Treating status epilepticus in adults. / Behandling av status epilepticus hos voksne.

This clinical review examines the treatment of status epilepticus, a condition in which epileptic seizures are prolonged and pose a significant risk of brain damage and death. International guidelines recommend the use of benzodiazepines as first-line treatment, and these should be administered promptly and in appropriate doses. Second-line treatment involves the use of high-dose anti-seizure medications to stop and prevent seizures. If seizure activity persists, general anaesthesia should be administered as soon as possible. All neurological hospital departments should have established and rehearsed protocols for treating status epilepticus.

Overweight in epilepsy as a risk factor for pregnancy and delivery complications.

OBJECTIVE: To investigate whether prepregnancy overweight in women with epilepsy increases their risk for complications during pregnancy and delivery. METHODS: This study is based on The Norwegian Mother and Child Cohort Study (MoBa) linked to the Medical Birth Registry of Norway. A diagnosis of epilepsy was reported in 706 pregnancies. Overweight was defined as body mass index ≥ 25 prepregnancy. Overweight women with epilepsy (n = 259) were compared to normal-weight women with epilepsy (n = 416), and to women without epilepsy with and without overweight (n = 30,516 and n = 67,977, respectively). The risks of pregnancy and delivery complications were calculated as odds ratios (ORs) with 95% confidence intervals (CIs) adjusted for adverse socioeconomic factors, age, parity, and smoking. RESULTS: Women with epilepsy were more often overweight than women without epilepsy (38.4% vs. 31.3%, p < 0.001). The majority of pregnancy and delivery complications were more frequent in overweight women with epilepsy. Compared to overweight women without epilepsy, the risk was increased for cesarean section (OR 1.6, CI 1.2-2.2, p < 0.001), excessive bleeding (OR 1.4, CI 1.0-1.8, p = 0.04), peripartum anxiety and depressive symptoms (OR 1.9, CI 1.3-2.8, p < 0.001), small for gestational age children (OR 2.4, CI 1.2-4.8, p = 0.02), and transfer of the infant to a neonatal ward (OR 1.5, CI 1.1-2.2, p = 0.02). Compared to normal-weight women with epilepsy, the risk of cesarean section (OR 1.6, CI 1.1-2.3, p < 0.05), gestational hypertension (OR 2.0, CI 1.1-3.5, p < 0.05), preeclampsia (OR 2.3, CI 1.2-4.5, p < 0.05), and transfer of the infant to a neonatal ward (OR 2.2, CI 1.3-3.6, p < 0.01) was increased. SIGNIFICANCE: Prepregnancy overweight in combination with epilepsy entails a strong negative effect on risk of complications during pregnancy and delivery. In women with epilepsy and overweight referral to a nutritionist should be considered when an antiepileptic drug is started as well as when pregnancy is planned. These women should be regarded as a high-risk group.

Life satisfaction in women with epilepsy during and after pregnancy.

OBJECTIVE: The aim of this study was to investigate life satisfaction in women with epilepsy during and after pregnancy. METHODS: The study was based on the Norwegian Mother and Child Cohort Study, including 102,265 women with and without epilepsy from the general population. Investigation took place at pregnancy weeks 15-19 and 6 and 18months postpartum. Women with epilepsy were compared with a reference group without epilepsy. RESULTS: The proportion of women with epilepsy was 0.6-0.7% at all three time points. Women with epilepsy reported lower life satisfaction and self-esteem both during and after pregnancy compared with the references. Single parenting correlated negatively with life satisfaction in epilepsy during the whole study period. Epilepsy was associated with lower levels of relationship satisfaction and higher levels of work strain during pregnancy and lower levels of self-efficacy and satisfactory somatic health 18months postpartum. Adverse life events, such as divorce, were more common in women with epilepsy compared with the references, and fewer women with epilepsy had a paid job 18months postpartum. SIGNIFICANCE: Reduced life satisfaction associated with epilepsy during and after pregnancy showed that, even in a highly developed welfare society, women with epilepsy struggle. Mothers with epilepsy and their partners should be examined for emotional complaints and partnership satisfaction during and after pregnancy. Validated screening tools are available for such measures.

