Risk of Perinatal and Maternal Morbidity and Mortality Among Pregnant Women With Epilepsy.

Importance: Maternal epilepsy is associated with adverse pregnancy and neonatal outcomes. A better understanding of this condition and the associated risk of mortality and morbidity at the time of delivery could help reduce adverse outcomes. Objective: To determine the risk of severe maternal and perinatal morbidity and mortality among women with epilepsy. Design, Setting, Participants: This prospective population-based register study in Denmark, Finland, Iceland, Norway, and Sweden took place between January 1, 1996, and December 31, 2017. Data analysis was performed from August 2022 to November 2023. Participants included all singleton births at 22 weeks' gestation or longer. Births with missing or invalid information on birth weight or gestational length were excluded. The study team identified 4 511 267 deliveries, of which 4 475 984 were to women without epilepsy and 35 283 to mothers with epilepsy. Exposure: Maternal epilepsy diagnosis recorded before childbirth. Prenatal exposure to antiseizure medication (ASM), defined as any maternal prescription fills from conception to childbirth, was also examined. Main outcomes and measures: Composite severe maternal morbidity and mortality occurring in pregnancy or within 42 days postpartum and composite severe neonatal morbidity (eg, neonatal convulsions) and perinatal mortality (ie, stillbirths and deaths) during the first 28 days of life. Multivariable generalized estimating equations with logit-link were used to obtain adjusted odds ratios (aORs) and 95% CIs. Results: The mean (SD) age at delivery for women in the epilepsy cohort was 29.9 (5.3) years. The rate of composite severe maternal morbidity and mortality was also higher in women with epilepsy compared with those without epilepsy (36.9 vs 25.4 per 1000 deliveries). Women with epilepsy also had a significantly higher risk of death (0.23 deaths per 1000 deliveries) compared with women without epilepsy (0.05 deaths per 1000 deliveries) with an aOR of 3.86 (95% CI, 1.48-8.10). In particular, maternal epilepsy was associated with increased odds of severe preeclampsia, embolism, disseminated intravascular coagulation or shock, cerebrovascular events, and severe mental health conditions. Fetuses and infants of women with epilepsy were at elevated odds of mortality (aOR, 1.20; 95% CI, 1.05-1.38) and severe neonatal morbidity (aOR, 1.48; 95% CI, 1.40-1.56). In analyses restricted to women with epilepsy, women exposed to ASM compared with those unexposed had higher odds of severe maternal morbidity (aOR ,1.24; 95% CI, 1.10-1.48) and their neonates had an increased odd of mortality and severe morbidity (aOR, 1.37; 95% CI, 1.23-1.52). Conclusion and relevance: This multinational study shows that women with epilepsy were at considerably higher risk of severe maternal and perinatal outcomes and increased risk of death during pregnancy and postpartum. Maternal epilepsy and maternal use of ASM were associated with increased maternal morbidity and perinatal mortality and morbidity.

Socioeconomic differences in use of antiseizure medication in pregnancies with maternal epilepsy: A population-based study from Nordic universal health care systems.

OBJECTIVE: Research points to disparities in disease burden and access to medical care in epilepsy. We studied the association between socioeconomic status (SES) and antiseizure medication (ASM) use in pregnancies with maternal epilepsy. METHODS: We conducted a cross-sectional study consisting of 21 130 pregnancies with maternal epilepsy identified from Nordic registers during 2006-2017. SES indicators included cohabitation status, migrant background, educational attainment, and household income. Main outcomes were the proportion and patterns of ASM use from 90 days before pregnancy to birth. We applied multiple imputation to handle SES variables with 2%-4% missingness. We estimated adjusted risk ratios (aRRs) and 95% confidence intervals (CIs) using modified Poisson regression with the highest SES category as reference. RESULTS: Mothers with the highest education and the highest income quintile used ASMs least frequently (56% and 53%, respectively). We observed increased risks of ASM discontinuation prior to or during the first trimester for low SES. The risk estimates varied depending on the SES indicator from aRR = 1.27 for low income (95% CI: 1.03-1.57) to aRR = 1.66 for low education (95% CI: 1.30-2.13). Migrant background was associated with ASM initiation after the first trimester (aRR 2.17; 95% CI 1.88-2.52). Low education was associated with the use of valproate during pregnancy in monotherapy (aRR 1.70; 95% CI 1.29-2.24) and in polytherapy (aRR 2.65; 95% CI 1.66-4.21). Low education was also associated with a 37% to 39% increased risk of switching from one ASM to another depending on the ASM used. For the other SES indicators, aRRs of switching varied from 1.16 (foreign origin; 95% CI 1.08-1.26) to 1.26 (not married or cohabiting; 95% CI 1.17-1.36). SIGNIFICANCE: Low SES was associated with riskier patterns of ASM use: discontinuation, late initiation, and switching during pregnancy. These findings may reflect unplanned pregnancies, disparities in access to preconception counseling, and suboptimal care.

