Risk of Major Congenital Malformations and Exposure to Antiseizure Medication Monotherapy.

Importance: Women with epilepsy (WWE) require treatment with antiseizure medications (ASMs) during pregnancy, which may be associated with an increased risk of major congenital malformations (MCMs) in their offspring. Objective: To investigate the prevalence of MCMs after prenatal exposure to 8 commonly used ASM monotherapies and changes in MCM prevalence over time. Design, Setting, and Participants: This was a prospective, observational, longitudinal cohort study conducted from June 1999 to October 2022. Since 1999, physicians from more than 40 countries enrolled ASM-treated WWE before pregnancy outcome was known and followed up their offspring until 1 year after birth. Participants aged 14 to 55 years who were exposed to 8 of the most frequently used ASMs during pregnancy were included in this study. Data were analyzed from April to September 2023. Exposure: Maternal use of ASMs at conception. Main Outcomes and Measures: MCMs were assessed 1 year after birth by a committee blinded to type of exposure. Teratogenic outcomes across exposures were compared by random-effects logistic regression adjusting for potential confounders and prognostic factors. Results: A total of 10 121 prospective pregnancies exposed to ASM monotherapy met eligibility criteria. Of those, 9840 were exposed to the 8 most frequently used ASMs. The 9840 pregnancies occurred in 8483 women (mean [range] age, 30.1 [14.1-55.2] years). MCMs occurred in 153 of 1549 pregnancies for valproate (9.9%; 95% CI, 8.5%-11.5%), 9 of 142 for phenytoin (6.3%; 95% CI, 3.4%-11.6%), 21 of 338 for phenobarbital (6.2%; 95% CI, 4.1%-9.3%), 121 of 2255 for carbamazepine (5.4%; 95% CI, 4.5%-6.4%), 10 of 204 for topiramate (4.9%; 95% CI, 2.7%-8.8%), 110 of 3584 for lamotrigine (3.1%; 95% CI, 2.5%-3.7%), 13 of 443 for oxcarbazepine (2.9%; 95% CI, 1.7%-5.0%), and 33 of 1325 for levetiracetam (2.5%; 95% CI, 1.8%-3.5%). For valproate, phenobarbital, and carbamazepine, there was a significant increase in the prevalence of MCMs associated with increasing dose of the ASM. Overall prevalence of MCMs decreased from 6.1% (153 of 2505) during the period 1998 to 2004 to 3.7% (76 of 2054) during the period 2015 to 2022. This decrease over time was significant in univariable logistic analysis but not after adjustment for changes in ASM exposure pattern. Conclusions and Relevance: Of all ASMs with meaningful data, the lowest prevalence of MCMs was observed in offspring exposed to levetiracetam, oxcarbazepine, and lamotrigine. Prevalence of MCMs was higher with phenytoin, valproate, carbamazepine, and phenobarbital, and dose dependent for the latter 3 ASMs. The shift in exposure pattern over time with a declining exposure to valproate and carbamazepine and greater use of lamotrigine and levetiracetam was associated with a 39% decline in prevalence of MCMs, a finding that has major public health implications.

The phenotypic presentation of adult individuals with SLC6A1-related neurodevelopmental disorders.

