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Purpose: Cancer and birth defects cluster in families more often than expected by chance, but the reasons are neither well known nor well studied.Methods: From singletons born alive in Denmark between 1 January 1977 and 31 December 2007, we identified children who had no congenital malformations but had a full or half sibling with a congenital malformation (CM) diagnosed in the first year of life; this constituted the exposed group, while children whose siblings had no such condition constituted a reference group. We estimated cancer risks for children who had a full sibling or a half sibling with a CM using a Cox proportional hazards regression model. To control for confounding related to change of family structure, we estimated cancer risks for children from core families and children from broken families separately. Children were followed from birth up to 30 years of age (median follow-up 13.6 years). We obtained information on CMs and cancer from the Danish National Hospital Register and the Danish Cancer Registry.Results: We identified 991,454 (78%) children from core families with 53,995 children who had a full sibling with a CM and 277,773 (22%) children from broken families with 7200 children who had a full sibling with a CM and 6194 children who had a half sibling with a CM. Children who had a full sibling with a CM from both core and broken families showed, in general, no increased cancer risk compared with children whose siblings had no CM, except in the case of children who had a full sibling with a CM in the nervous system (HR=2.61, 95%CI:1.60-4.27) or in the eye, ear, face, or neck (HR=2.47, 95%CI: 1.46-4.18). Children who had a half sibling with a CM seemed to have a higher cancer risk in early adulthood (HR=1.87, 95%CI: 0.98-3.56).Conclusions: Children who had a full sibling with a CM had no increased risk of cancer except for those who had a full sibling with a CM in the nervous system or in the eye, ear, face or neck. Children with a half-sibling with a CM tended to have an increased cancer risk in early adulthood, perhaps a result of chance. This study should be replicated using other data sources. [ABSTRACT FROM AUTHOR]

Background: Term birth is a gestational age from 259 days to 293 days. However trends in mortality according to gestational ages in days have not yet been described in this time period. Methods and Findings: Based on nation-wide registries, we conducted a population-based cohort study among all children born at term in Denmark from 1997 to 2004 to estimate differences in mortality across gestational ages in days among singletons born at term. We studied early-neonatal mortality, neonatal mortality, infant mortality, and five-year mortality. Children were followed from birth up to the last day of the defined mortality period or December 31, 2009. A total of 360,375 singletons born between 259 and 293 days of gestation were included in the study. Mortality decreased with increasing gestational age in days and the highest mortality was observed among children born at 37 week of gestation. A similar pattern was observed when analyses were restricted to children born to by mothers without pregnancy complications. Conclusions: This study demonstrates heterogeneity in mortality rates even among singletons born at term. The highest mortality was observed among children born 37 weeks of gestation, which call for cautions when inducing labor in term pregnancies just reaching 37 weeks of gestation. The findings support that 37 weeks of gestation should be defined as early term. [ABSTRACT FROM AUTHOR]

Background: Depression is common after a cancer diagnosis and is associated with an increased mortality, but it is unclear whether depression occurring before the cancer diagnosis affects cancer mortality. We aimed to study cancer mortality of people treated with antidepressants before cancer diagnosis. Methods and Findings: We conducted a population based cohort study of all adults diagnosed with cancer between January 2003 and December 2010 in Denmark (N = 201,662). We obtained information on cancer from the Danish Cancer Registry, on the day of death from the Danish Civil Registry, and on redeemed antidepressants from the Danish National Prescription Registry. Current users of antidepressants were defined as those who redeemed the latest prescription of antidepressant 0–4 months before cancer diagnosis (irrespective of earlier prescriptions), and former users as those who redeemed the latest prescription five or more months before cancer diagnosis. We estimated an all-cause one-year mortality rate ratio (MRR) and a conditional five-year MRR for patients who survived the first year after cancer diagnosis and confidence interval (CI) using a Cox proportional hazards regression model. Overall, 33,111 (16.4%) patients redeemed at least one antidepressant prescription in the three years before cancer diagnosis of whom 21,851 (10.8%) were current users at the time of cancer diagnosis. Current antidepressant users had a 32% higher one-year mortality (MRR = 1.32, 95% CI: 1.29–1.35) and a 22% higher conditional five-year mortality (MRR = 1.22, 95% CI: 1.17–1.26) if patients survived the first year after the cancer diagnosis than patients not redeeming antidepressants. The one-year mortality was particularly high for patients who initiated antidepressant treatment within four months before cancer diagnosis (MRR = 1.54, 95% CI: 1.47–1.61). Former users had no increased cancer mortality. Conclusions: Initiation of antidepressive treatment prior to cancer diagnosis is common and is associated with an increased mortality. [ABSTRACT FROM AUTHOR]