Depression and anxiety in women with epilepsy during pregnancy and after delivery: a prospective population-based cohort study on frequency, risk factors, medication, and prognosis.

OBJECTIVE: To assess incidence, prevalence, risk factors, and prognosis of peripartum depression and anxiety in a prospective study of women with epilepsy. METHOD: Pregnancies in women with epilepsy (n=706) were compared to pregnancies in all women without epilepsy (n=106,511) including women with specified nonepileptic chronic diseases (n=8,372) in the Norwegian Mother and Child Cohort Study. The database was linked to the Medical Birth Registry of Norway. Depression and anxiety were assessed with validated questionnaires five times from the second trimester to 36 months after delivery. Blood was drawn for analysis of antiepileptic drug (AED) concentrations. RESULTS: Women with epilepsy more often had peripartum depression (26.7%) or anxiety (22.4%) than women without epilepsy (18.9% and 14.8%, respectively, p<0.001 for both comparisons) and women with other chronic diseases (23.1% and 18.4%, respectively, p=0.03 and 0.01). Women using AEDs during pregnancy were especially at risk regardless of AED type. The risk further increased with the use of multiple AEDs and with high doses and/or plasma levels. Risk factors associated with peripartum depression and/or anxiety in the epilepsy cohort were high seizure frequency, a history of physical and/or sexual abuse, adverse socioeconomic factors, previous loss of a child, AED use, unplanned pregnancy, and prepregnancy depression and/or anxiety. The recovery rate 3 years after delivery was lower for women with epilepsy with a history of depression/anxiety or physical/sexual abuse than for women without epilepsy. Depressed women with epilepsy were less frequently treated with antidepressive drugs during pregnancy than women without epilepsy. SIGNIFICANCE: Women with epilepsy frequently have depression and anxiety during and after pregnancy. Patients at risk should be identified before delivery as depressive symptoms could be undertreated in this group.

Exposure to antiepileptic drugs in utero and child development: a prospective population-based study.

PURPOSE: Antiepileptic drugs may cause congenital malformations. Less is known about the effect on development in infancy and childhood. The aim of this study was to examine whether exposure to antiepileptic drugs during pregnancy has an effect on early child development. METHODS: From mid-1999 through December 2008, children of mothers recruited at 13-17 weeks of pregnancy were studied in the ongoing prospective Norwegian Mother and Child Cohort Study. Information on birth outcomes were obtained from the Medical Birth Registry (108,264 children), and mothers reported on their child's motor development, language, social skills, and autistic traits using items from standardized screening tools at 18 months (61,351 children) and 36 months (44,147 children) of age. The relative risk of adverse outcomes in children according to maternal or paternal epilepsy with and without prenatal exposure to antiepileptic drugs was estimated as odds ratios (ORs), using logistic regression with adjustment for maternal age, parity, education, smoking, depression/anxiety, folate supplementation, and child congenital malformation or low birth weight. KEY FINDINGS: A total of 333 children were exposed to antiepileptic drugs in utero. At 18 months, the exposed children had increased risk of abnormal scores for gross motor skills (7.1% vs. 2.9%; OR 2.0, 95% confidence interval [CI] 1.1-3.7) and autistic traits (3.5% vs. 0.9%; OR 2.7, CI 1.1-6.7) compared to children of parents without epilepsy. At 36 months, the exposed children had increased risk of abnormal score for gross motor skills (7.5% vs. 3.3%; OR 2.2, CI 1.1-4.2), sentence skills (11.2% vs. 4.8%; OR 2.1, CI 1.2-3.6), and autistic traits (6.0% vs. 1.5%; OR 3.4, CI 1.6-7.0). The drug-exposed children also had increased risk of congenital malformations (6.1% vs. 2.9%; OR 2.1, CI 1.4-3.4), but exclusion of congenital malformations did not affect the risk of adverse development. Children born to women with epilepsy who did not use antiepileptic drugs had no increased risks. Children of fathers with epilepsy generally scored within the normal range. SIGNIFICANCE: Exposure to antiepileptic drugs during pregnancy is associated with adverse development at 18 and 36 months of age, measured as low scores within key developmental domains rated by mothers. Exposures to valproate, lamotrigine, carbamazepine, or multiple antiepileptic drugs were associated with adverse outcome within different developmental domains.