Introduction: SLC6A1 is one of the most common monogenic causes of epilepsy and is a well-established cause of neurodevelopmental disorders. SLC6A1-neurodevelopmental disorders have a consistent phenotype of mild to severe intellectual disability (ID), epilepsy, language delay and behavioral disorders. This phenotypic description is mainly based on knowledge from the pediatric population. Method: Here, we sought to describe patients with SLC6A1 variants and age above 18 years through the ascertainment of published and unpublished patients. Unpublished patients were ascertained through international collaborations, while previously published patients were collected through a literature search. Results: A total of 15 adult patients with SLC6A1 variants were included. 9/13 patients had moderate to severe ID (data not available in two). Epilepsy was prevalent (11/15) with seizure types such as absence, myoclonic, atonic, and tonic-clonic seizures. Epilepsy was refractory in 7/11, while four patients were seizure free with lamotrigine, valproate, or lamotrigine in combination with valproate. Language development was severely impaired in five patients. Behavioral disorders were reported in and mainly consisted of autism spectrum disorders and aggressive behavior. Schizophrenia was not reported in any of the patients. Discussion: The phenotype displayed in the adult patients presented here resembled that of the pediatric cohort with ID, epilepsy, and behavioral disturbances, indicating that the phenotype of SLC6A1-NDD is consistent over time. Seizures were refractory in >60% of the patients with epilepsy, indicating the lack of targeted treatment in SLC6A1-NDDs. With increased focus on repurposing drugs and on the development of new treatments, hope is that the outlook reflected here will change over time. ID appeared to be more severe in the adult patients, albeit this might reflect a recruitment bias, where only patients seen in specialized centers were included or it might be a feature of the natural history of SLC6A1-NDDs. This issue warrants to be explored in further studies in larger cohorts.

Local networks from different parts of the human cerebral cortex generate and share the same population dynamic.

A major goal of neuroscience is to reveal mechanisms supporting collaborative actions of neurons in local and larger-scale networks. However, no clear overall principle of operation has emerged despite decades-long experimental efforts. Here, we used an unbiased method to extract and identify the dynamics of local postsynaptic network states contained in the cortical field potential. Field potentials were recorded by depth electrodes targeting a wide selection of cortical regions during spontaneous activities, and sensory, motor, and cognitive experimental tasks. Despite different architectures and different activities, all local cortical networks generated the same type of dynamic confined to one region only of state space. Surprisingly, within this region, state trajectories expanded and contracted continuously during all brain activities and generated a single expansion followed by a contraction in a single trial. This behavior deviates from known attractors and attractor networks. The state-space contractions of particular subsets of brain regions cross-correlated during perceptive, motor, and cognitive tasks. Our results imply that the cortex does not need to change its dynamic to shift between different activities, making task-switching inherent in the dynamic of collective cortical operations. Our results provide a mathematically described general explanation of local and larger scale cortical dynamic.

Update on Sudden Unexpected Death in Epilepsy.

Persons with epilepsy (PWE) have an up to 34-fold increased risk of dying suddenly and unexpectedly compared with the general population. Despite being potentially preventable by optimal care, sudden unexpected death in epilepsy (SUDEP) is one of the most frequent causes of death in PWE, especially in children and younger adults. The incidence of SUDEP in the general epilepsy population is rather consistent at 1.2 to 1.3 per 1000 person-year across series. Several risk factors for SUDEP have been identified, but with focal-to-bilateral or generalized tonic-clonic seizures and sleeping alone as the most significant. Thereby, optimal care and nocturnal surveillance might decrease the risk of SUDEP. Finally, PWE wants information about SUDEP, and providing this information might increase adherence to the treatment and thereby good seizure control. This narrative review provides an update on SUDEP.

[Basic and advanced treatment of children and adults with epilepsy].

This review finds that, in children and adults with epilepsy, there are several treatment options. Multiple antiseizure medications are available and in case of drug-resistant epilepsy, a non-pharmacological approach is recommended, including epilepsy surgery, vagus nerve stimulation, or ketogenic diet treatment. The aim of the treatment is to avoid further seizures, but also to avoid negative cognitive, psychological, and social consequences of epilepsy.

Transcutaneous Vagal Nerve Stimulation in Treatment-Resistant Depression: A Feasibility Study.