Highlights: [•] The study estimated the association between 25 maternal antigen-specific antibodies and risk of epilepsy in childhood. [•] Higher levels of maternal antibodies against herpes simples virus type 1 (HSV1) were associated with a higher risk of childhood epilepsy. [•] Higher levels of maternal antibodies against pneumoccocal polysaccharide 18 (PnPS18) were associated with a lower risk of childhood epilepsy. [•] The associations were stronger for certain types of epilepsy. [ABSTRACT FROM AUTHOR]

The article discusses a study of the risk of febrile seizures and epilepsy after diphtheria-tetanus toxoids-acellular pertussis-inactivated poliovirus-Haemophilus influenzae type b (DTaP-IPV-Hib) vaccination in Denmark. The study involved 388,817 children born from 2003 to 2008. Results show that 2.1% of the children exposed to DTap-IPV-Hib vaccination were diagnosed with febrile seizures before 18 months. Also cited is the finding that febrile seizure risks increased on the day of the first and second vaccinations. It concludes that there is no correlation between the vaccination and increased risk for epilepsy.

Sun Y, Vestergaard M, Christensen J, Olsen J. Prenatal exposure to elevated maternal body temperature and risk of epilepsy in childhood: a population-based pregnancy cohort study. Paediatric and Perinatal Epidemiology 2010. Elevated maternal body temperature during pregnancy is of clinical concern as side effects have been reported. We estimated the association between maternal fever and sauna bathing during pregnancy and risk of epilepsy in the offspring. We identified 86 810 liveborn singletons from the Danish National Birth Cohort (DNBC) and followed them for up to 9 years of age. Information on fever including number, timing, level, duration, and symptoms of each fever episodes was collected in two computer-assisted telephone interviews around 17 and 32 gestational weeks; information on maternal use of a sauna was collected in the latter interview, and information on epilepsy was obtained from the Danish National Hospital Register. We applied Cox regression models to estimate the incidence rate ratios (IRR) of epilepsy for children exposed to maternal fever and sauna bathing during pregnancy. Maternal sauna bathing during pregnancy was not associated with an increased risk of epilepsy. Maternal fever during pregnancy in general was not associated with an increased risk of epilepsy in the offspring [IRR = 1.01, 95% confidence interval (CI) 0.85, 1.19], and no dose-response pattern was found according to number, level and duration of fever. However we did find an increased risk of epilepsy among children exposed to at least 3 fever episodes (IRR = 1.88, 95% CI 1.19, 2.98), to maternal fever with symptoms in the urinary system (IRR = 4.86, 95% CI 1.56, 15.17), and to one-day maternal fever of 39.0-39.4°C (IRR = 2.79, 95% CI 1.60, 4.84). Our findings do not support a strong association between hyperthermia and epilepsy but the associations between underlying causes of fever, especially prenatal infections, call for more research. [ABSTRACT FROM AUTHOR]

