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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 4â¯511â¯267 deliveries, of which 4â¯475â¯984 were to women without epilepsy and 35â¯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.
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To evaluate the risk of epilepsy in children who received neonatal phototherapy. A cohort of live singletons born at a Danish hospital (2002-2016) with a gestational age ≥ 35 weeks. We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of epilepsy in children treated with neonatal phototherapy compared to children not treated with neonatal phototherapy in the general population, and in a subpopulation of children who had serum bilirubin measurement. Adjusted HRs (aHR) were computed using multivariable and propensity score matching models to take maternal and neonatal factors into consideration. Children were followed from day 29 after birth to diagnosis of epilepsy, death, emigration, or December 31, 2016. Among 65,365 children, 958 (1.5%) received neonatal phototherapy. Seven children (incidence rates (IRs): 10.8 /10,000 person-years) who received neonatal phototherapy and 354 children (IR: 7.7) who did not receive neonatal phototherapy were diagnosed with epilepsy. Neonatal phototherapy was not associated with an increased risk of epilepsy using the multivariable (aHR 0.95, 95% CI: 0.43-2.09) and propensity score matched (aHR 0.94, 95% CI: 0.39-2.28) models. In the subpopulation of 9,378 children with bilirubin measurement, 928 (9.9%) received neonatal phototherapy. In the analysis of the subpopulation in which bilirubin level and age at the time of bilirubin measurement were further taking into consideration, neonatal phototherapy was not associated with an increased risk of epilepsy using the multivariable (aHR 1.26, 95% CI: 0.54-2.97) and propensity score matched (aHR 1.24, 95% CI: 0.47-3.25) models,Conclusions: Neonatal phototherapy was not associated with an increased risk of epilepsy after taking maternal and neonatal factors into consideration. What is known: ⢠A few studies have suggested that neonatal phototherapy for hyperbilirubinemia may increase the risk of childhood epilepsy. ⢠Whether the observed associations contribute to hyperbilirubinemia, phototherapy, or underlying factors requires further investigation. What is new: ⢠This study revealed no increased risk of epilepsy in children treated with neonatal phototherapy compared to children not treated with phototherapy after taking maternal and neonatal factors into consideration. ⢠After further taking bilirubin level and age at the time of bilirubin measurement into consideration, neonatal phototherapy was not associated with an increased risk of epilepsy.
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Epilepsia , Fototerapia , Humanos , Dinamarca/epidemiología , Femenino , Epilepsia/epidemiología , Epilepsia/etiología , Epilepsia/terapia , Masculino , Recién Nacido , Fototerapia/efectos adversos , Fototerapia/métodos , Factores de Riesgo , Incidencia , Lactante , Bilirrubina/sangre , Puntaje de Propensión , Hiperbilirrubinemia Neonatal/terapia , Hiperbilirrubinemia Neonatal/epidemiología , Hiperbilirrubinemia Neonatal/etiología , Modelos de Riesgos ProporcionalesRESUMEN
BACKGROUND: The association between stroke revascularization therapies and poststroke epilepsy is only sparsely investigated, and results are conflicting. The aim of this study is to investigate whether stroke revascularization therapies are associated with different risks of poststroke epilepsy. METHODS AND RESULTS: We conducted a nationwide, register-based, propensity score-matched cohort study. We identified 40 816 patients admitted with a first ischemic stroke and no prior history of epilepsy in Denmark between January 1, 2011, and December 16, 2018. Of these, 6541 were treated with thrombolysis, 379 with thrombectomy, and 1005 with both thrombolysis and thrombectomy. The 3 treatment groups were each matched 1:1 to patients with stroke not treated with revascularization. Exact matching was done for sex, while propensity scores included information on stroke severity, cortical involvement, age, comorbidities, and socioeconomic parameters. Outcome was any diagnosis of epilepsy. We used Cox regressions to estimate adjusted hazard ratios (HRs) of epilepsy after ischemic stroke. Compared with matched patients with ischemic stroke not receiving revascularization treatment, patients who received thrombolysis alone had 32% lower risk of epilepsy (adjusted HR, 0.68 [95% CI, 0.57-0.81]) and patients who received thrombolysis and thrombectomy had 45% lower risk of epilepsy (adjusted HR, 0.55 [95% CI, 0.41-0.73]). Thrombectomy alone was not associated with significantly lower risk of epilepsy compared with matched patients with ischemic stroke not receiving revascularization therapy (adjusted HR, 0.78 [95% CI, 0.57-1.29]). CONCLUSIONS: Thrombolysis alone and in combination with thrombectomy in ischemic stroke was associated with lower risk of epilepsy, whereas thrombectomy alone was not associated with lower risk of epilepsy.
