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.

Proposal for reference values for the developmental effects of valproate based on human data using a benchmark dose approach.

Following accidental release of valproate into ambient air during manufacture at a French production site in 2018, concerns were raised for inhabitants of the surrounding area. As no toxicological reference value (TRV) was available, the risks could not be properly assessed. The French Agency for Food, Environmental and Occupational Health and Safety (ANSES) was mandated to determine a TRV by inhalation to be used for risk assessment. Major congenital malformations (MCMs) in offsprings of mothers exposed to valproate during pregnancy have been reported in international scientific literature. As these adverse effects were the most sensitive effect identified, they were retained as the critical effect to be used for the TRV. The data from a robust registry on MCMs established by the International Registry of Antiepileptic Drugs and Pregnancy (EURAP) were modellized and support a strong DRR between the prevalence of MCMs in the fetus and in utero exposure. A benchmark dose (BMD) was then calculated as the dose that may trigger a 5% increase in this risk. A lower 95% confidence limit (BMD5%L95%) of 2.26 mg/kg/day, leading to an oral TRV of 0.08 mg/kg/day and a respiratory TRV of 0.26 mg.m-3 after applying an uncertainty factor of 30, was determined.

Breastfeeding while on treatment with antiseizure medications: a systematic review from the ILAE Women Task Force

We carried out a systematic review of published information on transfer of antiseizure medications (ASMs) into breastmilk, ASM serum concentrations in breastfed infants, and the wellbeing of infants breastfed by mothers on ASM treatment. Information was extracted from 85 relevant articles. No data on ASM levels in breastmilk or in breastfed infants was identified for cannabidiol, cenobamate, clobazam, eslicarbazepine-acetate, everolimus, felbamate, fenfluramine, retigabine, rufinamide, stiripentol, tiagabine, and vigabatrin. For ASMs, with available information on levels in breastfed infants, very low concentrations (in the order of 10% or less of maternal serum concentrations) were reported for carbamazepine, gabapentin, levetiracetam, oxcarbazepine, phenytoin, valproate, and clonazepam. Slightly higher levels (up to approximately 30% of maternal serum concentrations) have been observed with lamotrigine and topiramate, and in single case reports for brivaracetam, lacosamide, and perampanel. High infant levels (30% up to 100% of maternal serum concentrations) have been reported with ethosuximide, phenobarbital and zonisamide. Adverse infant effects during breastfeeding by mothers on ASMs appear to be rare regardless of the type of ASM, but systematic study is limited. Prospective long-term follow-up studies of developmental outcomes among children who have been breastfed by mothers taking ASMs are sparse and have mainly involved children whose mothers were taking carbamazepine, lamotrigine, levetiracetam, phenytoin or valproate as monotherapy while breastfeeding. Although these studies have not indicated poorer outcome among breastfed children compared with those who were not breastfed, further data on long-term outcomes are needed to draw firm conclusions. It is concluded that breastfeeding should in general be encouraged in women taking ASMs, given the well-established benefits of breastfeeding with regard to both short- and long-term infant health in the general population. Counselling needs to be individualized including information on the current knowledge regarding the woman's specific ASM treatment.

Global Survey of Guidelines for the Management of Epilepsy in Pregnancy: A report from the International League Against Epilepsy Task Force on Women and Pregnancy.

The ILAE Task Force on Women and Pregnancy conducted a survey among ILAE Chapters of their use of guidelines or recommendations for the management of women with epilepsy during pregnancy. A web-based questionnaire including 10 questions was sent to the 118 ILAE Chapters in December 2017 with repeated reminders until the end of February 2018. In total, 77 chapters (65%) responded, although not to all questions. Out of those responding, 68% reported having guidelines or recommendations, 34% of which were from 2014 or earlier. At least 20% of the guidelines did not include information on possible risk to cognitive development, information regarding specific risks with specific antiepileptic drugs, nor recommendations regarding selection of antiepileptic drugs. Among those responding to the question, 91% reported that recommendations were made regarding folate supplementation, but the recommended dose ranged from 0.4 mg/d to 4 mg/d or more; 34% did not include recommendations regarding drug level monitoring during pregnancy, and 19% did not include guidelines on breastfeeding. Our survey demonstrates that there is a need for the development of up-to-date, globally applicable recommendations for the management of epilepsy during pregnancy.

Antiepileptic Drug Teratogenicity and De Novo Genetic Variation Load.