Summary: Aim of the study: To estimate if maternal intake of n-3 long-chain polyunsaturated fatty acids (LCPUFA) during pregnancy is related to the risk of epilepsy in the offspring. Methods: We identified 65,754 live-born singletons from the Danish National Birth Cohort (DNBC, 1996–2002) and followed them for up to 11 years of age. Information on maternal diet in the 4 weeks around the 25th gestational week was obtained from a self-administered food frequency questionnaire and maternal intake of n-3 LCPUFA was estimated from the reported amount and type of fish in diet. Information on epilepsy was obtained from the Danish National Hospital Register. Cox regression models were used to estimate the incidence rate ratios (IRR) of epilepsy. Results: Children born to mothers in the lowest (IRR=1.28, 95% CI: 0.98, 1.67) and highest (IRR=1.33, 95% CI: 1.02, 1.74) quintile of n-3 LCPUFA intake had an increased risk of epilepsy after adjustment for potential confounders compared to children born to mothers with an average intake. The associations may be related to the age of onset of epilepsy. Conclusions: Maternal deficiency of n-3 LCPUFA and a high intake of n-3 LCPUFA perhaps related to a high consumption of contaminated fish may be associated with an increased risk of epilepsy in early childhood. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective Methods Results Significance 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.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.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).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. [ABSTRACT FROM AUTHOR]

Objectives: Traumatic brain injury (TBI) and perinatal adversities such as low gestational age at birth, low birth weight, low Apgar, and being born small for gestational age are well‐established risk factors for epilepsy. We examined whether perinatal adversities modified the risk of epilepsy after TBI in a nationwide cohort study of Danish singletons born from 1982 to 2011. Materials and Methods: We categorized perinatal adversities as a composite measure of preterm delivery, low birth weight, low Apgar score, or being born small for gestational age. Cox regression and competing risk regression were used to estimate the risk of epilepsy after TBI according to such perinatal adversities. The study included 1,715,095 singletons (51.1% males). The mean age at end of follow‐up was 19.3 years (Interquartile range [IQR] = 12.1–26.3). During follow‐up, 85,636 persons (58.2% males) sustained a TBI and 18,064 developed epilepsy (50.7% males), of whom 1329 persons had a preceding TBI. Results: The hazard ratio (HR) of epilepsy in persons with perinatal adversities was 1.19 (95% confidence interval [CI] 1.15–1.24), compared to persons without. The HR of epilepsy in persons with TBI was 2.31 (95% CI 2.18–2.45) compared to persons without TBI, but this risk was not modified by perinatal adversities (p = 0.2460). Conclusions: Perinatal adversities and TBI both increased the risk of epilepsy, but the risk of epilepsy after TBI was not modified by these perinatal adversities. [ABSTRACT FROM AUTHOR]

Objective: We examined how maternal epilepsy and use of antiseizure medications in pregnancy was associated with offspring mortality. Methods: This population‐based cohort study included all live‐ and stillborn singletons in Denmark between 1981 and 2016. We used nation‐wide registers to retrieve information on pregnancy characteristics, epilepsy diagnoses, use of antiseizure medications, and mortality. Adjusted mortality rate ratios (MRR) were estimated using log‐linear Poisson regression. Results: The cohort consisted of 1,862,474 children. In total, 12,026 live‐born children died during follow‐up, of whom 170 (1.4%) were offspring of mothers with epilepsy. Overall mortality was increased in offspring of mothers with epilepsy compared to offspring of mothers without epilepsy (MRR = 1.46, 95% CI: 1.23–1.71), driven by an excess mortality only in the first year of life. Mortality was increased for natural deaths (MRR = 1.50, 95% CI: 1.25–1.78) but not from unnatural deaths (MRR = 1.38, 95% CI: 0.84–2.14), and only in offspring of women with epilepsy who used antiseizure medications during pregnancy (MRR = 1.51, 95% CI: 1.00–2.17), but not in offspring of women with epilepsy who did not use antiseizure medications while pregnant (MRR = 0.97, 95% CI: 0.69–1.31). When analyses were restricted to children born from 2000 and onwards, the excess mortality that was observed in the first year of life among children of mothers with epilepsy, was no longer evident. Interpretation: During the 1981 to 1999 epoch, offspring of women with epilepsy were at increased risk of dying in the first year of life. However, this risk did not extend to children born after 2000. Future retrospective studies of the effects of maternal epilepsy on the health of the offspring should take this difference into account. ANN NEUROL 2022;91:455–465 [ABSTRACT FROM AUTHOR]