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Epilepsia , Accidente Cerebrovascular Isquémico , Sistema de Registros , Terapia Trombolítica , Humanos , Dinamarca/epidemiología , Femenino , Masculino , Accidente Cerebrovascular Isquémico/epidemiología , Accidente Cerebrovascular Isquémico/diagnóstico , Accidente Cerebrovascular Isquémico/cirugía , Epilepsia/epidemiología , Anciano , Persona de Mediana Edad , Terapia Trombolítica/efectos adversos , Factores de Riesgo , Medición de Riesgo , Trombectomía/efectos adversos , Anciano de 80 o más Años , Puntaje de Propensión , Resultado del TratamientoRESUMEN
Importance: Concerns exist about teratogenic and long-term neurodevelopmental outcomes of paternal use of valproate during spermatogenesis. Objective: To evaluate the association between paternal use of valproate during spermatogenesis and offspring risk of congenital malformations and neurodevelopmental disorders. Design, Setting, and Participants: This nationwide cohort study included 1â¯235â¯353 singletons born in Denmark between January 1, 1997, and December 31, 2017, identified in the Medical Birth Register; 1336 children had fathers who had filled prescriptions for valproate during spermatogenesis. Congenital malformations were identified in the first year of life and neurodevelopmental disorders were identified from 1 year of age until December 31, 2018. Statistical analysis was performed March 2024. Exposures: Paternal valproate exposure was defined as fathers who filled 1 or more prescriptions for valproate immediately before or during the time of spermatogenesis (ie, 3 months prior to conception). Main Outcomes and Measures: Children with major congenital malformations in the first year of life and with neurodevelopmental disorders before death or end of follow-up were identified in Danish health registers. Log-binomial regression was used to estimate adjusted relative risks (ARRs) of congenital malformations, and Cox proportional hazards regression was used to estimate adjusted hazards ratios (AHRs) of neurodevelopmental disorders, adjusted for relevant confounders. Results: Among 1â¯235â¯353 live births (634â¯415 boys [51.4%] and 600â¯938 girls [48.6%]), 1336 children (0.1%) had fathers who filled prescriptions for valproate during spermatogenesis. The median follow-up was 10.1 years (IQR, 5.1-14.8 years) for valproate-exposed children and 10.3 years (IQR, 5.2-15.6 years) for valproate-unexposed children. A total of 43â¯903 children (3.6%) received a diagnosis of major congenital malformations in the first year of life, and 51â¯633 children (4.2%) received a diagnosis of neurodevelopmental disorders during follow-up. When comparing the risk among valproate-exposed children with that among unexposed children, the ARR of major congenital malformations was 0.89 (95% CI, 0.67-1.18), the AHR of neurodevelopmental disorders was 1.10 (95% CI, 0.88-1.37), and the AHR of autism spectrum disorder was 0.92 (95% CI, 0.65-1.30). In analyses addressing the robustness of the findings (ie, dose-response analyses, sibling analyses, analyses restricted to children of fathers with epilepsy, analyses that used children with paternal lamotrigine exposure as active comparator, and analyses that used children with paternal exposure to valproate only before spermatogenesis as a negative control exposure), there still was no increased risk of any of the included end points. Conclusions and Relevance: In all analyses based on this large Danish cohort study, results suggest that exposure to valproate during spermatogenesis was not associated with offspring risk of congenital malformations or neurodevelopmental disorders, including autism spectrum disorder.