OBJECTIVE: The mechanisms by which antiepileptic drugs (AEDs) cause birth defects (BDs) are unknown. Data suggest that AED-induced BDs may result from a genome-wide increase of de novo variants in the embryo, a mechanism that we investigated. METHODS: Whole exome sequencing data from child-parent trios were interrogated for de novo single-nucleotide variants/indels (dnSNVs/indels) and de novo copy number variants (dnCNVs). Generalized linear models were applied to assess de novo variant burdens in children exposed prenatally to AEDs (AED-exposed children) versus children without BDs not exposed prenatally to AEDs (AED-unexposed unaffected children), and AED-exposed children with BDs versus those without BDs, adjusting for confounders. Fisher exact test was used to compare categorical data. RESULTS: Sixty-seven child-parent trios were included: 10 with AED-exposed children with BDs, 46 with AED-exposed unaffected children, and 11 with AED-unexposed unaffected children. The dnSNV/indel burden did not differ between AED-exposed children and AED-unexposed unaffected children (median dnSNV/indel number/child [range] = 3 [0-7] vs 3 [1-5], p = 0.50). Among AED-exposed children, there were no significant differences between those with BDs and those unaffected. Likely deleterious dnSNVs/indels were detected in 9 of 67 (13%) children, none of whom had BDs. The proportion of cases harboring likely deleterious dnSNVs/indels did not differ significantly between AED-unexposed and AED-exposed children. The dnCNV burden was not associated with AED exposure or birth outcome. INTERPRETATION: Our study indicates that prenatal AED exposure does not increase the burden of de novo variants, and that this mechanism is not a major contributor to AED-induced BDs. These results can be incorporated in routine patient counseling. ANN NEUROL 2020;87:897-906.

Management of epilepsy in pregnancy: a report from the International League Against Epilepsy Task Force on Women and Pregnancy.

The risks associated with use of antiepileptic drugs during pregnancy are a major concern for all women with epilepsy with childbearing potential. These risks have to be balanced against foetal and maternal risks associated with uncontrolled seizures. This report from the International League Against Epilepsy Task Force on Women and Pregnancy aims to provide a summary of relevant data on these risks as a basis for expert opinion recommendations for the management of epilepsy in pregnancy. The report reviews data on maternal and foetal risks associated with seizures as well as teratogenic risks associated with antiepileptic drug exposure, including effects on intrauterine growth, major congenital malformations, and developmental and behavioural outcomes. The impact of pregnancy on seizure control and on the pharmacokinetics of antiepileptic drugs are also discussed. This information is used to discuss how treatment may be optimized before conception and further managed during pregnancy.

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.

Levetiracetam Pregnancy Registry: Final results and a review of the impact of registry methodology and definitions on the prevalence of major congenital malformations.

BACKGROUND: To evaluate pregnancy outcomes among women participating in the antiepileptic drug (AED) Levetiracetam Registry (LEV-Registry), and to review the impact of using two other registries' outcome definitions on the number of major congenital malformations (MCMs). METHODS: This US-based prospective study (ClinicalTrials.gov NCT00345475) was overseen by an independent Expert Panel. Women exposed to levetiracetam at any time during pregnancy enrolled, directly, or via their healthcare provider. The primary outcome was prevalence of MCMs, defined according to a modified version of the Metropolitan Atlanta Congenital Defects Program criteria. RESULTS: Of 491 women enrolled, 465 (94.7%) had a documented outcome. Most (92.3%) received levetiracetam for epilepsy; 323 (69.4%) as monotherapy and 142 (30.5%) as polytherapy. With three twin pregnancies, there were 468 outcomes-444 livebirths, 3 stillbirths, 19 miscarriages, and 2 terminations. Based on the MCM definition used by LEV-Registry, 46 infants among 444 livebirths had MCMs resulting in 10.4% (95% CI 7.7, 13.6) for overall prevalence, 9.4% (95% CI 6.4, 13.2) with monotherapy, and 12.6% (95% CI 7.5, 19.4) with polytherapy. When MCM reports were reviewed independently by staff at EURAP (International Registry of AEDs) and North American AED Pregnancy Registry according to their respective criteria, only 22 and 7 infants of the 46, respectively, were classified as having MCMs. CONCLUSION: The LEV-Registry Expert Panel did not find evidence suggestive of teratogenic association with prenatal exposure to levetiracetam. The substantial differences in which physical findings were considered MCMs highlight the major impact of pregnancy registry methodology on MCM prevalence estimates.

Perinatal outcome and healthcare resource utilization in the first year of life after antiepileptic exposure during pregnancy.