BACKGROUND: Major depression (MD) contributes significantly to the global burden of disease with up to one-third of patients being treatment resistant. Therefore, the development of new treatment options for treatment-resistant depression (TRD) is needed. Vagus nerve stimulation (VNS) has shown mood improvements in patients with TRD. However, due to high costs related to the implantation and the invasive nature of VNS, an application with transcutaneous VNS (t-VNS) has been developed stimulating a vagal nerve branch in the earlobe (Arnold's nerve). A few studies with t-VNS in MD have shown a possible antidepressant effect, but feasibility is poorly described and patients with TRD have not been investigated. OBJECTIVES: As the full antidepressant effect of t-VNS takes months we wanted to assess feasibility and side effects of daily treatments. MATERIALS AND METHODS: Single-arm feasibility trial assessing compliance, usability, side effects, cognitive speed, and depression in a four-week period with a recommended t-VNS stimulation duration of four hours per day in patients with TRD. The primary outcome was compliance with 80% of the recommended daily treatment time. RESULTS: Compliance threshold was reached for 80.0% of the 20 included participants. Usability was acceptable. Side effects were few, mild or moderate, mostly as local effects at the contact point in the ear. The device was difficult to use for some participants. A statistically significant reduction in depression severity and an increase in cognitive speed were seen with unchanged suicidal ideation and sleep. CONCLUSIONS: We would recommend larger long-term randomized studies of t-VNS to access any antidepressant effect in TRD. The design of the device might be improved for higher usability.

Epilepsy-Related Mortality in Children and Young Adults in Denmark: A Nationwide Cohort Study.

BACKGROUND AND OBJECTIVES: Mortality is increased in epilepsy, but the important issue is that a proportion of epilepsy-related death is potentially preventable by optimized therapy and therefore needs to be identified. A new systematic classification of epilepsy-related mortality has been suggested to identify these preventable deaths. We applied this classification to an analysis of premature mortality in persons with epilepsy who were <50 years of age. METHODS: The study was a population-based retrospective cohort of all Danish citizens with and without epilepsy 1 to 49 years of age during 2007 to 2009. Information on all deaths was retrieved from the Danish Cause of Death Registry, autopsy reports, death certificates, and the Danish National Patient Registry. The primary cause of death in persons with epilepsy was evaluated independently by 3 neurologist, 1 neuro-pediatrician, and 2 cardiologists. In case of uncertainty, a pathologist was consulted. All deaths were classified as either epilepsy related or not epilepsy related, and the underlying causes or modes of death were compared between persons with and without epilepsy. RESULTS: During the study period, 700 deaths were identified in persons with epilepsy, and 440 (62.9%) of these were epilepsy related, 169 (38%) directly related to seizures and 181 (41%) due to an underlying neurologic disease. Sudden unexpected death in epilepsy accounted for 80% of deaths directly related to epilepsy. Aspiration pneumonia was the cause of death in 80% of cases indirectly related to epilepsy. Compared with the background population, persons with epilepsy had a nearly 4-fold increased all-cause mortality (adjusted mortality hazard ratio 3.95 [95% confidence interval [CI] 3.64-4.27], p < 0.0001) and a higher risk of dying of various underlying causes, including alcohol-related conditions (hazard ratio 2.91 [95% CI 2.23-3.80], p < 0.0001) and suicide (hazard ratio 2.10 [95% CI 1.18-3.73], p = 0.01). DISCUSSION: The newly proposed classification for mortality in persons with epilepsy was useful in an unselected nationwide cohort. It helped in classifying unnatural causes of death as epilepsy related or not and in identifying potentially preventable deaths. The leading causes of premature mortality in persons <50 years of age were related to epilepsy and were thus potentially preventable by good seizure control.

Feasibility of transcutaneous auricular vagus nerve stimulation in treatment of drug resistant epilepsy: A multicenter prospective study.