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Trastornos del Neurodesarrollo , Espermatogénesis , Ácido Valproico , Humanos , Ácido Valproico/efectos adversos , Ácido Valproico/uso terapéutico , Masculino , Dinamarca/epidemiología , Espermatogénesis/efectos de los fármacos , Femenino , Trastornos del Neurodesarrollo/epidemiología , Trastornos del Neurodesarrollo/inducido químicamente , Lactante , Adulto , Estudios de Cohortes , Preescolar , Niño , Exposición Paterna/efectos adversos , Anticonvulsivantes/efectos adversos , Anticonvulsivantes/uso terapéutico , Sistema de Registros , Recién Nacido , Anomalías Inducidas por Medicamentos/epidemiología , Factores de Riesgo , Anomalías Congénitas/epidemiología , Efectos Tardíos de la Exposición Prenatal/epidemiología , Efectos Tardíos de la Exposición Prenatal/inducido químicamenteRESUMEN
PURPOSE: The purpose was to examine the correlation of antiseizure medication drug dose estimated from prescription fill records from prescription registers with blood levels during pregnancy. METHODS: We conducted a Nation-wide study of mothers who gave birth in Denmark between 1 January 2014 and 31 December 2018 using data from Danish Prescription and Laboratory Registers. We identified mothers with blood level measurements of antiseizure medication. The main exposure was estimated antiseizure medication dosage estimated from pregnancy-filled prescriptions in the Danish Prescription Register. The main outcome was the correlation of estimated dose with mean blood level of antiseizure medication in pregnancy. For privacy reasons, the number of blood level measurement and prescription fills were rounded to nearest 10, but proportions reported as exact values. RESULTS: Among 298 560 pregnancies, we identified pregnancies with recorded prescription fill from the prescription register for valproate (N = 90), lamotrigine (N = 1360), levetiracetam (N = 340), topiramate (N = 100), and carbamazepine (N = 60). In these pregnancies, blood level measurements were available in 50 (53%) pregnancies for valproate, 850 (62%) pregnancies for lamotrigine, 320 (93%) pregnancies for levetiracetam, 50 (68%) pregnancies for carbamazepine, and 40 (35%) pregnancies for topiramate. Pearsons's correlation coefficients for the correlation of estimated antiseizure medication dose with mean blood levels were 0.67 (p < 0.0001) for valproate, 0.63 (p < 0.0001) for lamotrigine, 0.63 (p < 0.0001) for levetiracetam, 0.76 (<0.0001) for carbamazepine and 0.89 (<0.0001) for topiramate. CONCLUSIONS: Dose of antiseizure medication estimated from prescription fills was a good proxy for blood levels and thus for biological exposure in pregnancy, suggesting that administrative prescription fill records may be a valuable resource for estimating exposure to antiseizure medication in pregnancy.
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Anticonvulsivantes , Sistema de Registros , Humanos , Femenino , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/sangre , Embarazo , Dinamarca , Adulto , Complicaciones del Embarazo/tratamiento farmacológico , Complicaciones del Embarazo/sangre , Prescripciones de Medicamentos/estadística & datos numéricos , Adulto Joven , Carbamazepina/administración & dosificación , Ácido Valproico/administración & dosificación , Ácido Valproico/sangre , Epilepsia/tratamiento farmacológico , Lamotrigina/administración & dosificación , Levetiracetam/administración & dosificación , Topiramato/administración & dosificaciónRESUMEN
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.
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Anticonvulsivantes , Epilepsia , Complicaciones del Embarazo , Humanos , Femenino , Epilepsia/tratamiento farmacológico , Epilepsia/epidemiología , Embarazo , Anticonvulsivantes/uso terapéutico , Adulto , Complicaciones del Embarazo/tratamiento farmacológico , Complicaciones del Embarazo/epidemiología , Estudios Transversales , Factores Socioeconómicos , Países Escandinavos y Nórdicos/epidemiología , Adulto Joven , Clase Social , Sistema de RegistrosRESUMEN
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).