Introduction: Factors that influence antidepressant (AD) prescription and use during pregnancy are multiple including, in particular, the balance between the potential risk of untreated depression and the potential risk of AD treatment. Surveillance of temporal trends of AD use might identify areas requiring further research. We studied the use of ADs before, during, and after pregnancy using national data across two decades in Denmark. Methods: We included 1,232,233 pregnancies leading to live birth in Denmark between 1 January 1997 and 31 December 2016. Information on redemption of AD prescriptions was obtained from the Danish National Prescription Register. Results: We identified 29,504 (2.4%) pregnancies having at least one AD prescription (96,232 AD prescriptions) during pregnancy. The majority redeemed more than one prescription (69.7%) often for a single kind of AD (83.5%), and in 94% of the AD‐exposed pregnancies, the estimated duration of treatment was 1 month or longer. Prescription of ADs during pregnancy increased steadily from 0.4% in 1997 to 4.6% in 2011, but decreased thereafter to 3.1% in 2016. The proportion of pregnancies with ADs in 2011 was 6.05‐fold higher than that in 1997. The temporal trends in AD prescription in the years before and after pregnancy were similar to the trend during pregnancy. The decreasing use of ADs during pregnancy after 2011 was mainly driven by a decrease in the use of selective serotonin reuptake inhibitors (SSRIs), especially citalopram, the main type of SSRIs used in Denmark. Conclusion: Prescription of ADs during pregnancy in Denmark increased steadily from 1997 to 2011 but decreased sharply thereafter. More research is needed to show whether the same trend exists in other populations, like women of reproductive age, men of reproductive age, and old people, and other countries. We also need to find explanation for the decreasing trend in recent years and potential risk for untreated depression. [ABSTRACT FROM AUTHOR]

Objective: Prenatal exposure to the antiseizure medication (ASM) valproate is associated with an increased risk of congenital malformations, but warnings against the use of valproate in pregnancy were not issued until 2009. The objective was to study how early administrative health registers could have identified the teratogenic risk associated with valproate. Methods: This was a population‐based cohort study of individual‐linked data from Danish health care and socioeconomic registers including children born in Denmark between January 1, 1997 and December 31, 2014. Information on ASM use, including valproate, in pregnancy was obtained from the Danish National Prescription Registry. Children identified with major congenital malformations from the Danish National Patient Register and the Danish Register of Causes of Death were included. Using logistic regression models, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) for major congenital malformations during the first year of life in children with and without prenatal exposure to ASMs adjusted for potential confounders. Results: Among the 895 507 children (males, 51.3%), 31 790 (3.6%) were diagnosed with a major congenital malformation in the first year of life. In the analyses including children born in 1997, the risk of major congenital malformations among children prenatally exposed to valproate compared with children not exposed to ASMs was increased by a fully adjusted OR (aOR) of 3.95 (95% CI = 1.65–9.47). With the addition of data from the following years, the teratogenic effect of valproate was further substantiated, as the precision of the estimate improved (1997–2014: aOR = 2.44, 95% CI = 1.80–3.30). Significance: Using Danish health care data, we were able to identify a teratogenic risk associated with prenatal valproate exposure in children born in 1997, which is much earlier than prospective clinical cohorts. Health registry data represent an important tool for early identification of risk associated with drugs in pregnancy. [ABSTRACT FROM AUTHOR]