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.

Prescribing patterns for higher dose folic acid in pregnant women with epilepsy treated with antiseizure medication.

OBJECTIVE: This study was undertaken to characterize the use of higher doses of folic acid (≥1 mg daily) in relation to pregnancy in Denmark, Norway, and Sweden in women with epilepsy treated with antiseizure medication (ASM). METHODS: In this observational study, we used data from national medical birth, patient, and prescription registers in Denmark, Norway, and Sweden to retrospectively identify pregnancies in women with epilepsy treated with ASM from 2006 to 2017. The proportion of higher dose folic acid supplementation in pregnancies among women receiving ASM for epilepsy was calculated according to country of origin, time period, and type of ASM. Logistic regression with restricted cubic splines was used to model country-specific time trends. RESULTS: Among a total of 2 748 882 pregnancies, we identified 8695 (.3%) pregnancies after restricting the population to women with ASM-treated epilepsy. A prescription for higher dose folic acid was filled in 4719 (54.3%) of these pregnancies. The proportion supplemented with higher dose folic acid was highest in Sweden (74.3%) and lower in Norway (41.4%) and Denmark (34.3%). Furthermore, we observed a decreasing trend of higher dose folic acid use in Denmark and Norway from year 2012 to 2017. Among those who used higher dose folic acid, 42% did not start preconception supplementation with higher dose folic acid. SIGNIFICANCE: Supplementation with higher dose folic acid occurred in approximately half of pregnancies in women with ASM-treated epilepsy, with many not starting supplementation until after becoming pregnant. Considerable variability was observed in the use of higher dose folic acid across the countries, despite similar population characteristics and health care systems. Future guidelines should be simplified with clear recommendations developed in a collaborative manner by relevant specialists including neurologists, obstetricians, pediatricians, and public health specialists to enhance real-world applicability.

Prenatal exposure to antiseizure medications and fetal growth: a population-based cohort study from the Nordic countries.

Background: The short- and long-term consequences of restricted fetal growth cause considerable concern, and how prenatal exposure to different antiseizure medications (ASMs) affects fetal growth remains uncertain. Methods: This was a population-based cohort study of liveborn singleton children born in Denmark, Finland, Iceland, Norway, and Sweden from 1996 to 2017. Prenatal exposure was defined as maternal filling of prescriptions for ASM during pregnancy registered in national prescription registries and primary outcomes were adjusted odds ratios (aORs) of microcephaly or being born small for gestational age. Findings: We identified 4,494,918 children (males: 51.3%, 2,306,991/4,494,918), including 38,714 (0.9%) children of mothers with epilepsy. In the overall population, prenatal monotherapy exposure with carbamazepine (aOR: 1.25 (95% CI: 1.12-1.40)), pregabalin (aOR: 1.16 (95% CI: 1.02-1.31)), oxcarbazepine (aOR: 1.48 (95% CI: 1.28-1.71)), clonazepam (aOR: 1.27 (95% CI: 1.10-1.48)), and topiramate (aOR: 1.48 (95% CI: 1.18-1.85)) was associated with risk of being born small for gestational age, and carbamazepine was associated with microcephaly (aOR: 1.43 (95% CI: 1.17-1.75)). In children of mothers with epilepsy, prenatal exposure to carbamazepine (aOR: 1.27 (95% CI: 1.11-1.47)), oxcarbazepine (aOR: 1.42 (95% CI: 1.18-1.70)), clonazepam (aOR: 1.40 (95% CI: 1.03-1.89)), and topiramate (aOR: 1.86 (95% CI: 1.36-2.54)) was associated with being born small for gestational age; carbamazepine, with microcephaly (aOR: 1.51 (95% CI: 1.17-1.95)). No associations with small for gestational age and microcephaly were identified after prenatal exposure to lamotrigine, valproate, gabapentin, levetiracetam, phenobarbital, acetazolamide, phenytoin, clobazam, primidone, zonisamide, vigabatrin, ethosuximide and lacosamide, but except for lamotrigine, valproate, gabapentin, and levetiracetam, numbers of exposed children were small. Interpretation: Prenatal exposure to carbamazepine, oxcarbazepine, clonazepam, and topiramate was associated with increased risk of being born small for gestational age in both the overall population and in children of women with epilepsy suggesting that prenatal exposure to these drugs is associated with fetal growth restriction. Funding: The NordForsk Nordic Program on Health and Welfare (83539), the Independent Research Fund Denmark (1133-00026B), the Danish Epilepsy Association, the Central Denmark Region, the Novo Nordisk Foundation (NNF16OC0019126 and NNF22OC0075033), and the Lundbeck Foundation (R400-2022-1205).