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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.
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Anticonvulsivantes , Epilepsia , Ácido Fólico , Pautas de la Práctica en Medicina , Complicaciones del Embarazo , Humanos , Femenino , Ácido Fólico/administración & dosificación , Ácido Fólico/uso terapéutico , Epilepsia/tratamiento farmacológico , Anticonvulsivantes/uso terapéutico , Anticonvulsivantes/administración & dosificación , Embarazo , Adulto , Noruega/epidemiología , Dinamarca/epidemiología , Pautas de la Práctica en Medicina/estadística & datos numéricos , Pautas de la Práctica en Medicina/tendencias , Complicaciones del Embarazo/tratamiento farmacológico , Suecia/epidemiología , Estudios Retrospectivos , Adulto Joven , Suplementos DietéticosRESUMEN
BACKGROUND: Stroke is associated with a risk of epilepsy, but associations with age, sex, stroke type and severity, time trends, and mortality are uncertain. We studied the risk of epilepsy after stroke while accounting for sex, age, stroke types and severity, calendar time, and death. METHODS: This was a prospective nationwide register-based, matched cohort study of patients admitted with a validated first stroke in Denmark from April 1, 2004, to December 16, 2018, excluding those with prior epilepsy. Patients with stroke were matched 10:1 on age, sex, and calendar time with reference people without prior epilepsy or stroke. We estimated the cumulative incidence of an epilepsy diagnosis in the Danish National Patient Registry (International Classification of Diseases Tenth Revision: G40) with death as a competing risk using competing risk regression and estimated adjusted hazard ratios by Cox regression models. RESULTS: We identified 101â 034 patients with stroke (46.5% female; mean age, 70.4 years) who survived 14 days after stroke along with 1â 010â 333 matched reference people. Two years after the stroke, the cumulative incidence of epilepsy was 3.0% (95% CI, 2.9-3.2) after ischemic stroke and 8.6% (95% CI, 8.0-9.2) after intracerebral hemorrhage versus 0.7% (95% CI, 0.7-0.7) in the matched references. Compared with the reference population, the 2-year hazard ratio of epilepsy was 21.7 (95% CI, 20.3-23.2) after ischemic stroke and 61.3 (95% CI, 51.1-73.4) after intracerebral hemorrhage. The risk of epilepsy increased with stroke severity; the 2-year cumulative incidence of epilepsy was 10.5% (95% CI, 9.5-11.4) for very severe ischemic stroke and 13.1% (95% CI, 11.1-15.1) after very severe intracerebral hemorrhage. CONCLUSIONS: In this population-based study of patients with validated stroke, the absolute and relative risk estimates of poststroke epilepsy were lower compared with previous studies. Reasons for the lower risk estimates include accounting for the high mortality associated with stroke, which had a significant impact on risk especially for severe stroke.