Psychiatric comorbidity and social aspects in pregnant women with epilepsy - the Norwegian Mother and Child Cohort Study.

OBJECTIVE: The objective of this study was to investigate psychiatric disease and social aspects in young women with epilepsy before and during pregnancy. METHOD: The study included self-reported data from 106,935 pregnancies. RESULTS: Seven hundred eleven women reported having epilepsy, and 45.9% of them were using antiepileptic drugs (AEDs). Compared to the reference group, self-reported eating disorders and depression were increased in the untreated epilepsy group before pregnancy. Both AED-treated and untreated women with epilepsy reported higher depression scores as assessed by the Hopkins Symptom Checklist, and the Lifetime Major Depression scale was increased in AED-treated women. Antiepileptic drug treatment was linked to low income (27.4% vs. 18.4%, p<0.001) and no income (5.5% vs. 2.6%, p=0.001). Low educational level was associated with epilepsy in AED-treated and untreated women (50.5%, p<0.001 and 46.9%, p<0.001 vs. 32.2%), as was unemployment due to disability (7.9%, p<0.001 and 6.5%, p<0.001 vs. 1.5%) and single parenting (4.4%, p=0.016 and 4.5%, p=0.007 vs. 2.4%). No difference was found for smoking, alcohol use, or narcotic use. CONCLUSION: Symptoms of depression were associated with epilepsy both during and before pregnancy. Epilepsy was linked to eating disorders before pregnancy. Unemployment, single parenting, and low educational level were linked to epilepsy in young pregnant females. Efforts aiming at treatment and screening for psychiatric comorbidity in pregnant women with epilepsy are important in the follow-up of these patients.

Pregnancy, delivery, and outcome for the child in maternal epilepsy.

PURPOSE: To investigate pregnancy, delivery, and child outcome in an unselected population of women with both treated and untreated epilepsy. METHODS: In the compulsory Medical Birth Registry of Norway, all 2,861 deliveries by women with epilepsy recorded from 1999-2005 were compared to all 369,267 nonepilepsy deliveries in the same period. RESULTS: The majority (66%, n = 1900) in the epilepsy group did not use antiepileptic drugs (AEDs) during pregnancy. A total of 961 epilepsy-pregnancies were exposed to AEDs. Compared to nonepilepsy controls, AED-exposed infants were more often preterm (p = 0.01), and more often had birth weight <2,500 g (p < 0.001), head circumference <2.5 percentile (p < 0.001), and low Apgar score (p = 0.03). Small-for-gestational-age (SGA) infants (<10 percentile) occurred more frequently in both AED-exposed (p = 0.05) and unexposed (p = 0.02) epilepsy-pregnancies. Frequency of major congenital malformations (MCMs) was 2.8% (n = 81) in the epilepsy group versus 2.5% in controls (p = 0.3). Increased risk for MCMs could be demonstrated only for exposure to valproate (5.6%, p = 0.005) and AED polytherapy (6.1%, p = 0.02). Neonatal spina bifida was not significantly increased, but was a major indication for elective pregnancy termination among women with epilepsy. Cesarean section was performed more often in maternal epilepsy, regardless of AED-exposure (p < 0.001). DISCUSSION: Adverse pregnancy and birth outcome in women with epilepsy is mainly confined to AED-exposed pregnancies, although some risks are associated also with untreated epilepsy. The risk for congenital malformations was lower than previously reported. This could be due to a shift in AED selection, folic acid supplement, or possibly reflect the true risks in an unselected epilepsy population.

No effect of electrical transcranial direct current stimulation adjunct treatment for epilepsia partialis continua in POLG disease.