Importance: Concerns exist about long-term neurodevelopmental consequences of prenatal exposure to antidepressants.Objective: To evaluate whether maternal prescription fill for antidepressants in pregnancy was associated with performance in standardized tests among Danish schoolchildren.Design, Setting, and Participants: Population-based retrospective cohort study of children born in Denmark between January 1, 1997, and December 31, 2009, attending public primary and lower secondary school. The children included had completed a language or mathematics test as part of the Danish National Test Program between January 1, 2010, and December 31, 2018. The age range of the eligible schoolchildren was 7 to 17 years.Exposures: Maternal prescription fill for antidepressants during pregnancy, obtained from the Danish Prescription Register.Main Outcomes and Measures: The difference in standardized scores between children with and without maternal prescription fill for antidepressants in mathematics and language tests (scale, 1-100; higher scores indicate better test results) was estimated using linear regression models, adjusted for relevant confounders. Ten sensitivity analyses were performed, including a sibling-controlled analysis.Results: Among the 575 369 children included (51.1% males), 10 198 (1.8%) were born to mothers filling an antidepressant prescription during pregnancy. The mean (SD) age of children at the time of testing spanned from 8.9 (0.4) years in grade 2 to 14.9 (0.4) years in grade 8. Maternal prescription fill for antidepressants was significantly associated with a poorer performance in mathematics (mean test scores for the group exposed to maternal antidepressant fill: 52.1 [95% CI, 51.7-52.6] and for the group not exposed to maternal antidepressant fill: 57.4 [95% CI, 57.3-57.4]; adjusted difference, -2.2 [95% CI, -2.7 to -1.6]), but not in language (mean test scores for the exposed group: 53.4 [95% CI, 53.1-53.7] and for the not exposed group: 56.6 [95% CI, 56.5-56.6]; adjusted difference, -0.1 [95% CI, -0.6 to 0.3]). In the sibling-controlled analysis, the adjusted difference in mathematics (mean scores for the exposed group: 53.5 [95% CI, 52.7-54.3] and for the not exposed group: 59.0 [95% CI, 58.9-59.1]) was -2.8 (95% CI, -4.5 to -1.2) and in language (mean test scores for the exposed group: 53.9 [95% CI, 53.2-54.6] and for the not exposed group: 56.6 [95% CI, 56.5-56.7]) was -0.3 (95% CI, -1.9 to 1.2).Conclusions and Relevance: In this study of public schoolchildren in Denmark, children whose mothers had filled prescriptions for antidepressants during pregnancy, compared with children whose mothers did not fill prescriptions for antidepressants during pregnancy, had a 2-point lower standardized test score in mathematics, a difference that was statistically significant, but had no significant difference in language test scores. The magnitude of the difference in the mathematics test score was small and of uncertain clinical importance, and the findings must be weighed against the benefits of treating maternal depression during pregnancy. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to investigate the accident‐related mortality among people younger than 55 years of age with epilepsy compared with the general population and to study how psychiatric comorbidity influences this risk. Methods: This is a population‐based cohort study of individuals born in Denmark between 1960 and 2015 (n = 3, 665 616). Persons diagnosed with epilepsy and psychiatric disorders were identified in the Danish National Patient Register and the Danish Central Psychiatric Central Register. We estimated the hazard ratio (HR) with 95% confidence intervals (CIs) of accidental death in people with epilepsy compared with persons without epilepsy. Results: We identified 61 330 persons (1.7%) diagnosed with epilepsy. Median age at end of follow‐up was 27.8 years. In people with epilepsy, 5253 died during follow‐up, 480 (9%) of whom died from accidents. Among people without epilepsy, 52 588 died during follow‐up, of whom 1280 (2.4%) died from accidents. People with epilepsy had a 3.7‐fold (95% CI 3.4‐4.1) increased risk of accidental death compared with persons without epilepsy. When we adjusted for psychiatric disorders, the risk remained significantly elevated in people with epilepsy compared to people without epilepsy (adjusted HR [aHR] 2.44, 95% CI 2.22‐2.69). When stratifying the analyses on epilepsy and psychiatric disorders, people with epilepsy and psychiatric disorders had an aHR of 4.95 (95% CI 3.82‐6.41) when compared with persons without epilepsy and psychiatric disorders. Significance: The risk of accidental death was increased in people with epilepsy and was particularly high among people with epilepsy with psychiatric comorbidity. The findings highlight the need for awareness and prevention strategies in people with epilepsy, especially in people with comorbid psychiatric disorders. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose The aim of the study was to estimate the association between newborn children treated with phototerapy for hyperbilirubinemia and the subsequent risk of febrile seizures or epilepsy in early childhood. Methods We conducted a follow-up study of singleton children (N = 70 230) born between February 1998 and May 2003 from the Danish National Birth Cohort (DNBC). Information on exposure to phototherapy for hyperbilirubinemia was obtained from a questionnaire in the DNBC. Information on epilepsy and febrile seizures were obtained from the Danish National Hospital Registry (DNHR). Cox proportional hazard regression model was used to calculate hazard ratios (HRs) with 95% confidence intervals (CI). Results Newborns treated with phototherapy for hyperbilirubinemia had a higher risk of developing epilepsy in early childhood (HR: 1.66, 95% CI: 1.23–2.24) but not febrile seizures (HR: 1.04, 95% CI: 0.86–1.27). The increases risk of epilepsy were only present for boys (HR: 1.98, 95% CI: 1.40–2.78) not for girls (HR: 1.14, 95% CI: 0.64–2.02) Conclusion Phototherapy for hyperbilirubinemia in newborns was associated with an increased risk of epilepsy for males in early childhood. No excess risk was seen with febrile seizures. [ABSTRACT FROM AUTHOR]