BACKGROUND: Transcutaneous auricular vagus nerve stimulation (ta-VNS) is a new non-invasive technique developed as treatment option for drug resistant epilepsy. A few studies have been carried out showing that the efficacy and tolerability of ta-VNS is comparable with traditional implanted VNS but the feasibility of the therapy has been poorly described. This study aimed to explore potential clinical benefits of ta-VNS and to evaluate adaptation, compliance, as well as the usability of the device from a service design perspective. METHODS: A prospective, multicenter, clinical, investigator-initiated trial was conducted using the NEMOS® ta-VNS device. After eight weeks baseline, all subjects started ta-VNS with individually adjusted currents for four hours per day for six-months (first endpoint) followed by optional 12 months follow-up (second endpoint). The primary outcome was six months retention rate of ta-VNS therapy. Secondary outcomes included the user retention rate at 12 months follow-up, compliance, changes in scores of psychometric measures. For the study of feasibility, a service design questionnaire on medical devices used in the home was developed. RESULTS: In total 37 subjects had been included in the study after 45 months where the study was prematurely terminated due to recruitment problems and due to a high drop-out rate. Twenty-two subjects (59 %) completed the first six months of the study and in total six subjects (16 %) completed the following 12 months follow-up. The reasons for discontinuation were a mixture of medical and practical issues of which the majority were related to a combination of both. Those, who managed to continue to use ta-VNS throughout the study, gave generally higher scores for the device usability and compatibility with lifestyle. The study turned out to be inadequately powered to reach any conclusion in terms of the clinical benefits of ta-VNS but present an example of difficulties that are encountered in conducting high-quality studies with digital devices. CONCLUSION: The feasibility of ta-VNS therapy showed to be relatively modest which is most likely due to practical usability issues and lifestyle fits. The results of this study stress the importance of generating data based on patients experiences at an early stage during the development phase and when designing clinical trials on medical devices that depend on patient's active participation and motivation.

Comparing Seizure-Related Death and Suicide in Younger Adults with Epilepsy.

Younger adults with epilepsy have an increased mortality. Some deaths are seizure-related, for example, sudden unexpected death in epilepsy (SUDEP), whereas others, for example, suicide, have multiple causes, including adverse effects of the treatment on mood. In this retrospective population-based study of all Danish persons with epilepsy aged 18 to 49 years during 2007 to 2009 we evaluated the risk of death from seizures and suicide. SUDEP comprised 82.7% of all seizure-related death. Younger adults with epilepsy had an 8.3-fold increased risk of death from seizure-related causes compared with suicide. This underpins the importance of effective seizure control in preventing premature death. ANN NEUROL 2021;90:983-987.

Sudden unexpected death in epilepsy in persons younger than 50 years: A retrospective nationwide cohort study in Denmark.

OBJECTIVE: Persons with epilepsy have an increased mortality including a high risk of sudden unexplained death (SUD), also referred to as sudden unexpected death in epilepsy (SUDEP). We aimed to evaluate the risk of SUDEP in comparison to other causes of death and the risk of SUD in persons with and without epilepsy. METHODS: We undertook a retrospective population-based cohort study of all Danish citizens with and without epilepsy aged 1-49 years during 2007-2009. All deaths in the population were evaluated, and all cases of SUD identified. Primary causes of death in persons with epilepsy were evaluated independently by three neurologists and one neuropediatrician, using the unified SUDEP criteria. RESULTS: The three most frequent causes of death in persons with epilepsy were cancer (2.38 per 1000 person-years), SUDEP (1.65 per 1000 person-years), and pneumonia (1.09 per 1000 person-years) compared with cancer (.17 per 1000 person-years), accident-related deaths (.14 per 1000 person-years), and cardiovascular disease (.09 per 1000 person-years) in persons without epilepsy. Considering definite, definite plus, and probable cases, the SUDEP incidence was .27 per 1000 person-years (95% confidence interval [CI] = .11-.64) in children aged 1-17 years and 1.21 per 1000 person-years (95% CI = .96-1.51) in adults aged 18-49 years. Adjusted for age and sex, persons with epilepsy younger than 50 years had a 10.8-fold (95% CI = 9.97-11.64, p < .0001) increased all-cause mortality and a 34.4-fold (95% CI = 23.57-50.28, p < .0001) increased risk of SUD compared with persons without epilepsy. SUDEP accounted for 23.3% of all SUD. SIGNIFICANCE: This nationwide study of all deaths in persons with epilepsy younger than 50 years found a lower SUDEP risk in children compared with adults, and that epilepsy was a major risk factor for SUD in the background population. This underlines the importance of addressing risk factors for SUDEP to prevent premature death.

Transcutaneous Vagus Nerve Stimulation in Patients With Severe Traumatic Brain Injury: A Feasibility Trial.