We report a 15-year-old female with POLG-related mitochondrial disease who developed severe multifocal epilepsia partialis continua, unresponsive to standard anti seizure drug treatment and general anesthesia. Based on an earlier case report, we treated her focal seizures that affected her right upper limb with 20-min sessions of transcranial direct current stimulation (tDCS) at an intensity of 2 mA on each of five consecutive days. The cathode was placed over the left primary motor cortex, the anode over the contralateral orbitofrontal cortex. Surface electromyography (EMG) were recorded 20 min before, 20 min during, and 20 min after four of five tDCS sessions to measure its effect on the muscle jerks. The electroencephalography (EEG) was recorded before and after tDCS to measure the frequency of spikes. Our results showed no statistically or clinically significant reduction of seizures or epileptiform activity using EEG and EMG, with this treatment protocol. To our knowledge, this is only the second time that adjunct tDCS treatment of epileptic seizures has been tried in POLG-related mitochondrial disease. Taken together with the positive findings from the earlier case report, the present study highlights that more data are needed to determine if, and under which parameters, the treatment is effective.

Association of Folic Acid Supplementation During Pregnancy With the Risk of Autistic Traits in Children Exposed to Antiepileptic Drugs In Utero.

Importance: Strategies to prevent autism in children exposed to antiepileptic drugs (AEDs) during pregnancy are important. Objective: To explore whether folic acid supplementation and folate status in pregnancy are associated with reduced risk of autistic traits owing to in utero AED exposure. Design, Setting, and Participants: The population-based, prospective Norwegian Mother and Child Cohort Study approached Norwegian-speaking women attending routine ultrasonographic examinations from June 1999 through December 31, 2008 (163 844 of 277 702 women refused). No exclusion criteria were applied beyond language. Questionnaires during and after pregnancy, analysis of blood samples, and linkage to the Medical Birth Registry of Norway were performed. Children aged 18 to 36 months of women with available information on use of AEDs and of folic acid supplementation (n = 104 946) were included in the analysis from March 1, 2016, through June 13, 2017. Exposures: Maternal folic acid supplementation 4 weeks before to 12 weeks after conception. Plasma folate concentration was analyzed at gestational weeks 17 to 19. Main Outcomes and Measures: Autistic traits were evaluated using the Modified Checklist for Autism in Toddlers and Social Communication Questionnaire. Odds ratios (ORs) for autistic traits in children by maternal use vs nonuse of folic acid supplements were adjusted for maternal health and socioeconomic factors. Folate concentrations and folic acid doses were associated with the degree of autistic traits. Results: The overall mean (SD) age of the 104 946 mothers of participating children was 29.8 (4.6) years, with complete information available for analysis in 103 868. Mean (SD) age of women with epilepsy who received AED treatment was 29.4 (4.9); women with epilepsy who did not receive AED treatment, 29.1 (4.9); and without epilepsy, 29.8 (4.6) years. In the 335 children exposed to AEDs, the risk for autistic traits was significantly higher at 18 months of age (adjusted OR [AOR], 5.9; 95% CI, 2.2-15.8) and 36 months of age (AOR, 7.9; 95% CI, 2.5-24.9) when their mothers had not used folic acid supplements compared with children of mothers who had used supplements. Among women without epilepsy, the corresponding risks were lower at 18 months of age (AOR, 1.3; 95% CI, 1.2-1.4) and 36 months of age (AOR, 1.7; 95% CI, 1.5-1.9); among the 389 children of women with untreated epilepsy, the corresponding risks were not significant at 18 months of age (AOR, 1.0; 95% CI, 0.4-3.0) and 36 months of age (AOR, 2.5; 95% CI, 0.4-16.6). Degree of autistic traits was inversely associated with maternal plasma folate concentrations (ß = -0.3; P = .03) and folic acid doses (ß = -0.5; P < .001). Concentrations of AEDs were not associated with the degree of autistic traits. Conclusions and Relevance: Risk of autistic traits in children exposed to AEDs in utero may be mitigated by periconceptional folic acid supplementation and folate status. Fertile women using AEDs should take folic acid supplements continuously.

Pregnancy, delivery and perinatal outcome in female survivors of polio.