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Epilepsia , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Humanos , Femenino , Anciano , Masculino , Estudios de Cohortes , Estudios Prospectivos , Factores de Riesgo , Accidente Cerebrovascular/complicaciones , Hemorragia Cerebral/complicaciones , Epilepsia/epidemiología , Accidente Cerebrovascular Isquémico/complicaciones , Dinamarca/epidemiologíaRESUMEN
Importance: Use of valproate and certain other antiseizure medications (ASMs) in pregnancy is associated with abnormal fetal brain development with potential long-term implications for the child. Objective: To examine whether use of valproate and other ASMs in pregnancy among mothers with epilepsy is associated with epilepsy risk in their children. Design, Setting, and Participants: This prospective, population-based register cohort study included singletons born to mothers with epilepsy in Denmark, Finland, Iceland, Norway, and Sweden from January 1, 1996, to December 31, 2017. Data analysis was performed from October 2022 to December 2023. Exposure: Redeemed prescription for an ASM from 30 days before pregnancy until birth. Main Outcomes and Measures: The main outcome was epilepsy in children, assessed using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnoses from hospital care. Adjusted hazard ratios (AHRs) and 95% CIs were estimated using Cox proportional hazards regression. Secondary analyses included dose-response analyses, analyses using children of mothers who discontinued ASM prior to pregnancy as the reference, and sibling analyses. Results: This cohort study included 38â¯663 children of mothers with epilepsy (19â¯854 [51.4%] boys). Children were followed up from birth; the mean length of follow-up was 7.2 years (range 0-22 years). Compared with 22â¯207 children of mothers not using an ASM in pregnancy, increased risks of epilepsy in children of mothers who used valproate in pregnancy (monotherapy: AHR, 2.18; 95% CI, 1.70-2.79; polytherapy: AHR, 2.10; 95% CI, 1.49-2.96) were observed. However, there was no dose-dependent association, and there was a similar risk of epilepsy in siblings who were exposed and unexposed to valproate (AHR, 0.95; 95% CI, 0.50-1.82). Prenatal exposure to topiramate monotherapy was associated with increased risk of epilepsy (AHR, 2.32; 95% CI, 1.30-4.16), and the risk was greater for higher doses, but the risk attenuated in comparisons with children of mothers who discontinued topiramate before pregnancy (AHR, 1.19; 95% CI, 0.26-5.44). Prenatal exposure to clonazepam monotherapy was also associated with increased epilepsy risk (AHR, 1.90; 95% CI, 1.16-3.12), but limited follow-up and low numbers precluded further analyses. No associations were observed for prenatal exposure to lamotrigine (AHR, 1.18; 95% CI, 0.95-1.47), levetiracetam (AHR, 1.28; 95% CI, 0.77-2.14), carbamazepine (AHR, 1.13; 95% CI, 0.85-1.50), or oxcarbazepine (AHR, 0.68; 95% CI, 0.44-1.05). Conclusions and Relevance: In this cohort study of children born to mothers with epilepsy, the associations found between prenatal exposure to certain ASMs and the child's risk of epilepsy did not persist in sensitivity analyses, suggesting that maternal ASM use in pregnancy may not increase epilepsy risk in children beyond that associated with the maternal epilepsy itself. These findings are reassuring for women in need of treatment with ASM in pregnancy.
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Epilepsia , Efectos Tardíos de la Exposición Prenatal , Masculino , Niño , Embarazo , Humanos , Femenino , Ácido Valproico/efectos adversos , Topiramato , Estudios de Cohortes , Efectos Tardíos de la Exposición Prenatal/epidemiología , Estudios Prospectivos , Epilepsia/tratamiento farmacológico , Epilepsia/epidemiología , Vitaminas , MadresRESUMEN
BACKGROUND: Depression is detrimental to partnership stability. However, it remains unclear if and how the duration and timing of depression affect the risk of family dissolution. METHODS: We conducted a Danish register-based cohort study of newly-formed cohabiting and married couples in 2008 and 2009, who were followed from the second year after family formation. Depressive episodes were defined by individual-level prescription patterns of antidepressant drugs (ATC codes N06A) in either partner. Family dissolution was characterized by the discontinuation of a shared residential address. Using Longitudinal Targeted Minimum Loss-based Estimation, we estimated the risk of family dissolution after 5 years of follow-up under various lengths and timings of depressive episodes. RESULTS: There were 102,335 families included. The covariate-adjusted risk of family dissolution in families without depressive episodes was 30.0 % (95 % CI 29.6-30.4 %) and 35.5 % (95 % CI 29.5-41.5 %) in families with at least one depressive episode during follow-up. The risk of family dissolution increased with the duration of depressive episodes to 42.2 % (95 % CI 40.8-43.6 %) for five coherent years of depression. Depression shortly after family formation carried higher risk of family dissolution; this risk was 42.3 % (95 % CI 38.4-46.3 %) for depression experienced in the first year of family formation versus 32.9 % (95 % CI 31.8-34.0 %) in the fifth year of family formation. LIMITATIONS: Proxy measures of depression by antidepressant prescriptions fails to identify milder depression. Annual measures of family dissolution precluded more fine-grained analyses of time-intervals. CONCLUSIONS: Depression is disruptive to family stability, particularly with longer duration and early onset after family formation.