OBJECTIVES: Preclinical studies have shown that surgically implanted vagus nerve stimulation (VNS) promotes recovery of consciousness and cognitive function following experimental traumatic brain injury (TBI). The aim of this study is to report the feasibility and safety of a noninvasive transcutaneous vagus nerve stimulation (tVNS) in patients with persistent impairment of consciousness following severe TBI. MATERIALS AND METHODS: The feasibility of tVNS was evaluated in five patients presenting with diffuse axonal injury and reduced dominant EEG activity one month following severe TBI. tVNS was applied to the left cymba conchae of the external ear using a skin electrode four hours daily for eight weeks. Possible effects of tVNS on physiological parameters and general side effects were recorded. In addition, we report the rate of recovery using coma recovery scale revised (CRS-R). RESULTS: The tVNS regime of four hours daily for eight weeks was feasible and well tolerated with little side effects and no clinically relevant effects on physiological parameters. Three patients showed improvements (>3 points) in the CRS-R following eight weeks tVNS. CONCLUSION: We demonstrated that tVNS is a feasible and safe VNS strategy for patients following severe TBI. Controlled studies are needed to clarify whether tVNS has a potential to promote recovery of consciousness following severe TBI.

Why are antiepileptic drugs continued after successful epilepsy surgery in adults?

OBJECTIVE: Studies have demonstrated that a substantial number of patients continue treatment with antiepileptic drugs (AEDs) for many years after epilepsy surgery despite seizure freedom. In this study, we aimed to investigate why AED treatment is maintained in patients three and seven years after successful epilepsy surgery. To our knowledge, an analysis of this specific subgroup of completely seizure-free patients has not been done before. MATERIAL AND METHODS: Danish patients with medically refractory epilepsy and histopathologically proven hippocampal sclerosis operated between 1995 and 2014 who were reported seizure-free at one-year postsurgery were contacted by telephone in 2017 and retrospectively asked about the reasons to continue or taper AED at three and seven years after the operation. RESULTS: Fifty patients were completely seizure-free three years after the operation. Of those, 31 (62%) were still taking AEDs at three years, thereof 10 (20%) in the same dose and number and half of those on their own wish. At seven years, nine patients were still taking AEDs, two in unchanged number and dose, both on their own wish. Fear of relapse was the most common reason not to withdraw medication. Presurgery seizure frequency for patients taking AEDs at three and seven years was not higher than for those who had discontinued taking AEDs. CONCLUSIONS: A large portion of completely seizure-free patients still take AEDs even seven years after epilepsy surgery. This seems to be largely due to the patients' own wishes and fear of relapse, and unrelated to presurgery seizure frequency. Our results could aid in counseling patients on the decision to withdraw AEDs after successful epilepsy surgery.

Declining malformation rates with changed antiepileptic drug prescribing: An observational study.

OBJECTIVE: Changes in prescribing patterns of antiepileptic drugs (AEDs) in pregnant women with epilepsy would be expected to affect the risk of major congenital malformations (MCMs). To test this hypothesis, we analyzed data from an international pregnancy registry (EURAP). METHODS: EURAP is an observational prospective cohort study designed to determine the risk of MCMs after prenatal exposure to AEDs. The Cochrane-Armitage linear trend analysis was used to assess changes in AED treatment, prevalence of MCMs, and occurrence of generalized tonic-clonic seizures (GTCs) over 3 time periods: 2000-2005 (n = 4,760), 2006-2009 (n = 3,599), and 2010-2013 (n = 2,949). RESULTS: There were pronounced changes in the use of specific AEDs over time, with a decrease in the use of valproic acid and carbamazepine and an increase in the use of lamotrigine and levetiracetam. The prevalence of MCMs with monotherapy exposure decreased from 6.0% in 2000-2005 to 4.4% in 2010-2013. The change over time in MCM frequency after monotherapy exposure showed a significant linear trend in the crude analysis (p = 0.0087), which was no longer present after adjustment for changes in AED treatment (p = 0.9923). There was no indication of an increase over time in occurrence of GTCs during pregnancy. CONCLUSIONS: There have been major changes in AED prescription patterns over the years covered by the study. In parallel, we observed a significant 27% decrease in the prevalence of MCMs. The results of adjusting the trend analysis for MCMs for changes in AED treatment suggest that changes in prescription patterns played a major role in the reduction of teratogenic events.