Summary: Objective: This study aimed to determine the prevalence of epilepsy in four European countries (Austria, Denmark, Ireland, and Romania) employing a standard methodology. The study was conducted under the auspices of ESBACE (European Study on the Burden and Care of Epilepsy). Methods: All hospitals and general practitioners serving a region of at least 50 000 persons in each country were asked to identify patients living in the region who had a diagnosis of epilepsy or experienced a single unprovoked seizure. Medical records were accessed, where available, to complete a standardized case report form. Data were sought on seizure frequency, seizure type, investigations, etiology, comorbidities, and use of antiseizure medication. Cases were validated in each country, and the degree of certainty was graded as definite, probable, or suspect cases. Results: From a total population of 237 757 in the four countries, 1988 (.8%) patients were identified as potential cases of epilepsy. Due to legal and ethical issues in the individual countries, medical records were available for only 1208 patients, and among these, 113 had insufficient clinical information. The remaining 1095 cases were classified as either definite (n = 706, 64.5%), probable (n = 191, 17.4%), suspect (n = 153, 14.0%), or not epilepsy (n = 45, 4.1%). Significance: Although a precise prevalence estimate could not be generated from these data, the study found a high validity of epilepsy classification among evaluated cases (95.9%). More generally, this study highlights the significant challenges facing epidemiological research methodologies that are reliant on patient consent and retrospective chart review, largely due to the introduction of data protection legislation during the study period. Documentation of the epilepsy diagnosis was, in some cases, relatively low, indicating a need for improved guidelines for assessment, follow‐up, and documentation. This study highlights the need to address the concerns and requirements of recruitment sites to engage in epidemiological research. [ABSTRACT FROM AUTHOR]

Background: Maternal infections during pregnancy have been associated with an increased risk for neurological outcomes in the child, including epilepsy. We examined cystitis antibiotics commonly used during pregnancy, as a marker of cystitis, and the risk of childhood epilepsy in a population-based cohort in Denmark. Methods: We examined all liveborn singletons born in Denmark between January 1996 and September 2004, identified from the Danish National Birth Registry. Epilepsy diagnoses were obtained from the Danish National Hospital Register and maternal antibiotic use from the National Register of Medicinal Product Statistics. Cystitis antibiotics consisted of pivmecillinam, sulphamethizole and nitrofurantoin. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated with Cox proportional hazard regression models. Results: The study followed 447 629 singletons for up to 9.9 years and identified 2848 children diagnosed with epilepsy. We found slightly increased risks of epilepsy in children whose mothers had redeemed prescriptions during pregnancy for pivmecillinam HR = 1.2 [95% CI 1.0, 1.4], sulphamethizole HR = 1.2 [95% CI 1.1, 1.4] or nitrofurantoin HR = 1.1 [95% CI 0.8, 1.5], compared with those unexposed. Among mothers with multiple redeemed prescriptions during pregnancy, adjusted HR were for pivmecillinam HR = 1.3 [95% CI 1.1, 1.5], sulphamethizole HR = 1.3 [95% CI 1.1, 1.5] and nitrofurantoin HR = 1.3 [95% CI 1.0, 1.8]. Conclusions: Similar magnitudes of associations between chemically different drugs, used almost exclusively to treat cystitis, may suggest an impact of maternal infection on the fetal brain. However, direct drug effects or confounding factors are also possible explanations. [ABSTRACT FROM AUTHOR]