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Depresión , Trastorno Depresivo , Humanos , Estudios de Cohortes , Depresión/epidemiología , Trastorno Depresivo/tratamiento farmacológico , Antidepresivos/uso terapéutico , Dinamarca/epidemiologíaRESUMEN
Importance: Studies are lacking summarizing how the association between mental disorders and mortality varies by socioeconomic position (SEP), particularly considering different aspects of SEP, specific types of mental disorders, and causes of death. Objective: To investigate the role of SEP in the association between mental disorders and mortality and the association between SEP and mortality among people with mental disorders. Data Sources: MEDLINE, Embase, PsycINFO, and Web of Science were searched from January 1, 1980, through April 3, 2023, and a snowball search of reference and citation lists was conducted. Study Selection: Inclusion criteria were observational studies estimating the associations between different types of mental disorders and mortality, stratified by SEP and between SEP and mortality in people with mental disorders. Data Extraction and Synthesis: Pairs of reviewers independently extracted data using a predefined data extraction form and assessed the risk of bias using the adapted Newcastle-Ottawa scale. Graphical analyses of the dose-response associations and random-effects meta-analyses were performed. Heterogeneity was explored through meta-regressions and sensitivity analyses. Main Outcomes and Measures: All-cause and cause-specific mortality. Results: Of 28â¯274 articles screened, 71 including more than 4 million people with mental disorders met the inclusion criteria (most of which were conducted in high-income countries). The relative associations between mental disorders and mortality were similar across SEP levels. Among people with mental disorders, belonging to the highest rather than the lowest SEP group was associated with lower all-cause mortality (pooled relative risk [RR], 0.79; 95% CI, 0.73-0.86) and mortality from natural causes (RR, 0.73; 95% CI, 0.62-0.85) and higher mortality from external causes (RR, 1.18; 95% CI, 0.99-1.41). Heterogeneity was high (I2 = 83% to 99%). Results from subgroup, sensitivity, and meta-regression analyses were consistent with those from the main analyses. Evidence on absolute scales, specific diagnoses, and specific causes of death was scarce. Conclusion and Relevance: This study did not find a sufficient body of evidence that SEP moderated the relative association between mental disorders and mortality, but the underlying mortality rates may differ by SEP group, despite having scarcely been reported. This information gap, together with our findings related to SEP and a possible differential risk between natural and external causes of death in individuals with specific types of mental disorders, warrants further research.
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Trastornos Mentales , Humanos , Factores SocioeconómicosRESUMEN
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.
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Ácido Fólico , Neoplasias , Embarazo , Femenino , Humanos , Niño , Ácido Fólico/efectos adversos , Suplementos Dietéticos/efectos adversos , Riesgo , Familia , Neoplasias/inducido químicamente , Neoplasias/epidemiología , Neoplasias/tratamiento farmacológicoRESUMEN
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 4â¯546â¯605 singleton children born alive in Denmark, Finland, Iceland, Norway, and Sweden from January 1, 1996, to December 31, 2017. Of the 4â¯546â¯605 children, 54â¯953 with chromosomal disorders or uncertain birth characteristics were excluded, and 38â¯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 38â¯661 children of mothers with epilepsy (16â¯458 [42.6%] exposed to ASM; 19â¯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.