Comparative Risk of Major Congenital Malformations With Antiseizure Medication Combinations vs Valproate Monotherapy in Pregnancy.

BACKGROUND AND OBJECTIVES: Valproate should be avoided in pregnancy, but it is the most effective drug for generalized epilepsies. Alternative treatment may require combinations of other drugs. Our objectives were to describe first trimester use of antiseizure medication (ASM) combinations that are relevant alternatives to valproate and determine whether specific combinations were associated with a lower risk of major congenital malformations (MCM) compared with valproate monotherapy. METHODS: We conducted a population-based cohort study using linked national registers from Denmark, Finland, Iceland, Norway, and Sweden and administrative health care data from the United States and New South Wales, Australia. We described first trimester use of ASM combinations among pregnant people with epilepsy from 2000 to 2020. We compared the risk of MCM after first trimester exposure to ASM combinations vs valproate monotherapy and low-dose valproate plus lamotrigine or levetiracetam vs high-dose valproate (≥1,000 mg/d). We used log-binomial regression with propensity score weights to calculate adjusted risk ratios (aRRs) and 95% CIs for each dataset. Results were pooled using fixed-effects meta-analysis. RESULTS: Among 50,905 pregnancies in people with epilepsy identified from 7.8 million total pregnancies, 788 used lamotrigine and levetiracetam, 291 used lamotrigine and topiramate, 208 used levetiracetam and topiramate, 80 used lamotrigine and zonisamide, and 91 used levetiracetam and zonisamide. After excluding pregnancies with use of other ASMs, known teratogens, or a child diagnosed with MCM of infectious or genetic cause, we compared 587 exposed to lamotrigine-levetiracetam duotherapy and 186 exposed to lamotrigine-topiramate duotherapy with 1959 exposed to valproate monotherapy. Pooled aRRs were 0.41 (95% CI 0.24-0.69) and 1.26 (0.71-2.23), respectively. Duotherapy combinations containing low-dose valproate were infrequent, and comparisons with high-dose valproate monotherapy were inconclusive but suggested a lower risk for combination therapy. Other combinations were too rare for comparative safety analyses. DISCUSSION: Lamotrigine-levetiracetam duotherapy in first trimester was associated with a 60% lower risk of MCM than valproate monotherapy, while lamotrigine-topiramate was not associated with a reduced risk. Duotherapy with lamotrigine and levetiracetam may be favored to treat epilepsy in people with childbearing potential compared with valproate regarding MCM, but whether this combination is as effective as valproate remains to be determined. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in people with epilepsy treated in the first trimester of pregnancy, the risk of major congenital malformations is lower with lamotrigine-levetiracetam duotherapy than with valproate alone, but similar with lamotrigine-topiramate.

High-dose folic acid and cancer risk; unjustified concerns by von Wrede and colleagues regarding our paper.

Women using antiseizure medication in pregnancy are often advised to use high doses of folic acid supplements (1mg to 5 mg) to reduce the risk of teratogenicity. Recently, we published a report showing an association between maternal prescription fill of high dose folic acid in relation to pregnancy and childhood cancer in the offspring. The report has sparked a debate about which dose of folic acid that should be recommended in pregnancy in women in need of antiseizure medication. In this Commentary, we explain our findings and the method used in our report, and answer recent questions that have emerged.