OBJECTIVE: To investigate possible effects on pregnancy, delivery and perinatal outcome in female survivors of polio. METHODS: In a cohort design, data from the national population based Medical Birth Registry of Norway (MBRN) were used to compare all 2495 births recorded 1967-1998 by female survivors of polio with all 1.9 mill non-polio deliveries. The results were adjusted for time period, maternal age, and birth order by unconditional logistic regression, with effects presented as adjusted Odds Ratios (OR) with a corresponding 95% Confidence Interval (CI) and p values. RESULTS: Female polio survivors had a higher occurrence of pre-eclampsia (3.4% vs. 2.8%, p=0.003, OR=1.4, CI=1.1-1.7), gestational proteinuria (1.3% vs. 0.5%, p<0.001, OR=2.0, CI=1.4-2.8), renal disease prior to pregnancy (1.4% vs. 0.9%, p=0.001, OR=1.8, CI=1.2-2.5), vaginal bleeding (3.8% vs. 2.0%, p<0.001, OR=1.7, CI=1.4-2.1), and urinary tract infection during pregnancy (3.5% vs. 2.4%, p<0.001, OR=1.7, CI=1.4-2.1). Deliveries complicated by obstruction of the birth process were more common in the polio group (6.1% vs. 2.0%, p<0.001, OR=4.8, CI=4.0-5.6), and cesarean section was performed at a higher rate throughout the time period (13.2% vs. 8.3%, p<0.001, OR=2.7, CI=2.4-3.1). Infants of polio mothers had a lower mean birth weight (3383 g vs. 3483 g, p<0.001), and more often had a birth weight below 2500 g (6.9% vs. 5.2%, p=0.001, OR=1.3, CI=1.1-1.5). There was no difference regarding pregnancy length. The risk of perinatal death was increased (2.1% vs. 1.1%, p=0.05, OR=1.3, CI=1.0-1.7). CONCLUSION: Pregnancy in female survivors of polio is associated with an increased risk for complications during pregnancy and delivery, as well as an adverse perinatal outcome. Awareness towards risk factors should improve pre-natal care and possibly prevent complications.

Epilepsy and recommendations for breastfeeding.

PURPOSE: The objective of this paper is to provide a synopsis of benefits and potential harmful effects of exposure to antiepileptic drugs (AEDs) via breastmilk, and present recommendations for breastfeeding in women with epilepsy. METHODS: The article is based on a discretionary selection of English language articles retrieved by a literature search in the PubMed database, the LactMed database, and the authors' clinical experience. RESULTS: Breastfeeding is associated with benefits for the infant, including nutrition, protection against infectious and immunological disease, and promotion of development and psychological attachment. Exposure to AEDs via breastmilk could potentially produce side effects or negatively affect development. Most studies on AED transfer through breastmilk report infant serum levels well below the limit of an expected pharmacological effect. Some drugs have the potential to reach significant serum levels in breastfed infants, such as barbiturates, benzodiazepines, lamotrigine, and ethosuximide. Thus, breastfed infants should be monitored for side effects. Still, adverse symptoms are rarely reported in breastfed infants of mothers taking AEDs, and prospective studies have failed to demonstrate any negative developmental effects in children that have been exposed to AEDs via breastmilk. The nursing infant's degree of drug exposure can be minimized by breastfeeding when drug concentrations in the milk are low, reducing maternal AED dosage to prepregnancy levels, and administering mixed nutrition. CONCLUSION: Most AEDs are considered safe or moderately safe during breastfeeding. Mothers with epilepsy should be encouraged to breastfeed, provided careful monitoring of the infant.

Depression and anxiety during pregnancy and the postpartum period in women with epilepsy: A review of frequency, risks and recommendations for treatment.

PURPOSE: To review available data and provide treatment recommendations concerning peripartum depression, anxiety and fear of birth in women with epilepsy (WWE). METHOD: The PubMed, the LactMed, the DART and the Cochrane database were searched for original articles concerning psychiatric disease in the peripartum period in WWE. RESULTS: Point prevalence of depression from 2nd trimester to 6 months postpartum ranged from 16 to 35% in women with epilepsy compared to 9-12% in controls. The highest estimates were found early in pregnancy and in the perinatal period. Anxiety symptoms 6 months postpartum were reported by 10 and 5%, respectively. Fear of birth symptoms were increased in primiparous WWE compared to controls. Previous psychiatric disease, sexual/physical abuse, antiepileptic drug (AED) polytherapy, and high seizure frequency emerged as strong risk factors. Depressed WWE rarely used antidepressive medication during pregnancy. No evidence was available concerning treatment effects or impact on the developing child. CONCLUSION: Peripartum depression is frequent in WWE and seldom medically treated. Health personnel should screen WWE for psychiatric disease and risk factors during pre-pregnancy planning, pregnancy and postpartum follow up. Treatment decisions should rely on efficacy and safety data in peripartum patients without epilepsy and non-pregnant people with epilepsy. Consequences of in utero exposure to AED therapy in combination with antidepressants are not known, and non-pharmacological treatment should be tried first.

