595 cases and 3589 controls. Based on the quality evaluation with the NOS, the overall quality of eight studies was scored from seven to eight which indicated good quality. A significant association between SCN1A rs3812718 polymorphism and the risk of epilepsy was detected in the homozygote comparison (OR = 1.64, 95% CI, 1.25-2.15, P = .001, P(BON) = 0.004), and dominant model (OR = 1.36, 95% CI, 1.08-1.72, P < .001, P(BON) < 0.001), but not in heterozygote comparison (OR = 1.22, 95% CI, 0.98-1.53, P = .003, P(BON) = 0.001), and recessive model (OR = 1.35, 95% CI, 1.22-1.49, P = .104, P(BON) = 0.104). In conclusion, our results suggest that SCN1A rs3812718 polymorphism is associated with the risk of epilepsy.
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6.
Methylenetetrahydrofolate reductase C677T polymorphism and susceptibility to epilepsy.
Rai, V, Kumar, P
Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2018;(12):2033-2041
Abstract
BACKGROUND Methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism was reported as risk factor for multiple diseases due to its role in conversion of homocysteine to methionine. The aim of the present meta-analysis was to find out the validity of association of C677T polymorphism with epilepsy susceptibility. METHODS Pubmed, Science Direct, Springer Link and Google Scholar, databases were searched for relevant studies up to January, 31, 2018. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were performed using five genetic models. All statistical analysis was done by MetaAnalyst and Mix programs. RESULTS Except recessive model, significant association was found between MTHFR C677T polymorphism and epilepsy risk in other four genetic models (T vs C: OR = 1.29, 95% CI = 1.08-1.52, p = 0.004; TT vs CC: OR = 1.48, 95% CI = 1.19-1.82, p = 0.0003; TT + CT vs CC: OR = 1.20, 95% CI = 1.05-1.38, p = 0.008; TT vs CT + CC: OR = 1.35, 95% CI = 1.11-1.62, p = 0.002). Similarly, in the subgroup analysis based on ethnicity, significant association was found in Asian (T vs C: OR = 1.85; 95% CI = 1.15-2.99; p = 0.03) and Caucasian populations (TT vs CC: OR = 1.38; 95% CI = 1.10-1.1.73; p = 0.005). No evidence of heterogeneity and publication bias was detected in present meta-analysis. CONCLUSION In conclusion, results of present meta-analysis suggested that 677T allele of MTHFR is significantly increases the epilepsy susceptibility.
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7.
Antiepileptic drug monotherapy for epilepsy: a network meta-analysis of individual participant data.
Nevitt, SJ, Sudell, M, Weston, J, Tudur Smith, C, Marson, AG
The Cochrane database of systematic reviews. 2017;(12):CD011412
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Abstract
BACKGROUND Epilepsy is a common neurological condition with a worldwide prevalence of around 1%. Approximately 60% to 70% of people with epilepsy will achieve a longer-term remission from seizures, and most achieve that remission shortly after starting antiepileptic drug treatment. Most people with epilepsy are treated with a single antiepileptic drug (monotherapy) and current guidelines from the National Institute for Health and Care Excellence (NICE) in the United Kingdom for adults and children recommend carbamazepine or lamotrigine as first-line treatment for partial onset seizures and sodium valproate for generalised onset seizures; however a range of other antiepileptic drug (AED) treatments are available, and evidence is needed regarding their comparative effectiveness in order to inform treatment choices. OBJECTIVES To compare the time to withdrawal of allocated treatment, remission and first seizure of 10 AEDs (carbamazepine, phenytoin, sodium valproate, phenobarbitone, oxcarbazepine, lamotrigine, gabapentin, topiramate, levetiracetam, zonisamide) currently used as monotherapy in children and adults with partial onset seizures (simple partial, complex partial or secondary generalised) or generalised tonic-clonic seizures with or without other generalised seizure types (absence, myoclonus). SEARCH METHODS We searched the following databases: Cochrane Epilepsy's Specialised Register, CENTRAL, MEDLINE and SCOPUS, and two clinical trials registers. We handsearched relevant journals and contacted pharmaceutical companies, original trial investigators, and experts in the field. The date of the most recent search was 27 July 2016. SELECTION CRITERIA We included randomised controlled trials of a monotherapy design in adults or children with partial onset seizures or generalised onset tonic-clonic seizures (with or without other generalised seizure types). DATA COLLECTION AND ANALYSIS This was an individual participant data (IPD) review and network meta-analysis. Our primary outcome was 'time to