Prenatal Exposure to Antiseizure Medication and Incidence of Childhood- and Adolescence-Onset Psychiatric Disorders.

Importance: Prenatal antiseizure medication (ASM) exposure has been associated with adverse early neurodevelopment, but associations with a wider range of psychiatric end points have not been studied. Objective: To examine the association between prenatal exposure to ASM with a spectrum of psychiatric disorders in childhood and adolescence in children of mothers with epilepsy. Design, Setting, and Participants: This prospective, population-based register study assessed 4 546 605 singleton children born alive in Denmark, Finland, Iceland, Norway, and Sweden from January 1, 1996, to December 31, 2017. Of the 4 546 605 children, 54 953 with chromosomal disorders or uncertain birth characteristics were excluded, and 38 661 children of mothers with epilepsy were identified. Data analysis was performed from August 2021 to January 2023. Exposures: Prenatal exposure to ASM was defined as maternal prescription fills from 30 days before the first day of the last menstrual period until birth. Main Outcomes and Measures: The main outcome measure was diagnosis of psychiatric disorders (a combined end point and 13 individual disorders). Estimated adjusted hazard ratios (aHRs) using Cox proportional hazards regression and cumulative incidences with 95% CIs are reported. Results: Among the 38 661 children of mothers with epilepsy (16 458 [42.6%] exposed to ASM; 19 582 [51.3%] male; mean [SD] age at the end of study, 7.5 [4.6] years), prenatal valproate exposure was associated with an increased risk of the combined psychiatric end point (aHR, 1.80 [95% CI, 1.60-2.03]; cumulative risk at 18 years in ASM-exposed children, 42.1% [95% CI, 38.2%-45.8%]; cumulative risk at 18 years in unexposed children, 31.3% [95% CI, 28.9%-33.6%]), which was driven mainly by disorders within the neurodevelopmental spectrum. Prenatal exposure to lamotrigine, carbamazepine, and oxcarbazepine was not associated with an increased risk of psychiatric disorders, whereas associations were found for prenatal exposure to topiramate with attention-deficit/hyperactivity disorder (aHR, 2.38; 95% CI, 1.40-4.06) and exposure to levetiracetam with anxiety (aHR, 2.17; 95% CI, 1.26-3.72) and attention-deficit/hyperactivity disorder (aHR, 1.78; 95% CI, 1.03-3.07). Conclusions and Relevance: Findings from this explorative study strengthen the evidence for the warning against the use of valproate in pregnancy and raise concern of risks of specific psychiatric disorders associated with topiramate and levetiracetam. This study provides reassuring evidence that lamotrigine, carbamazepine, and oxcarbazepine are not associated with long-term behavioral or developmental disorders but cannot rule out risks with higher doses.

Identification of novel genomic risk loci shared between common epilepsies and psychiatric disorders.

Psychiatric disorders and common epilepsies are heritable disorders with a high comorbidity and overlapping symptoms. However, the causative mechanisms underlying this relationship are poorly understood. Here we aimed to identify overlapping genetic loci between epilepsy and psychiatric disorders to gain a better understanding of their comorbidity and shared clinical features. We analysed genome-wide association study data for all epilepsies (n = 44 889), genetic generalized epilepsy (n = 33 446), focal epilepsy (n = 39 348), schizophrenia (n = 77 096), bipolar disorder (n = 406 405), depression (n = 500 199), attention deficit hyperactivity disorder (n = 53 293) and autism spectrum disorder (n = 46 350). First, we applied the MiXeR tool to estimate the total number of causal variants influencing the disorders. Next, we used the conjunctional false discovery rate statistical framework to improve power to discover shared genomic loci. Additionally, we assessed the validity of the findings in independent cohorts, and functionally characterized the identified loci. The epilepsy phenotypes were considerably less polygenic (1.0 K to 3.4 K causal variants) than the psychiatric disorders (5.6 K to 13.9 K causal variants), with focal epilepsy being the least polygenic (1.0 K variants), and depression having the highest polygenicity (13.9 K variants). We observed cross-trait genetic enrichment between genetic generalized epilepsy and all psychiatric disorders and between all epilepsies and schizophrenia and depression. Using conjunctional false discovery rate analysis, we identified 40 distinct loci jointly associated with epilepsies and psychiatric disorders at conjunctional false discovery rate <0.05, four of which were associated with all epilepsies and 39 with genetic generalized epilepsy. Most epilepsy risk loci were shared with schizophrenia (n = 31). Among the identified loci, 32 were novel for genetic generalized epilepsy, and two were novel for all epilepsies. There was a mixture of concordant and discordant allelic effects in the shared loci. The sign concordance of the identified variants was highly consistent between the discovery and independent datasets for all disorders, supporting the validity of the findings. Gene-set analysis for the shared loci between schizophrenia and genetic generalized epilepsy implicated biological processes related to cell cycle regulation, protein phosphatase activity, and membrane and vesicle function; the gene-set analyses for the other loci were underpowered. The extensive genetic overlap with mixed effect directions between psychiatric disorders and common epilepsies demonstrates a complex genetic relationship between these disorders, in line with their bi-directional relationship, and indicates that overlapping genetic risk may contribute to shared pathophysiological and clinical features between epilepsy and psychiatric disorders.