Healthcare administrative databases of Italy's Lombardy Region were analyzed with the aim to assess perinatal outcomes and healthcare resource utilization during the first year of life in infants exposed to antiepileptic drugs (AEDs) during pregnancy. Drug prescriptions dispensed in the 12 months before delivery to women, who delivered between 2005 and 2011, were analyzed. Neonates were classified as cases if exposed to AEDs, and each case was randomly matched to seven controls. No significant differences were observed in the risk of congenital malformations between 526 cases and 3682 controls except for valproic acid (odds ratio (OR): 2.29; 95% confidence interval (CI): 1.24-4.22) where cases were more likely to be small for gestational age (χ2 = 7.66; p = 0.006). Cases also had a higher probability than controls of needing at least one specialist visit in a child neuropsychiatry outpatient service (OR: 1.74; 95% CI: 1.22-2.49).

Teratogenicity of antiepileptic drugs.

PURPOSE OF REVIEW: We review data on the comparative teratogenicity of antiepileptic drugs (AEDs), focusing on major congenital malformations (MCMs), intrauterine growth restriction, impaired cognitive development, and behavioral adverse effects following prenatal exposure. RECENT FINDINGS: Prospective registries and meta-analyses have better defined the risk of MCMs in offspring exposed to individual AEDs at different dose levels. Valproate is the drug with the highest risk, whereas prevalence of MCMs is lowest with lamotrigine, levetiracetam, and oxcarbazepine. For valproate, phenobarbital, phenytoin, carbamazepine, and lamotrigine, the risk of MCMs is dose-dependent. Prenatal exposure to valproate has also been confirmed to cause an increased risk of cognitive impairments and autistic traits. In a population-based study, the risk of AED-induced autistic traits was attenuated by periconceptional folate supplementation. SUMMARY: The risk of adverse fetal effects differs in relation to the type of AED and for some AEDs also the daily dose. Although for MCMs the risk is primarily associated with the first trimester of gestation, influences on cognitive and behavioral development could extend throughout pregnancy. Available information now permits a more rational AED selection in women of childbearing potential, and evidence-based counseling on optimization of AED treatment before conception.

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.

Maternal and fetal outcomes associated with vagus nerve stimulation during pregnancy.

OBJECTIVE: To access the effect of vagus nerve stimulation (VNS) on the outcome of pregnancy. METHODS: We used the International Registry of Antiepileptic Drugs and Pregnancy (EURAP) and its network to search for women receiving adjunctive VNS during pregnancy. Data on maternal and fetal outcomes were extracted from the registry databases and outcomes were evaluated. RESULTS: Twenty-six pregnancies were identified in 25 women. All women were exposed to a relative high VNS stimulation level (mean duty cycle 18%, range 5%-51%). Most women had seizures during pregnancy and almost 70% were on antiepileptic drug (AED) polytherapy. The proportion of women with obstetrical interventions was 53.9% (95% confidence interval [CI] 33.4%-73.4%) which was higher compared to the EURAP average (48.2%; 95% CI 47.2%-49.1%). One infant (3.9%; 95% CI 0.1%-19.6%) was born with a major malformation (unilateral congenital glaucoma), which is within the range expected among offspring of AED-treated women. CONCLUSION: Although the present series of VNS-exposed pregnancies is the largest reported to date, the sample size is insufficient to draw any firm conclusions on the safety of VNS in pregnancy but the findings suggest an increased rate of obstetrical interventions, and no clear signal of VNS-related teratogenicity.

Withdrawal of valproic acid treatment during pregnancy and seizure outcome: Observations from EURAP.

Based on data from the EURAP observational International registry of antiepileptic drugs (AEDs) and pregnancy, we assessed changes in seizure control and subsequent AED changes in women who underwent attempts to withdraw valproic acid (VPA) during the first trimester of pregnancy. Applying Bayesian statistics, we compared seizure control in pregnancies where VPA was withdrawn (withdrawal group, n = 93), switched to another AED (switch group, n = 38), or maintained (maintained-therapy group, n = 1,588) during the first trimester. The probability of primarily or secondarily generalized tonic-clonic seizures (GTCS) was lower in the maintained-therapy group compared with the other two groups, both in the first trimester and for the entire duration of pregnancy. GTCS were twice as common during pregnancy in the withdrawal (33%) and switch groups (29%) compared with the maintained-treatment group (16%). Limitations in the data and study design do not allow to establish a cause-effect relationship between treatment changes and seizure outcome, but these observations provide a signal that withdrawal of, or switch from, VPA during the first trimester could lead to loss of seizure control, and highlight the need for a specifically designed prospective observational study.

Valproic acid after five decades of use in epilepsy: time to reconsider the indications of a time-honoured drug.