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Trastorno por Déficit de Atención con Hiperactividad , Epilepsia , Efectos Tardíos de la Exposición Prenatal , Embarazo , Niño , Femenino , Masculino , Adolescente , Humanos , Preescolar , Ácido Valproico/uso terapéutico , Lamotrigina/uso terapéutico , Incidencia , Levetiracetam/uso terapéutico , Topiramato/uso terapéutico , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Estudios Prospectivos , Anticonvulsivantes/uso terapéutico , Epilepsia/tratamiento farmacológico , Oxcarbazepina/uso terapéutico , Carbamazepina/uso terapéutico , Trastorno por Déficit de Atención con Hiperactividad/epidemiologíaRESUMEN
Attention Deficit Hyperactivity Disorder (ADHD) medication is increasingly being used during pregnancy. Concerns have been raised as to whether ADHD medication has long-term adverse effects on the offspring. The authors investigated whether in utero exposure to ADHD medication was associated with adverse long-term neurodevelopmental and growth outcomes in offspring. The population-based cohort study in the Danish national registers included 1,068,073 liveborn singletons from 1998 to 2015 followed until any developmental diagnosis, death, emigration, or December 31, 2018. Children of mothers who continued ADHD medication (methylphenidate, amphetamine, dexamphetamine, lisdexamphetamine, modafinil, atomoxetine, clonidine) during pregnancy and children of mothers who discontinued ADHD medication before pregnancy were compared using Cox regression. Main outcomes were neurodevelopmental psychiatric disorders, impairments in vision or hearing, epilepsy, seizures, or growth impairment during childhood or adolescence. In total, 898 children were exposed to ADHD medication during pregnancy compared to 1270 children whose mothers discontinued ADHD medication before pregnancy. After adjustment for demographic and psychiatric characteristics of the mother, no increased risk of any offspring developmental disorders was found combined (aHR 0.97, 95% CI 0.81 to 1.17) or for separate subcategories. Similarly, no increased risk was found for any sub-categories of outcomes in the negative control or sibling controlled analyses. Neurodevelopment and growth in offspring do not differ based on antenatal exposure to ADHD medication. These findings provide reassurance for women with ADHD who depend on ADHD medication for daily functioning and who consider continuing medication in pregnancy.
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Trastorno por Déficit de Atención con Hiperactividad , Metilfenidato , Madres , Efectos Tardíos de la Exposición Prenatal , Adulto , Preescolar , Femenino , Humanos , Lactante , Embarazo , Anfetaminas/efectos adversos , Anfetaminas/uso terapéutico , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Clonidina/efectos adversos , Clonidina/uso terapéutico , Estudios de Cohortes , Dinamarca/epidemiología , Edad Gestacional , Metilfenidato/efectos adversos , Metilfenidato/uso terapéutico , Modafinilo/efectos adversos , Modafinilo/uso terapéutico , Madres/psicología , Trastornos del Neurodesarrollo/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/epidemiología , Sistema de RegistrosRESUMEN
Purpose: Phototherapy is the standard treatment for neonatal hyperbilirubinemia. It is important to collect data on phototherapy to support research related to the efficacy and safety of phototherapy. We explored the registration of phototherapy in the Danish National Patient Registry (DNPR) and the clinical characteristics of neonates treated with phototherapy. Methods: We identified children born alive in Denmark from 1 January 2000 through 30 November 2016 from the DNPR (N=1,044,502). We calculated the proportion of children registered that received phototherapy during the neonatal period and examined temporal trends, both nationwide and at the level of individual hospitals. In a sub-cohort of children born at Aarhus University Hospital (AUH) in 2002-2016 (N=71,781), we analyzed the proportions of children registered that received phototherapy, according to sex, gestational age, birth weight, and neonatal characteristics, like Apgar score, birth asphyxia, and infections. Results: We identified 11,295 (1.1%) registered that received phototherapy. The proportions of children registered that received phototherapy differed among hospitals (range: 0 to 4.1%). Nationwide registration was low during the study period, but it increased to 1.8% in 2016. For the AUH sub-cohort the proportion of children registered with phototherapy averaged 4.4% (N=3182, range:3.9-5.1%). The proportion of children registered with phototherapy was inversely correlated with gestational age and birth weight, and positively correlated with neonatal characteristics, including low Apgar score, birth asphyxia, and infections. Conclusion: Phototherapy was under-reported in the DNPR and the proportions of children registered that received phototherapy differed among hospitals. The non-compulsory policy for reporting treatment and care in hospitals to the DNPR might explain the variation. The most consistent reporting was observed among children born in an university hospital, where 4.4% of children registered that received phototherapy, and phototherapy was inversely associated with gestational age, birth weight, and positively associated with clinical characteristics like birth asphyxia, and infections.