Epilepsy and eating disorders during pregnancy: Prevalence, complications and birth outcome.

PURPOSE: The aim was to investigate the prevalence of eating disorders and its relation to pregnancy and delivery complications in childbearing women with epilepsy (WWE). METHOD: This study is based on The Norwegian Mother and Child Cohort Study (MoBa) linked to the Medical Birth Registry of Norway. Epilepsy was reported in 706 pregnancies. The remaining cohort (n=106,511) served as the reference group. Eating disorders were diagnosed using DSM-IV criteria adjusted for pregnancy. The risk of preeclampsia, gestational hypertension, diabetes and weight gain during pregnancy as well as delivery outcome (small for gestational age, large for gestational age, ponderal index, low APGAR score, small head circumference) were calculated as odds ratios (ORs) with 95% confidence intervals (CIs) adjusted for maternal age, smoking, parity and socioeconomic factors. RESULTS: Pregnant WWE were significantly more likely to have binge eating disorder (6.5% vs. 4.7%, p<0.05). WWE and comorbid eating disorders had significantly more preeclampsia (7.9% vs. 3.7%, p<0.05), peripartum depression and/or anxiety (40.4% vs. 17.8%, p<0.001) and operative delivery (38.2% vs. 23.5%, p<0.001) than the reference group without epilepsy or eating disorders. After adjustment for confounders, a significantly increased risk of operative delivery (OR 1.96, CI 1.26-3.05) and peripartum depression and/or anxiety (OR 2.17, CI 1.40-3.36) was demonstrated. CONCLUSION: Eating disorders in WWE contribute to the increased risk of pregnancy and delivery complications. Health personnel should be aware of eating disorders in WWE and refer them for treatment before pregnancy.

Psychiatric Comorbidity, Social Aspects and Quality of Life in a Population-Based Cohort of Expecting Fathers with Epilepsy.

OBJECTIVES: To investigate psychiatric disorders, adverse social aspects and quality of life in men with epilepsy during partner's pregnancy. METHOD: We used data from the Norwegian Mother and Child Cohort Study, including 76,335 men with pregnant partners. Men with epilepsy were compared to men without epilepsy, and to men with non-neurological chronic diseases. RESULTS: Expecting fathers in 658 pregnancies (mean age 31.8 years) reported a history of epilepsy, 36.9% using antiepileptic drugs (AEDs) at the onset of pregnancy. Symptoms of anxiety or depression were increased in epilepsy (7.0% and 3.9%, respectively) vs. non-epilepsy (4.6% and 2.5%, respectively, p = 0.004 and 0.023), and so were new onset symptoms of depression (2.0% vs. 1.0%, p < 0.031) and anxiety (4.3% vs. 2.3%, p = 0.023). Low self-esteem (2.5%) and low satisfaction with life (1.7%) were more frequent among fathers with epilepsy compared to fathers without epilepsy (1.3% and 0.7%, respectively, p = 0.01 and 0.010). Adverse social aspects and life events were associated with epilepsy vs. both reference groups. Self-reported diagnoses of ADHD (2.2%) and bipolar disorder (1.8%) were more common in epilepsy vs. non-epilepsy (0.4% and 0.3%, respectively, p = 0.002 and 0.003) and non-neurological chronic disorders (0.5% and 0.5%, respectively, p = 0.004 and 0.018). A screening tool for ADHD symptoms revealed a higher rate compared to self-reported ADHD (9.5% vs. 2.2%, p < 0.001). CONCLUSION: Expecting fathers with epilepsy are at high risk of depression and anxiety, adverse socioeconomic aspects, low self-esteem, and low satisfaction with life. Focus on mental health in fathers with epilepsy during and after pregnancy is important. The use of screening tools can be particularly useful to identify those at risk.

Fetal growth restriction and birth defects with newer and older antiepileptic drugs during pregnancy.