Psychogenic nonepileptic seizures treated with psychotherapy: Long-term outcome on seizures and healthcare utilization.

Psychogenic nonepileptic seizures (PNES) are known to be associated with significant costs of healthcare services. Here, we report the impact of psychotherapy on behavior surrounding healthcare utilization and the potential economic benefits associated with long-term seizure control. METHODS: This retrospective study describes patients seen between 2010 and 2016 at the epilepsy clinic at Glostrup University Hospital in Denmark and offered a psychotherapeutic treatment program for PNES. Forty-two patients were interviewed about seizure outcome 12-24 months after psychotherapy, and the annual changes in healthcare utilization and associated costs of services provided in a period of 24 months before and up to 24 months after treatment were compared. RESULTS: At 12-month follow-up, 83% of the patients had achieved above 50% reduction in seizures. The 24-month pretreatment costs compared with the 24-month posttreatment costs directly associated with seizures dropped by 95.8%, and total healthcare costs were reduced by 63%. Estimation of annual savings from the program comes to 1060 € per patient. An association was found between seizure rate and number of healthcare contacts. CONCLUSION: This study adds to the evidence that psychotherapy is a cost-effective way of treating PNES. The economic benefits from this form of intervention appear not only to diminish costs directly associated with PNES, but also healthcare utilization in general.

Electromagnetic source imaging in presurgical workup of patients with epilepsy: A prospective study.

OBJECTIVE: To determine the diagnostic accuracy and clinical utility of electromagnetic source imaging (EMSI) in presurgical evaluation of patients with epilepsy. METHODS: We prospectively recorded magnetoencephalography (MEG) simultaneously with EEG and performed EMSI, comprising electric source imaging, magnetic source imaging, and analysis of combined MEG-EEG datasets, using 2 different software packages. As reference standard for irritative zone (IZ) and seizure onset zone (SOZ), we used intracranial recordings and for localization accuracy, outcome 1 year after operation. RESULTS: We included 141 consecutive patients. EMSI showed localized epileptiform discharges in 94 patients (67%). Most of the epileptiform discharge clusters (72%) were identified by both modalities, 15% only by EEG, and 14% only by MEG. Agreement was substantial between inverse solutions and moderate between software packages. EMSI provided new information that changed the management plan in 34% of the patients, and these changes were useful in 80%. Depending on the method, EMSI had a concordance of 53% to 89% with IZ and 35% to 73% with SOZ. Localization accuracy of EMSI was between 44% and 57%, which was not significantly different from MRI (49%-76%) and PET (54%-85%). Combined EMSI achieved significantly higher odds ratio compared to electric source imaging and magnetic source imaging. CONCLUSION: EMSI has accuracy similar to established imaging methods and provides clinically useful, new information in 34% of the patients. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that EMSI had a concordance of 53%-89% and 35%-73% (depending on analysis) for the localization of epileptic focus as compared with intracranial recordings-IZ and SOZ, respectively.

Antiepileptic drugs as prophylaxis for de novo brain tumour-related epilepsy after craniotomy: a systematic review and meta-analysis of harm and benefits.

OBJECTIVES: To investigate potential harm and benefits of antiepileptic drugs (AED) given prophylactically to prevent de novo brain tumour-related epilepsy after craniotomy. METHODS: Randomised controlled trials (RCT) and retrospective studies published before 27 November 2018 were included. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were applied. Eligible patients were diagnosed with a brain tumour, were seizure naïve and underwent craniotomy. The random effects model was used for quantitative synthesis. The analysis was adjusted for the confounding effect of including patients with a history of seizure prior to study inclusion. RESULTS: A total of 454 patients received prophylactic AED whereas 333 were allocated to placebo or no treatment. Two RCTs and four retrospective studies were identified. The OR was 1.09 (95% CI 0.7 to 1.8, p=0.7, I2=5.6%, χ2 p=0.5), indicating study consistency and no significant differences. An additional two RCTs and one retrospective study combined craniotomy and diagnostic biopsy, and were subgroup analysed-which supported no difference in odds for epilepsy. CONCLUSIONS: A prophylactic effect of AED could not be demonstrated (nor rejected statistically). Levetiracetam was associated with less adverse effects than phenytoin. The potential harm of AED was not balanced by the potential prophylactic benefit. This study suggests that prophylactic AED should not be administered to prevent brain tumour-related epilepsy after craniotomy.