withdrawal of allocated treatment', and our secondary outcomes were 'time to achieve 12-month remission', 'time to achieve six-month remission', 'time to first seizure post-randomisation', and 'occurrence of adverse events'. We presented all time-to-event outcomes as Cox proportional hazard ratios (HRs) with 95% confidence intervals (CIs). We performed pairwise meta-analysis of head-to-head comparisons between drugs within trials to obtain 'direct' treatment effect estimates and we performed frequentist network meta-analysis to combine direct evidence with indirect evidence across the treatment network of 10 drugs. We investigated inconsistency between direct estimates and network meta-analysis via node splitting. Due to variability in methods and detail of reporting adverse events, we have not performed an analysis. We have provided a narrative summary of the most commonly reported adverse events. MAIN RESULTS IPD was provided for at least one outcome of this review for 12,391 out of a total of 17,961 eligible participants (69% of total data) from 36 out of the 77 eligible trials (47% of total trials). We could not include IPD from the remaining 41 trials in analysis for a variety of reasons, such as being unable to contact an author or sponsor to request data, data being lost or no longer available, cost and resources required to prepare data being prohibitive, or local authority or country-specific restrictions.We were able to calculate direct treatment effect estimates for between half and two thirds of comparisons across the outcomes of the review, however for many of the comparisons, data were contributed by only a single trial or by a small number of participants, so confidence intervals of estimates were wide.Network meta-analysis showed that for the primary outcome 'Time to withdrawal of allocated treatment,' for individuals with partial seizures; levetiracetam performed (statistically) significantly better than current first-line treatment carbamazepine and other current first-line treatment lamotrigine performed better than all other treatments (aside from levetiracetam); carbamazepine performed significantly better than gabapentin and phenobarbitone (high-quality evidence). For individuals with generalised onset seizures, first-line treatment sodium valproate performed significantly better than carbamazepine, topiramate and phenobarbitone (moderate- to high-quality evidence). Furthermore, for both partial and generalised onset seizures, the earliest licenced treatment, phenobarbitone seems to perform worse than all other treatments (moderate- to high-quality evidence).Network meta-analysis also showed that for secondary outcomes 'Time to 12-month remission of seizures' and 'Time to six-month remission of seizures,' few notable differences were shown for either partial or generalised seizure types (moderate- to high-quality evidence). For secondary outcome 'Time to first seizure,' for individuals with partial seizures; phenobarbitone performed significantly better than both current first-line treatments carbamazepine and lamotrigine; carbamazepine performed significantly better than sodium valproate, gabapentin and lamotrigine. Phenytoin also performed significantly better than lamotrigine (high-quality evidence). In general, the earliest licenced treatments (phenytoin and phenobarbitone) performed better than the other treatments for both seizure types (moderate- to high-quality evidence).Generally, direct evidence and network meta-analysis estimates (direct plus indirect evidence) were numerically similar and consistent with confidence intervals of effect sizes overlapping.The most commonly reported adverse events across all drugs were drowsiness/fatigue, headache or migraine, gastrointestinal disturbances, dizziness/faintness and rash or skin disorders. AUTHORS' CONCLUSIONS Overall, the high-quality evidence provided by this review supports current guidance (e.g. NICE) that carbamazepine and lamotrigine are suitable first-line treatments for individuals with partial onset seizures and also demonstrates that levetiracetam may be a suitable alternative. High-quality evidence from this review also supports the use of sodium valproate as the first-line treatment for individuals with generalised tonic-clonic seizures (with or without other generalised seizure types) and also demonstrates that lamotrigine and levetiracetam would be suitable alternatives to either of these first-line treatments, particularly for those of childbearing potential, for whom sodium valproate may not be an appropriate treatment option due to teratogenicity.
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8.
Antiepileptic drug monotherapy for epilepsy: a network meta-analysis of individual participant data.
