Epilepsy In Offspring Research Articles

The impact of maternal prenatal psychological distress on the development of epilepsy in offspring: The Japan Environment and Children's Study.

The relationship between maternal prenatal psychological distress and epilepsy development in offspring has not yet been clarified. Herein, we used a dataset obtained from the Japan Environment and Children's Study, a nationwide birth cohort study, to evaluate the association between six-item Kessler Psychological Distress Scale (K6) scores and epilepsy among 1-3 years old. The data of 97,484 children were retrospectively analyzed. The K6 was administered to women twice: during the first half (M-T1) and second half (M-T2) of pregnancy. M-T1 ranged from 12.3-18.9 (median 15.1) weeks, and M-T2 ranged from 25.3-30.1 (median 27.4) weeks. Participants were divided into six groups based on K6 scores of two ranges (≤4 and ≥5) at M-T1 and M-T2. The numbers of children diagnosed with epilepsy at the ages of 1, 2, and 3 years were 89 (0.1%), 129 (0.2%), and 149 (0.2%), respectively. A maternal K6 score of ≥5 at both M-T1 and M-T2 was associated with epilepsy diagnosis ratios among 1-, 2-, and 3-year-old children in the univariate analysis. Moreover, multivariate analysis revealed that a maternal K6 score of ≥5 at both M-T1 and M-T2 was associated with epilepsy diagnosis ratios among 1-, 2-, and 3-year-olds. Continuous moderate-level maternal psychological distress from the first to the second half of pregnancy is associated with epilepsy among 1-, 2-, and 3-year-old children. Hence, environmental adjustments to promote relaxation such as mindfulness in pregnant women might be necessary.

Maternal pre-gestational and gestational diabetes and risk of offspring epilepsy: A cohort study

Abstract Background Despite growing evidence linking maternal diabetes to impaired brain physiology and neurodevelopment in offspring, evidence on its effect on epilepsy remains scarce. This study aims to determine if intrauterine exposure to maternal pre-existing and gestational diabetes mellitus is associated with risk of offspring epilepsy. Methods We studied >2.3 million singletons live-born in Sweden between 1998 and 2021, with final follow up until October 31, 2023. The Swedish Medical Birth Register was linked to the National Patient Register to identify gestational diabetes (GDM), maternal pre-gestational type 1 (T1DM) and type 2 diabetes (T2DM), and offspring epilepsy. The incidence of epilepsy, comparing offspring of mothers with versus without diabetes, was calculated as hazard ratios (HR), adjusting for maternal education, smoking, body mass index, hypertension, epilepsy and other important confounders. Paternal T1DM and T2DM were additionally analysed as negative control exposures to assess genetic confounding. Results Of the 2,335,245 offspring analysed (48.9% female), 13,883 (0.6%) were exposed to maternal T1DM, 4477 (0.2%) to T2DM, and 37,253 (1.6%) to GDM. During a median follow up of 13 years (range 0-26 years), 18,732 offspring were diagnosed with epilepsy. Maternal T1DM (HR 1.27, 95% confidence intervals [CI] 1.08-1.49) and T2DM (HR 1.34, 95% CI 1.00-1.49) were associated with higher hazards of epilepsy in offspring, compared with no exposure to maternal diabetes. Preterm birth and birth-asphyxia jointly mediated 63% and 39% of these associations, respectively. No association was found between maternal GDM and epilepsy. Paternal T1DM and T2DM did not show association with epilepsy. Conclusions In this nationwide population-based cohort study, children of mothers with T1DM or T2DM showed an elevated risk of epilepsy. The results from paternal comparison and mediation analyses suggest a key role of the intrauterine environment in the aetiology of epilepsy. Key messages • Maternal pre-existing T1DM and T2DM might be risk factors for epilepsy in offspring and are likely to influence the risk through the intrauterine environment independent of genetic mechanisms. • In the context of a globally rising prevalence of diabetes in women who get pregnant, it is crucial that the diabetes is well-regulated and birth complications associated with diabetes are prevented.

Evaluating the Inheritance Risk: Epilepsy Prevalence among Offspring of Adults with Epilepsy in a Tertiary Referral Epilepsy Center.

While significant strides have been made in comprehending the pathophysiology and treatment of epilepsy, further investigation is warranted to elucidate the factors impacting its development and transmission, particularly within familial contexts. This study sought to explore the prevalence and risk factors associated with epilepsy in the offspring of patients with epilepsy who were treated at a tertiary epilepsy center. Adult patients with confirmed epilepsy (PWE) receiving outpatient care were consecutively enrolled, starting from January 2021 to January 2023. Data were recorded for various variables, including age, gender, epilepsy pathophysiology, cognitive impairment, and family history of epilepsy. Descriptive statistics, various statistical tests, and multivariate logistic regression analyses were employed to analyze the data. A total of 1456 PWE were included. Among them, 463 patients (31.8%) had children. Twenty-five patients had offspring diagnosed with epilepsy, representing a prevalence of 5.4%. Analysis of the offspring with epilepsy revealed older ages, a higher proportion of parents with idiopathic epilepsy, and a greater prevalence of a positive family history of epilepsy. Multivariate logistic regression analysis demonstrated a significant association between a family history of epilepsy and increased epilepsy risk in offspring. Genetic syndrome-immanent predisposition, advanced age, and a family history of epilepsy were identified as significant risk factors for epilepsy in offspring by means of this mono-center study.