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PURPOSE: This study estimated epilepsy prevalence, psychiatric co-morbidity and annual costs associated with epilepsy. METHODS: We used Danish national health registers to identify persons diagnosed with epilepsy and psychiatric disorders, and persons using antiseizure medication and persons using drugs for psychiatric disorders. We calculated the prevalence of epilepsy and co-morbid psychiatric disorders in Denmark on December 31, 2016, using information on epilepsy and psychiatric disorders based on combinations of hospital contacts and use of antiseizure and psychoactive medication. Further, direct and indirect annual costs associated with epilepsy were calculated using individual-level data from a range of socioeconomic registers. RESULTS: There were 5,044,367 persons alive and living in Denmark on December 31, 2016, including 33,628 persons with at least one hospital contact with epilepsy in the previous five years (epilepsy prevalence 0.67% (0.69% males; 0.65% females)). Among these persons with epilepsy, we identified 12,562 (37.4%) persons with a psychiatric disorder or use of drugs used for psychiatric disorders as compared with 801,052 (15.9%) persons in the general population. The estimated total annual individual net costs associated with epilepsy was 30,683. Compared with prevalence estimates on December 31, 2006, the prevalence of epilepsy on December 31, 2016, was slightly higher in the older population and slightly lower in children CONCLUSIONS: Population estimates from national registers provide epilepsy prevalence estimates of approximately 0.6-0.7% - similar to previous reviews of epilepsy prevalence. In addition, the national sample allowed idenitfication of high prevalence of psychiatric disorders and high societal costs associated with epielspy.
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Epilepsia , Trastornos Mentales , Niño , Masculino , Femenino , Humanos , Prevalencia , Epilepsia/tratamiento farmacológico , Epilepsia/epidemiología , Comorbilidad , Trastornos Mentales/epidemiología , Costos y Análisis de Costo , Dinamarca/epidemiologíaRESUMEN
Mortality rates are two to three times higher in people with epilepsy than in the general population. This study aimed to quantify how this increased mortality translates into reduced life expectancy and to identify the underlying causes of deaths, thereby offering suggestions for how to reduce mortality associated with epilepsy. In this population-based cohort study, we included all individuals aged 0-94 years who were living in Denmark between 2000 and 2015. Using the nationwide registers, we identified people diagnosed with epilepsy and estimated the excess of life years lost due to 13 overall and nine specific causes of death. Among 6 022 160 people, we identified 129 598 with epilepsy (52.6% males), with a mean age of epilepsy onset of 36.5 years (standard deviation = 26.3 years). During the 16 years of follow-up, 851 087 individuals died, and of these 36 923 had been diagnosed with epilepsy. The average reduction in life expectancy in people with epilepsy was 11.84 years in males (95% confidence interval: 11.66-12.00) and 10.91 years in females (95% confidence interval: 10.70-11.11) compared to the general population. Life expectancy was reduced irrespective of epilepsy aetiology (symptomatic â¼14 years; idiopathic â¼8-10 years), and in particular in people with epilepsy and psychiatric comorbidity (â¼13-16 years). Excess mortality was evident across all causes of death including cardiovascular disorders, accidents, and suicide. People with epilepsy experience a substantial reduction in lifespan that can only partly be explained by underlying conditions. Prevention of epilepsy-related deaths should focus on the consequences of psychiatric comorbidity and on modifiable risk factors associated with preventable causes of death such as accidents and neurological and cardiovascular disorders.