Comparative Safety of Antiseizure Medication Monotherapy for Major Malformations.

OBJECTIVE: This study was undertaken to examine the comparative safety of antiseizure medication (ASM) monotherapy in pregnancy with respect to risk of major congenital malformations (MCMs), overall and by MCM subtype. METHODS: We conducted a population-based cohort study using national health register data from Denmark, Finland, Iceland, Norway, and Sweden (1996-2020). We compared pregnancies with first trimester exposure to lamotrigine monotherapy to ASM-unexposed, carbamazepine, valproate, oxcarbazepine, levetiracetam, and topiramate to lamotrigine monotherapy, and stratified monotherapy groups by dose. The outcome was nongenetic MCM and specific subtypes. We estimated adjusted risk ratios (aRRs) and 95% confidence intervals (CIs) with log-binomial regression and propensity score weights. RESULTS: There was a higher crude risk of any MCM in pregnancies exposed to lamotrigine monotherapy (n = 8,339) compared to ASM-unexposed pregnancies (n = 4,866,362), but not after confounder adjustment (aRR = 0.97, 95% CI = 0.87-1.08). Compared to lamotrigine, there was an increased risk of malformations associated with valproate (n = 2,031, aRR = 2.05, 95% CI = 1.70-2.46) and topiramate (n = 509, aRR = 1.81, 95% CI = 1.26-2.60), which increased in a dose-dependent manner. We found no differences in malformation risk for carbamazepine (n = 2,674, aRR = 0.91, 95% CI = 0.72-1.15), oxcarbazepine (n = 1,313, aRR = 1.09, 95% CI = 0.83-1.44), or levetiracetam (n = 1,040, aRR = 0.78, 95% CI = 0.53-1.13). Valproate was associated with several malformation subtypes, including nervous system, cardiac, oral clefts, clubfoot, and hypospadias, whereas lamotrigine and carbamazepine were not. INTERPRETATION: Topiramate is associated with an increased risk of MCM similar to that associated with valproate, but lower doses may mitigate the risks for both drugs. Conversely, we found no increased risks for lamotrigine, carbamazepine, oxcarbazepine, or levetiracetam, which is reassuring. ANN NEUROL 2023;93:551-562.

Cancer Risk in Children of Mothers With Epilepsy and High-Dose Folic Acid Use During Pregnancy.