Nevitt, SJ, Sudell, M, Weston, J, Tudur Smith, C, Marson, AG
The Cochrane database of systematic reviews. 2017;(6):CD011412
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Abstract
BACKGROUND Epilepsy is a common neurological condition with a worldwide prevalence of around 1%. Approximately 60% to 70% of people with epilepsy will achieve a longer-term remission from seizures, and most achieve that remission shortly after starting antiepileptic drug treatment. Most people with epilepsy are treated with a single antiepileptic drug (monotherapy) and current guidelines from the National Institute for Health and Care Excellence (NICE) in the United Kingdom for adults and children recommend carbamazepine or lamotrigine as first-line treatment for partial onset seizures and sodium valproate for generalised onset seizures; however a range of other antiepileptic drug (AED) treatments are available, and evidence is needed regarding their comparative effectiveness in order to inform treatment choices. OBJECTIVES To compare the time to withdrawal of allocated treatment, remission and first seizure of 10 AEDs (carbamazepine, phenytoin, sodium valproate, phenobarbitone, oxcarbazepine, lamotrigine, gabapentin, topiramate, levetiracetam, zonisamide) currently used as monotherapy in children and adults with partial onset seizures (simple partial, complex partial or secondary generalised) or generalised tonic-clonic seizures with or without other generalised seizure types (absence, myoclonus). SEARCH METHODS We searched the following databases: Cochrane Epilepsy's Specialised Register, CENTRAL, MEDLINE and SCOPUS, and two clinical trials registers. We handsearched relevant journals and contacted pharmaceutical companies, original trial investigators, and experts in the field. The date of the most recent search was 27 July 2016. SELECTION CRITERIA We included randomised controlled trials of a monotherapy design in adults or children with partial onset seizures or generalised onset tonic-clonic seizures (with or without other generalised seizure types). DATA COLLECTION AND ANALYSIS This was an individual participant data (IPD) review and network meta-analysis. Our primary outcome was 'time to withdrawal of allocated treatment', and our secondary outcomes were 'time to achieve 12-month remission', 'time to achieve six-month remission', 'time to first seizure post-randomisation', and 'occurrence of adverse events'. We presented all time-to-event outcomes as Cox proportional hazard ratios (HRs) with 95% confidence intervals (CIs). We performed pairwise meta-analysis of head-to-head comparisons between drugs within trials to obtain 'direct' treatment effect estimates and we performed frequentist network meta-analysis to combine direct evidence with indirect evidence across the treatment network of 10 drugs. We investigated inconsistency between direct estimates and network meta-analysis via node splitting. Due to variability in methods and detail of reporting adverse events, we have not performed an analysis. We have provided a narrative summary of the most commonly reported adverse events. MAIN RESULTS IPD was provided for at least one outcome of this review for 12,391 out of a total of 17,961 eligible participants (69% of total data) from 36 out of the 77 eligible trials (47% of total trials). We could not include IPD from the remaining 41 trials in analysis for a variety of reasons, such as being unable to contact an author or sponsor to request data, data being lost or no longer available, cost and resources required to prepare data being prohibitive, or local authority or country-specific restrictions.We were able to calculate direct treatment effect estimates for between half and two thirds of comparisons across the outcomes of the review, however for many of the comparisons, data were contributed by only a single trial or by a small number of participants, so confidence intervals of estimates were wide.Network meta-analysis showed that for the primary outcome 'Time to withdrawal of allocated treatment,' for individuals with partial seizures; levetiracetam performed (statistically) significantly better than both current first-line treatments carbamazepine and lamotrigine; lamotrigine performed better than all other treatments (aside from levetiracetam), and carbamazepine performed significantly better than gabapentin and phenobarbitone (high-quality evidence). For individuals with generalised onset seizures, first-line treatment sodium valproate performed significantly better than carbamazepine, topiramate and phenobarbitone (moderate- to high-quality evidence). Furthermore, for both partial and generalised onset seizures, the earliest licenced treatment, phenobarbitone seems to perform worse than all other treatments (moderate- to high-quality evidence).Network meta-analysis also showed that for secondary outcomes 'Time to 12-month remission of seizures' and 'Time to six-month remission of seizures,' few notable differences were shown for either partial or generalised seizure types (moderate- to high-quality evidence). For secondary outcome 'Time to first seizure,' for individuals with partial seizures; phenobarbitone performed significantly better than both current first-line treatments carbamazepine and lamotrigine; carbamazepine performed significantly better than sodium valproate, gabapentin and lamotrigine. Phenytoin also performed significantly better than lamotrigine (high-quality evidence). In general, the earliest licenced treatments (phenytoin and phenobarbitone) performed better than the other treatments for both seizure types (moderate- to high-quality evidence).Generally, direct evidence and network meta-analysis estimates (direct plus indirect evidence) were numerically similar and consistent with confidence intervals of effect sizes overlapping.The most commonly reported adverse events across all drugs were drowsiness/fatigue, headache or migraine, gastrointestinal disturbances, dizziness/faintness and rash or skin disorders. AUTHORS' CONCLUSIONS Overall, the high-quality evidence provided by this review supports current guidance (e.g. NICE) that carbamazepine and lamotrigine are suitable first-line treatments for individuals with partial onset seizures and also demonstrates that levetiracetam may be a suitable alternative. High-quality evidence from this review also supports the use of sodium valproate as the first-line treatment for individuals with generalised tonic-clonic seizures (with or without other generalised seizure types) and also demonstrates that lamotrigine and levetiracetam would be suitable alternatives to either of these first-line treatments, particularly for those of childbearing potential, for whom sodium valproate may not be an appropriate treatment option due to teratogenicity.