Since the serendipitous discovery of its anticonvulsant properties more than 50 years ago, valproic acid has become established as an effective broad-spectrum antiepileptic drug that is particularly useful for the management of generalised epilepsies, for which treatment alternatives are few. However, during the past few years increasing evidence has accumulated that intake of valproic acid during pregnancy is associated with a significant risk of dose-dependent teratogenic effects and impaired postnatal cognitive development in children. Because of these risks, valproic acid should not be used as a first-line drug in women of childbearing potential whenever equally or more effective alternative drugs are available-as in the case of focal epilepsy. In some generalised epilepsy syndromes, such as juvenile myoclonic epilepsy, valproic acid has better documented efficacy than alternative drugs and drug selection should be a shared decision between the clinician and the informed patient based on careful risk-benefit assessment.

Antiepileptic drugs and intrauterine death: A prospective observational study from EURAP.

OBJECTIVE: To compare the risk of spontaneous abortions and stillbirth associated with maternal use of different antiepileptic drugs (AEDs). METHODS: The EURAP registry is an observational international cohort study primarily designed to determine the risk of major congenital malformations (MCMs) after prenatal AED exposure. Using EURAP data, we prospectively monitored pregnancies exposed to the 6 most common AED monotherapies and to polytherapy. Intrauterine death (spontaneous abortion and stillbirth combined) was the primary endpoint. RESULTS: Of 7,055 pregnancies exposed to monotherapy with lamotrigine (n = 1,910), carbamazepine (n = 1,713), valproic acid (n = 1,171), levetiracetam (n = 324), oxcarbazepine (n = 262), or phenobarbital (n = 260), and to polytherapy (n = 1,415), 632 ended in intrauterine deaths (592 spontaneous abortions and 40 stillbirths). Rates of intrauterine death were similar across the different monotherapies (8.2%; 95% confidence interval [CI] 7.5%-8.9%), higher with polytherapy (12.1%; 95% CI 10.5%-13.9%), but showed no relationship with AED dose in monotherapy at conception. Multivariable analysis including 11 covariates in addition to the different AED exposures showed that the risk was greater with polytherapy vs monotherapy (risk ratio [RR] 1.38; 95% CI 1.14-1.66), parental history of MCMs (RR 1.92; 1.20-3.07), maternal age (RR 1.06; 1.04-1.07), and number of previous intrauterine deaths (RR 1.09; 1.00-1.19). The risk was greater with early enrollment and decreased with later gestational week at enrollment (RR 0.84; 0.82-0.86). CONCLUSIONS: The most important risk factors for intrauterine death in pregnancies of women with epilepsy include maternal exposure to AED polytherapy and the presence of MCMs in at least one of the parents.

Dose-dependent teratogenicity of valproate in mono- and polytherapy: an observational study.

OBJECTIVE: To assess the risk of major congenital malformations (MCMs) in association with maternal use of valproic acid (VPA) in monotherapy or adjunctive therapy, and its relationship with dose. METHODS: The analysis was based on prospectively acquired data from EURAP, a registry enrolling women treated with antiepileptic drugs (AEDs) in early pregnancy, in which the primary outcome is presence of MCMs at 1 year after birth. Exposure was defined as type and dose of AEDs at time of conception. A comparison was made among 3 exposure types: (1) VPA monotherapy (n = 1,224); (2) VPA combined with lamotrigine (LTG) (n = 159); and (3) VPA combined with another AED but not LTG (n = 205). RESULTS: The frequency of MCMs at 1 year after birth was 10.0% for VPA monotherapy, 11.3% for exposures to VPA and LTG, and 11.7% for exposures to VPA + another (non-LTG) AED. Regardless of exposure group, the frequency of MCMs increased with dose of VPA, being highest at doses ≥1,500 mg/d (24.0% for monotherapy, 31.0% for VPA + LTG, and 19.2% for VPA + other AEDs), and was similar across treatment groups at the lowest VPA dose level of <700 mg/d (5.9% for monotherapy, 7.0% for VPA + LTG, and 5.4% for VPA + other AEDs). CONCLUSIONS: The risk of MCMs associated with VPA exposure increases with increasing VPA dose, both in the presence and in the absence of one concomitant AED, and appears to be related primarily to the dose of VPA.

Major congenital malformations in children of women with epilepsy.

It has been long known that the risk of major congenital malformations is increased among children of mothers with epilepsy. This is mainly due to the teratogenic effects of antiepileptic drugs although other factors, such as genetically determined individual susceptibility, are likely to contribute. Recent large scale prospective epilepsy and pregnancy registries have indicated that the rate of major congenital malformations may be at most two-fold higher than expected with exposure in utero to the presently most frequently used antiepileptic drugs such as carbamazepine or lamotrigine. Higher rates are consistently reported with exposure to valproate. The risk of teratogenic effects appears to be dose dependent and the lowest effective dose should thus be established before pregnancy regardless of which antiepileptic drug the woman is taking. Major changes such as switches between drugs should be avoided when pregnancy is established.