Importance: Women with epilepsy are recommended high doses of folic acid before and during pregnancy owing to risk of congenital anomalies associated with antiseizure medications. Whether prenatal exposure to high-dose folic acid is associated with increases in the risk of childhood cancer is unknown. Objective: To assess whether high-dose folic acid supplementation in mothers with epilepsy is associated with childhood cancer. Design, Setting, and Participants: Observational cohort study conducted with nationwide registers in Denmark, Norway, and Sweden from 1997 to 2017. Analyses were performed during January 10, 2022, to January 31, 2022. Mother-child pairs were identified in medical birth registers and linked with information from patient, prescription, and cancer registers, as well as with sociodemographic information from statistical agencies, and were categorized by maternal diagnosis of epilepsy. The study population consisted of 3 379 171 children after exclusion of 126 711 children because of stillbirth or missing or erroneous values on important covariates. Exposures: Maternal prescription fills for high-dose folic acid tablets (≥1 mg daily) between 90 days before pregnancy start and birth. Main Outcomes and Measures: First onset of childhood cancer at younger than 20 years. Cox proportional hazards models were used to calculate adjusted hazard ratios with corresponding 95% CIs, adjusted for potential confounders. Cumulative incidence at aged 20 years was used as a measure of absolute risk. Results: The median age at the end of follow-up in the study population of 3 379 171 children was 7.3 years (IQR, 3.5-10.9 years). Among the 27 784 children (51.4% male) born to mothers with epilepsy, 5934 (21.4%) were exposed to high-dose folic acid (mean dose, 4.3 mg), with 18 exposed cancer cases compared with 29 unexposed, producing an adjusted hazard ratio of 2.7 (95% CI, 1.2-6.3), absolute risk if exposed of 1.4% (95% CI, 0.5%-3.6%), and absolute risk if unexposed of 0.6% (95% CI, 0.3%-1.1%). In children of mothers without epilepsy, 46 646 (1.4%) were exposed to high-dose folic acid (mean dose, 2.9 mg), with 69 exposed and 4927 unexposed cancer cases and an adjusted hazard ratio of 1.1 (95% CI, 0.9-1.4; absolute risk, 0.4% [95% CI, 0.3%-0.5%]). There was no association between children born to mothers with epilepsy who were prenatally exposed to antiseizure medications, but not high-dose folic acid, and an increased risk of cancer (absolute risk, 0.6%; 95% CI, 0.2%-1.3%). Conclusions and Relevance: Prenatal exposure to high-dose folic acid was associated with increased risk of cancer in children of mothers with epilepsy.

Association of Prenatal Exposure to Antiseizure Medication With Risk of Autism and Intellectual Disability.

Importance: Women with epilepsy frequently need antiseizure medication (ASM) to prevent seizures in pregnancy. Risk of neurodevelopmental disorders after prenatal exposure to AMSs is uncertain. Objective: To determine whether children exposed prenatally to ASMs in monotherapy and duotherapy have increased risk of neurodevelopmental disorders. Design, Setting, and Participants: The Nordic register-based study of antiepileptic drugs in pregnancy (SCAN-AED) is a population-based cohort study using health register and social register data from Denmark, Finland, Iceland, Norway, and Sweden (1996-2017; analysis performed February 2022). From 4 702 774 alive-born children with available mother-child identities and maternal prescription data, this study included 4 494 926 participants. Children from a multiple pregnancy or with chromosomal disorders or uncertain pregnancy length were excluded (n = 207 848). Exposures: Prenatal exposure to ASM determined from maternal prescription fills between last menstrual period and birth. Main Outcomes and Measures: We estimated cumulative incidence at age 8 years in exposed and unexposed children. Cox regression adjusted for potential confounders yielded adjusted hazard ratios (aHRs) with 95% CIs for autism spectrum disorder (ASD), intellectual disability (ID), or any neurodevelopmental disorder (ASD and/or ID). Results: A total of 4 494 926 children were included; 2 306 993 (51.3%) were male, and the median (IQR) age at end of follow-up was 8 (4.0-12.1) years. Among 21 634 unexposed children of mothers with epilepsy, 1.5% had a diagnosis of ASD and 0.8% (numerators were not available because of personal data regulations in Denmark) of ID by age 8 years. In same-aged children of mothers with epilepsy exposed to topiramate and valproate monotherapy, 4.3% and 2.7%, respectively, had ASD, and 3.1% and 2.4% had ID. The aHRs for ASD and ID after topiramate exposure were 2.8 (95% CI, 1.4-5.7) and 3.5 (95% CI, 1.4-8.6), respectively, and after valproate exposure were 2.4 (95% CI, 1.7-3.3) and 2.5 (95% CI, 1.7-3.7). The aHRs were elevated with higher ASM doses compared with children from the general population. The duotherapies levetiracetam with carbamazepine and lamotrigine with topiramate were associated with increased risks of neurodevelopmental disorders in children of women with epilepsy: levetiracetam with carbamazepine: 8-year cumulative incidence, 5.7%; aHR, 3.5; 95% CI, 1.5-8.2; lamotrigine with topiramate: 8-year cumulative incidence, 7.5%; aHR, 2.4; 95% CI, 1.1-4.9. No increased risk was associated with levetiracetam with lamotrigine (8-year cumulative incidence, 1.6%; aHR, 0.9; 95% CI, 0.3-2.5). No consistently increased risks were observed for neurodevelopmental disorders after prenatal exposure to monotherapy with lamotrigine, levetiracetam, carbamazepin, oxcarbazepine, gapapentin, pregabalin, clonazepam, or phenobarbital. Conclusions and Relevance: In this cohort study, prenatal exposure to topiramate, valproate, and several duotherapies were associated with increased risks of neurodevelopmental disorders.