Background and Aim: Maternal infections during pregnancy have been associated with several neurological disorders in the offspring. However, given the lack of specificity for both the exposures and the outcomes, other factors related to infection such as impaired maternal immune function may be involved in the causal pathway. If impaired maternal immune function plays a role, we would expect infection before pregnancy to be associated with these neurological outcomes. Methods/Principal Findings: The study population included all first-born singletons in Denmark between January 1 1982 and December 31 2004. We identified women who had hospital-recorded infections within the 5 year period before pregnancy, and women who had hospital-recorded infections during pregnancy. We grouped infections into either infections of the genitourinary system, or any other infections. Cox models were used to estimate adjusted hazard ratios (aHRs) with 95% confidence interval (CI). Maternal infection of the genitourinary system during pregnancy was associated with an increased risk of cerebral palsy (aHR = 1.63, 95% CI: 1.34–1.98) and epilepsy (aHR = 1.27, 95% CI: 1.13–1.42) in the children, compared to children of women without infections during pregnancy. Among women without hospital-recorded infections during pregnancy, maternal infection before pregnancy was associated with an increased risk of epilepsy (aHR = 1.35, 95% CI: 1.21–1.50 for infections of the genitourinary system, and HR = 1.12, 95% CI: 1.03–1.22 for any other infections) and a slightly higher risk of cerebral palsy (aHR = 1.20, 95% CI: 0.96–1.49 for infections of the genitourinary system, and HR = 1.23, 95% CI: 1.06–1.43 for any other infections) in the children, compared to children of women without infections before (and during) pregnancy. Conclusions: These findings indicate that the maternal immune system, maternal infections, or factors related to maternal immune function play a role in the observed associations between maternal infections before pregnancy and cerebral diseases in the offspring. [ABSTRACT FROM AUTHOR]

Background: There is a complex interaction between female and male sex hormones and the risk of epilepsy. Whether prenatal exposure to higher levels of sex hormones affects the development of epilepsy in childhood or later in life is not well known. The sex hormone environment of fetuses may be affected by the sex of the co-twin. We estimated the risk of epilepsy for twins with an opposite-sex (OS) co-twin compared with twins with a same-sex (SS) co-twin. Methods: From the Danish Twin Registry, we identified OS female twins (n = 11,078), SS female twins (n = 19,186), OS male twins (n = 11,080), and SS male twins (n = 20,207) born between 1977 and 2009. The SS twins include monozygotic twins, dizygotic twins, and twins with unknown zygosity. These children were followed up from day 29 after birth until diagnosis of epilepsy, death, emigration, or end of follow-up (31 December 2011) whichever came first. Information on diagnosis of epilepsy was obtained from the Danish National Patient Registry. We calculated hazard ratios (HRs) and 95% confidence intervals (CIs) for epilepsy in the OS twins using a Cox proportional hazards regression model compared with the SS twins. To account for the correlation of twins from the same mother when estimating standard errors, we used the cluster option in Stata. Results: We identified 152 OS female twins, 282 SS female twins, 162 OS male twins, and 335 SS male twins diagnosed with epilepsy corresponding to an incidence rate of 9.9 and 9.7 per 10,000 person years for the OS and SS female twins, and 10.6 and 10.9 per 10,000 person years for the OS and SS male twins, respectively. We found a similar risk of epilepsy among the OS and SS female twins [HR = 1.01; 95% CI 0.83–1.24] as well as among the OS and SS male twins [HR = 0.94; 95% CI 0.78–1.14] Conclusions: In this population-based study of Danish twins, we did not find difference in the risk of epilepsy between twins with an OS co-twin and twins with a SS co-twin. This applied to both female and male twins. The study therefore does not support the hypothesis that subtle hormone difference in fetal life due to co-twin may play a role in the development of epilepsy later in life. [ABSTRACT FROM AUTHOR]