The primary aim of this study was to assess the risks of fetal growth restriction and birth defects in children exposed prenatally to newer and older antiepileptic drugs, using an unselected epilepsy cohort. Deliveries recorded in the compulsory Medical Birth Registry of Norway 1999-2011 formed the study population. All 2,600 children exposed to antiepileptic drugs during pregnancy were compared to all 771,412 unexposed children born to women without epilepsy. Children of untreated mothers with epilepsy served as an internal control group. The main outcomes were small for gestational age birth weight and head circumference, and major congenital malformations. Children exposed to antiepileptic drugs had a moderate risk of growth restriction. Infants exposed to topiramate had a considerable risk of microcephaly (11.4 vs. 2.4 %; OR 4.8; CI 2.5-9.3) and small for gestational age birth weight (24.4 vs. 8.9 %; OR 3.1; 95 % CI 1.9-5.3). Carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, gabapentin, and pregabalin had low malformation rates, whereas topiramate tended to have an elevated malformation rate. Valproate monotherapy was associated with a significant risk of birth defects (6.3 vs. 2.9 %; OR 2.5; CI 1.6-3.8), and specifically with septal heart defects and hypospadias. For mothers using valproate, the presence of major birth defect in one child was associated with a markedly increased risk for the siblings (42.9 vs. 6.7 %; OR 10.4; CI 2.3-46.7). Children of untreated mothers with epilepsy had malformation risk similar to the reference group. In conclusion, topiramate was associated with a substantial risk of fetal growth restriction, and possibly an increased malformation rate. Other newer-generation antiepileptic drugs had a low malformation rate. Valproate monotherapy had a significant malformation risk, especially in repeated pregnancies.

Early child development and exposure to antiepileptic drugs prenatally and through breastfeeding: a prospective cohort study on children of women with epilepsy.

IMPORTANCE: Exposure to antiepileptic drugs during pregnancy is associated with adverse effects on psychomotor development. OBJECTIVES: To determine whether signs of impaired development appear already during the first months of life in children exposed prenatally to antiepileptic drugs, and to explore potential adverse effects of antiepileptic drug exposure through breastfeeding. DESIGN, SETTING, AND PARTICIPANTS: Mothers at 13 to 17 weeks of pregnancy were recruited in the population-based, prospective Norwegian Mother and Child Cohort Study from 1999 to 2009. The mothers reported on their child's motor and social skills, language, and behavior using items from standardized screening tools at 6 months (n = 78,744), 18 months (n = 61,351), and 36 months (n = 44,147) of age. The mothers also provided detailed information on breastfeeding during the first year. MAIN OUTCOMES AND MEASURES The risk of adverse development in children according to maternal or paternal epilepsy was estimated as the odds ratio with corresponding 95% confidence interval, adjusted for maternal age, parity, education, smoking, breastfeeding, depression/anxiety, folate supplementation, and congenital malformation in the child. RESULTS: At age 6 months, infants of mothers using antiepileptic drugs (n = 223) had a higher risk of impaired fine motor skills compared with the reference group (11.5% vs 4.8%, respectively; odds ratio = 2.1; 95% CI, 1.3-3.2). Use of multiple antiepileptic drugs compared with the reference group was associated with adverse outcome for both fine motor skills (25.0% vs 4.8%, respectively; odds ratio = 4.3; 95% CI, 2.0-9.1) and social skills (22.5% vs 10.2%, respectively; odds ratio = 2.6; 95% CI, 1.2-5.5). Continuous breastfeeding in children of women using antiepileptic drugs was associated with less impaired development at ages 6 and 18 months compared with those with no breastfeeding or breastfeeding for less than 6 months. At 36 months, prenatal antiepileptic drug exposure was associated with adverse development regardless of breastfeeding status during the first year. Children of women with epilepsy who did not use antiepileptic drugs and children of fathers with epilepsy had normal development at 6 months. CONCLUSIONS AND RELEVANCE: Prenatal exposure to antiepileptic drugs was associated with impaired fine motor skills already at age 6 months, especially when the child was exposed to multiple drugs. There were no harmful effects of breastfeeding. Women with epilepsy should be encouraged to breastfeed their children irrespective of antiepileptic drug treatment.