Folic Acid and Risk of Preterm Birth, Preeclampsia, and Fetal Growth Restriction Among Women With Epilepsy: A Prospective Cohort Study.

BACKGROUND AND OBJECTIVES: Women with epilepsy treated with antiseizure medication (ASM) have increased risk of pregnancy complications including preterm birth, fetal growth restriction, and preeclampsia. We aimed to investigate whether folic acid supplementation is associated with these pregnancy complications in women with epilepsy using ASM. METHODS: Singleton pregnancies in the prospective Norwegian Mother and Child Cohort Study (MoBa) (1999-2008) were included. Information on maternal epilepsy, ASM, folic acid supplementation, and pregnancy outcomes was obtained from the MoBa questionnaires and the Norwegian Medical Birth Registry. The main exposure, periconceptional folic acid supplementation, was defined as intake between 4 weeks before pregnancy and 12 weeks into pregnancy, retrospectively collected by recall of the mothers in weeks 17-19. The primary outcomes were preterm birth (gestational age <37 weeks at birth), small for gestational age (SGA), and preeclampsia. RESULTS: The study included 100,105 pregnancies: 99,431 without maternal epilepsy, 316 with maternal epilepsy and ASM exposure in pregnancy, and 358 with untreated maternal epilepsy. Among ASM-treated women with epilepsy, the risk of preterm birth was higher in those who did not use periconceptional folic acid (n = 64) compared with those who did (n = 245, the reference) (adjusted odds ratio [aOR] 3.3, 95% CI 1.2-9.2), while the risk of preterm birth among the reference was similar to the risk among women without epilepsy using folic acid periconceptionally (aOR 0.9, 95% CI 0.5-1.6). ASM-treated women with epilepsy starting folic acid after the first trimester had a higher risk compared with women without epilepsy with similar timing of folic acid (aOR 2.6, 95% CI 1.1-6.5), and even higher if not using folic acid (aOR 9.4, 95% CI 2.6-34.8). Folic acid was not associated with risk of preterm birth among women with epilepsy without ASM or among women without epilepsy. Folic acid was not associated with risk of preeclampsia or SGA among women with epilepsy. DISCUSSION: In women with epilepsy using ASM, periconceptional folic acid was associated with a lower risk of preterm birth. This finding supports the recommendation that ASM-treated women with epilepsy of childbearing potential should use folic acid supplementation on a regular basis. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for women with epilepsy using ASM, periconceptional folic acid supplementation decreases the risk of preterm birth.

Cardiac Structure and Function in Epilepsy Patients with Drug-Resistant Convulsive Seizures.

High frequency of convulsive seizures and long-lasting epilepsy are associated with an increased risk of sudden unexpected death in epilepsy (SUDEP). Structural changes in the myocardium have been described in SUDEP victims. It is speculated that these changes are secondary to frequent convulsive seizures and may predispose to SUDEP. The aim of this cross-sectional study was to investigate the impact of chronic drug-resistant epilepsy on cardiac function and structure in patients with a high frequency of convulsive seizures. We consecutively included 21 patients (17 women, 4 men) aged 18-40 years, with at least 10 years with epilepsy and a minimum of six convulsive seizures in the last year and without a history of status epilepticus or nonepileptic events. A complete clinical examination, resting 12-lead electrocardiogram, 72-h Holter monitoring, and echocardiography were recorded in all patients. Ten patients were assessed by 3-Tesla cardiac magnetic resonance imaging. Echocardiography and MRI data were compared with those from age- and sex-matched healthy control individuals. No significant changes in cardiac structure or function were found among patients with chronic drug-resistant epilepsy and high frequency of convulsive seizures. However, we cannot exclude that there are subgroups of patients who are more prone to epilepsy-associated cardiac alterations.