Comparative risk of major congenital malformations with eight different antiepileptic drugs: a prospective cohort study of the EURAP registry.

BACKGROUND: Evidence for the comparative teratogenic risk of antiepileptic drugs is insufficient, particularly in relation to the dosage used. Therefore, we aimed to compare the occurrence of major congenital malformations following prenatal exposure to the eight most commonly used antiepileptic drugs in monotherapy. METHODS: We did a longitudinal, prospective cohort study based on the EURAP international registry. We included data from pregnancies in women who were exposed to antiepileptic drug monotherapy at conception, prospectively identified from 42 countries contributing to EURAP. Follow-up data were obtained after each trimester, at birth, and 1 year after birth. The primary objective was to compare the risk of major congenital malformations assessed at 1 year after birth in offspring exposed prenatally to one of eight commonly used antiepileptic drugs (carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, topiramate, and valproate) and, whenever a dose dependency was identified, to compare the risks at different dose ranges. Logistic regression was used to make direct comparisons between treatments after adjustment for potential confounders and prognostic factors. FINDINGS: Between June 20, 1999, and May 20, 2016, 7555 prospective pregnancies met the eligibility criteria. Of those eligible, 7355 pregnancies were exposed to one of the eight antiepileptic drugs for which the prevalence of major congenital malformations was 142 (10·3%) of 1381 pregnancies for valproate, 19 (6·5%) of 294 for phenobarbital, eight (6·4%) of 125 for phenytoin, 107 (5·5%) of 1957 for carbamazepine, six (3·9%) of 152 for topiramate, ten (3·0%) of 333 for oxcarbazepine, 74 (2·9%) of 2514 for lamotrigine, and 17 (2·8%) of 599 for levetiracetam. The prevalence of major congenital malformations increased with the dose at time of conception for carbamazepine (p=0·0140), lamotrigine (p=0·0145), phenobarbital (p=0·0390), and valproate (p<0·0001). After adjustment, multivariable analysis showed that the prevalence of major congenital malformations was significantly higher for all doses of carbamazepine and valproate as well as for phenobarbital at doses of more than 80 mg/day than for lamotrigine at doses of 325 mg/day or less. Valproate at doses of 650 mg/day or less was also associated with increased risk of major congenital malformations compared with levetiracetam at doses of 250-4000 mg/day (odds ratio [OR] 2·43, 95% CI 1·30-4·55; p=0·0069). Carbamazepine at doses of more than 700 mg/day was associated with increased risk of major congenital malformations compared with levetiracetam at doses of 250-4000 mg/day (OR 2·41, 95% CI 1·33-4·38; p=0·0055) and oxcarbazepine at doses of 75-4500 mg/day (2·37, 1·17-4·80; p=0·0169). INTERPRETATION: Different antiepileptic drugs and dosages have different teratogenic risks. Risks of major congenital malformation associated with lamotrigine, levetiracetam, and oxcarbazepine were within the range reported in the literature for offspring unexposed to antiepileptic drugs. These findings facilitate rational selection of these drugs, taking into account comparative risks associated with treatment alternatives. Data for topiramate and phenytoin should be interpreted cautiously because of the small number of exposures in this study. FUNDING: Bial, Eisai, GlaxoSmithKline, Janssen-Cilag, Novartis, Pfizer, Sanofi-Aventis, UCB, the Netherlands Epilepsy Foundation, and Stockholm County Council.