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9.
Comparative safety of antiepileptic drugs for neurological development in children exposed during pregnancy and breast feeding: a systematic review and network meta-analysis.
Veroniki, AA, Rios, P, Cogo, E, Straus, SE, Finkelstein, Y, Kealey, R, Reynen, E, Soobiah, C, Thavorn, K, Hutton, B, et al
BMJ open. 2017;(7):e017248
Abstract
OBJECTIVES Compare the safety of antiepileptic drugs (AEDs) on neurodevelopment of infants/children exposed in utero or during breast feeding. DESIGN AND SETTING Systematic review and Bayesian random-effects network meta-analysis (NMA). MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials were searched until 27 April 2017. Screening, data abstraction and quality appraisal were completed in duplicate by independent reviewers. PARTICIPANTS 29 cohort studies including 5100 infants/children. INTERVENTIONS Monotherapy and polytherapy AEDs including first-generation (carbamazepine, clobazam, clonazepam, ethosuximide, phenobarbital, phenytoin, primidone, valproate) and newer-generation (gabapentin, lamotrigine, levetiracetam, oxcarbazepine, topiramate, vigabatrin) AEDs. Epileptic women who did not receive AEDs during pregnancy or breast feeding served as the control group. PRIMARY AND SECONDARY OUTCOME MEASURES Cognitive developmental delay and autism/dyspraxia were primary outcomes. Attention-deficit hyperactivity disorder, language delay, neonatal seizures, psychomotor developmental delay and social impairment were secondary outcomes. RESULTS The NMA on cognitive developmental delay (11 cohort studies, 933 children, 18 treatments) suggested that among all AEDs only valproate was statistically significantly associated with more children experiencing cognitive developmental delay compared with control (OR=7.40, 95% credible interval (CrI) 3.00 to 18.46). The NMA on autism (5 cohort studies, 2551 children, 12 treatments) suggested that oxcarbazepine (OR 13.51, CrI 1.28 to 221.40), valproate (OR 17.29, 95% CrI 2.40 to 217.60), lamotrigine (OR 8.88, CrI 1.28 to 112.00) and lamotrigine+valproate (OR 132.70, CrI 7.41 to 3851.00) were associated with significantly greater odds of developing autism compared with control. The NMA on psychomotor developmental delay (11 cohort studies, 1145 children, 18 treatments) found that valproate (OR 4.16, CrI 2.04 to 8.75) and carbamazepine+phenobarbital+valproate (OR 19.12, CrI 1.49 to 337.50) were associated with significantly greater odds of psychomotor delay compared with control. CONCLUSIONS Valproate alone or combined with another AED is associated with the greatest odds of adverse neurodevelopmental outcomes compared with control. Oxcarbazepine and lamotrigine were associated with increased occurrence of autism. Counselling is advised for women considering pregnancy to tailor the safest regimen. TRIAL REGISTRATION NUMBER PROSPERO database (CRD42014008925).
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10.
Treatment for epilepsy in pregnancy: neurodevelopmental outcomes in the child.