Assisted reproductive treatment in women with epilepsy. / Assistert befruktning blant kvinner med epilepsi.

BACKGROUND: Women with epilepsy give birth to fewer children than women without epilepsy. We wished to compare the use of assisted reproductive technology in Norwegian women who have epilepsy with Norwegian women in general. MATERIAL AND METHOD: In an international prospective registry study, the purpose of which was to identify the teratogenic effects of antiepileptic drugs, we included a total of 1510 births among Norwegian women who have epilepsy in the period 2000-2017. The women were recruited from 18 hospital neurological departments, and a protocol was completed for each pregnancy with demographic and clinical data. The use of assisted fertility among Norwegian women in general in the same period was retrieved from the medical birth registry. RESULTS: In women with epilepsy, altogether 96 of 1510 births (6.4 %) were a result of assisted reproductive technology, whereas the corresponding figure in the general population in the same period was 285 474 of 1 052 901 (2.7 %) (p<0.001). Among women with epilepsy, the proportion who used carbamazepine in pregnancy was significantly higher among those who conceived using assisted reproductive technology than among those who had become pregnant in the regular manner (p=0.02). INTERPRETATION: Compared to healthy Norwegian women, the use of assisted reproductive technology was more than twice as high among women with epilepsy. This may be an intimation of reduced fertility among these women.

Mislocalization of AQP4 precedes chronic seizures in the kainate model of temporal lobe epilepsy.

It has been suggested that loss of the astrocytic water channel aquaporin-4 (AQP4) from perivascular endfeet in sclerotic hippocampi contributes to increased seizure propensity in human mesial temporal lobe epilepsy (MTLE). Whether this loss occurs prior to or as a consequence of epilepsy development remains to be resolved. In the present study, we investigated whether the expression and distribution of AQP4 was altered prior to (i.e., in the latent phase) or after the onset of chronic epileptic seizures (i.e., in the chronic phase) in the kainate (KA) model of MTLE. Immunogold electron microscopic analysis revealed that AQP4 density in adluminal endfoot membranes was reduced in KA treated rats already in the latent phase, while the AQP4 density in the abluminal endfoot membrane was stable or slightly increased. The decrease in adluminal AQP4 immunogold labeling was accompanied by a reduction in the density of AQP4's anchoring protein alpha-syntrophin. The latent and chronic phases were associated with an upregulation of the M1 isoform of AQP4, as judged by semi-quantitative Western blot analysis. Taken together, the findings in this model suggest that a mislocalization of AQP4--reflecting a loss of astrocyte polarization--is an integral part of the epileptogenic process.

Reduced astrocytic contribution to the turnover of glutamate, glutamine, and GABA characterizes the latent phase in the kainate model of temporal lobe epilepsy.

The occurrence of spontaneous seizures in mesial temporal lobe epilepsy (MTLE) is preceded by a latent phase that provides a time window for identifying and treating patients at risk. However, a reliable biomarker of epileptogenesis has not been established and the underlying processes remain unclear. Growing evidence suggests that astrocytes contribute to an imbalance between excitation and inhibition in epilepsy. Here, astrocytic and neuronal neurotransmitter metabolism was analyzed in the latent phase of the kainate model of MTLE in an attempt to identify epileptogenic processes and potential biomarkers. Fourteen days after status epilepticus, [1-(13)C]glucose and [1,2-(13)C]acetate were injected and the hippocampal formation, entorhinal/piriform cortex, and neocortex were analyzed by (1)H and (13)C magnetic resonance spectroscopy. The (13)C enrichment in glutamate, glutamine, and γ-aminobutyric acid (GABA) from [1-(13)C]glucose was decreased in all areas. Decreased GABA content was specific for the hippocampal formation, together with a pronounced decrease in astrocyte-derived [1,2-(13)C]GABA and a decreased transfer of glutamine for the synthesis of GABA. Accumulation of branched-chain amino acids combined with decreased [4,5-(13)C]glutamate in hippocampal formation could signify decreased transamination via branched-chain aminotransferase in astrocytes. The results point to astrocytes as major players in the epileptogenic process, and (13)C enrichment of glutamate and GABA as potential biomarkers.