Bromley, R, Weston, J, Adab, N, Greenhalgh, J, Sanniti, A, McKay, AJ, Tudur Smith, C, Marson, AG
The Cochrane database of systematic reviews. 2014;(10):CD010236
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Abstract
BACKGROUND Accumulating evidence suggests an association between prenatal exposure to antiepileptic drugs (AEDs) and increased risk of both physical anomalies and neurodevelopmental impairment. Neurodevelopmental impairment is characterised by either a specific deficit or a constellation of deficits across cognitive, motor and social skills and can be transient or continuous into adulthood. It is of paramount importance that these potential risks are identified, minimised and communicated clearly to women with epilepsy. OBJECTIVES To assess the effects of prenatal exposure to commonly prescribed AEDs on neurodevelopmental outcomes in the child and to assess the methodological quality of the evidence. SEARCH METHODS We searched the Cochrane Epilepsy Group Specialized Register (May 2014), Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2014, Issue 4), MEDLINE (via Ovid) (1946 to May 2014), EMBASE (May 2014), Pharmline (May 2014) and Reprotox (May 2014). No language restrictions were imposed. Conference abstracts from the last five years were reviewed along with reference lists from the included studies. SELECTION CRITERIA Prospective cohort controlled studies, cohort studies set within pregnancy registers and randomised controlled trials were selected for inclusion. Participants were women with epilepsy taking AED treatment; the two control groups were women without epilepsy and women with epilepsy who were not taking AEDs during pregnancy. DATA COLLECTION AND ANALYSIS Three authors (RB, JW and JG) independently selected studies for inclusion. Data extraction and risk of bias assessments were completed by five authors (RB, JW, AS, NA, AJM). The primary outcome was global cognitive functioning. Secondary outcomes included deficits in specific cognitive domains or prevalence of neurodevelopmental disorders. Due to substantial variation in study design and outcome reporting only limited data synthesis was possible. MAIN RESULTS Twenty-two prospective cohort studies were included and six registry based studies. Study quality varied. More recent studies tended to be larger and to report individual AED outcomes from blinded assessments, which indicate improved methodological quality.The developmental quotient (DQ) was lower in children exposed to carbamazepine (CBZ) (n = 50) than in children born to women without epilepsy (n = 79); mean difference (MD) of -5.58 (95% confidence interval (CI) -10.83 to -0.34, P = 0.04). The DQ of children exposed to CBZ (n = 163) was also lower compared to children of women with untreated epilepsy (n = 58) (MD -7.22, 95% CI -12.76 to - 1.67, P = 0.01). Further analysis using a random-effects model indicated that these results were due to variability within the studies and that there was no significant association with CBZ. The intelligence quotient (IQ) of older children exposed to CBZ (n = 150) was not lower than that of children born to women without epilepsy (n = 552) (MD -0.03, 95% CI -3.08 to 3.01, P = 0.98). Similarly, children exposed to CBZ (n = 163) were not poorer in terms of IQ in comparison to the children of women with untreated epilepsy (n = 87) (MD 1.84, 95% CI -2.13 to 5.80, P = 0.36). The DQ in children exposed to sodium valproate (VPA) (n = 123) was lower than the DQ in children of women with untreated epilepsy (n = 58) (MD -8.72, 95% -14.31 to -3.14, P = 0.002). The IQ of children exposed to VPA (n = 76) was lower than for children born to women without epilepsy (n = 552) (MD -8.94, 95% CI -11.96 to -5.92, P < 0.00001). Children exposed to VPA (n = 89) also had lower IQ than children born to women with untreated epilepsy (n = 87) (MD -8.17, 95% CI -12.80 to -3.55, P = 0.0005).In terms of drug comparisons, in younger children there was no significant difference in the DQ of children exposed to CBZ (n = 210) versus VPA (n=160) (MD 4.16, 95% CI -0.21 to 8.54, P = 0.06). However, the IQ of children exposed to VPA (n = 112) was significantly lower than for those exposed to CBZ (n = 191) (MD 8.69, 95% CI 5.51 to 11.87, P < 0.00001). The IQ of children exposed to CBZ (n = 78) versus lamotrigine (LTG) (n = 84) was not significantly different (MD -1.62, 95% CI -5.44 to 2.21, P = 0.41). There was no significant difference in the DQ of children exposed to CBZ (n = 172) versus phenytoin (PHT) (n = 87) (MD 3.02, 95% CI -2.41 to 8.46, P = 0.28). The IQ abilities of children exposed to CBZ (n = 75) were not different from the abilities of children exposed to PHT (n = 45) (MD -3.30, 95% CI -7.91 to 1.30, P = 0.16). IQ was significantly lower for children exposed to VPA (n = 74) versus LTG (n = 84) (MD -10.80, 95% CI -14.42 to -7.17, P < 0.00001). DQ was higher in children exposed to PHT (n = 80) versus VPA (n = 108) (MD 7.04, 95% CI 0.44 to 13.65, P = 0.04). Similarly IQ was higher in children exposed to PHT (n = 45) versus VPA (n = 61) (MD 9.25, 95% CI 4.78 to 13.72, P < 0.0001). A dose effect for VPA was reported in six studies, with higher doses (800 to 1000 mg daily or above) associated with a poorer cognitive outcome in the child. We identified no convincing evidence of a dose effect for CBZ, PHT or LTG. Studies not included in the meta-analysis were reported narratively, the majority of which supported the findings of the meta-analyses. AUTHORS' CONCLUSIONS The most important finding is the reduction in IQ in the VPA exposed group, which are sufficient to affect education and occupational outcomes in later life. However, for some women VPA is the most effective drug at controlling seizures. Informed treatment decisions require detailed counselling about these risks at treatment initiation and at pre-conceptual counselling. We have insufficient data about newer AEDs, some of which are commonly prescribed, and further research is required. Most women with epilepsy should continue their medication during pregnancy as uncontrolled seizures also carries a maternal risk.