Familial factors rather than paternal age contribute to the aetiology of epilepsy.

Whether paternal age associated with offspring's epilepsy risk is a cause of de novo mutation as men age, or just an association due to confounding factors, is still unclear. We performed a population-based, multi-generation and sibling comparison study in Taiwan, which included 2 751 232 singletons born in 2001-17 who were followed until 2020. Of these, 819 371/826 087 with information on paternal/maternal grandparents were selected for multi-generation analyses and 1 748 382 with sibling(s) were selected for sibling comparison. Cox proportional hazard regression was used to estimate the hazard ratio (HR) and 95% confidence interval (CI). In the total cohort, there was an increased risk of epilepsy in individuals with advanced paternal age, e.g. the HR for paternal age ≥50 was1.36 (95% CI: 1.15-1.61) compared with paternal age 25-29, and fathers older than mothers, e.g. the HR for parental age difference ≥15 years was 1.29 (95% CI: 1.16-1.43). When accounting for parental age difference, the association between paternal age and epilepsy in offspring was attenuated (HR for paternal age ≥50 was 1.11, 95% CI: 0.93-1.34). Multi-generation analyses did not support the association of advanced grand-paternal age at childbirth of the parent with offspring's risk of epilepsy. Sibling comparison analyses did not support the association of older paternal age with increased risk of epilepsy (HR was 0.96 for per year increase in paternal age, 95% CI: 0.96-0.97). These results do not support the hypothesis that advanced paternal age is associated with epilepsy in offspring. Instead, familial factors may explain the observed paternal age association with the offspring's risk of epilepsy.

Mendelian randomization approach shows no causal effects of gestational age on epilepsy in offspring

BackgroundObservational studies have suggested that gestational age was associated with the risk of epilepsy later in life. However, it remains unclear whether the association is of a causal nature. MethodsTwo-sample Mendelian randomization (MR) was performed to assess the causal effect of fetal gestational age on epilepsy. Genome-wide association studies (GWAS) summary statistics of gestational duration, early preterm birth, preterm birth, and postterm birth were from the Early Growth Genetics (EGG) Consortium. GWAS summary-level data on epilepsy were obtained from the International League Against Epilepsy Consortium (ILAEC) and FinnGen Consortium. The inverse-variance weighted (IVW) was applied as the primary method to calculate estimates, which were further validated using other sensitivity analyses. ResultsThere was not yet strong evidence of causal associations between gestational age and epilepsy of ILAEC (early preterm birth: odds ratio [OR]=1.01, 95% CI: 0.99–1.03, P = 0.441; preterm birth: OR=1.01, 95% CI: 0.96–1.07, P = 0.617; postterm birth: OR=0.96, 95% CI: 0.89–1.04, P = 0.357; gestational duration: OR=0.90, 95% CI: 0.75–1.07, P = 0.214). Similar results were obtained in the replication stage using epileptic samples from the FinnGen Consortium. Finally, a meta-analysis of the causal estimates from the ILAEC and FinnGen Consortium showed consistent results. No obvious pleiotropy was found throughout the MR study. ConclusionsThe present study indicated that gestational age, either preterm birth or postterm birth, might not be causally associated with the risk of epilepsy. Further studies are warranted to evaluate the potential mechanisms underlying the epidemiological relationship between preterm birth and epilepsy.

Reproduction and genetic causal attribution of epilepsy.

This study addresses the contribution of genetics-related concerns to reduced childbearing among people with epilepsy. Surveys were completed by 606 adult patients with epilepsy of unknown cause at our medical center. Poisson regression analysis was used to assess the relations of number of offspring to: (1) genetic attribution (GA: participants' belief that genetics was a cause of their epilepsy), assessed via a novel scale developed from four survey items (Cronbach's alpha=.89), (2) participants' estimates of epilepsy risk in the child of a parent with epilepsy (1%, 5%-10%, 25%, and 50%-100%), and (3) participants' reports of the influence on their reproductive decisions of "the chance of having a child with epilepsy" (none/weak/moderate, strong/very strong). Analyses were adjusted for age, education, race/ethnicity, religion, type of epilepsy (generalized, focal, and both/unclassifiable), and age at epilepsy onset (<10, 10-19, and ≥20 years). Among participants 18-45 years of age, the number of offspring decreased significantly with increasing GA (highest vs lowest GA quartile rate ratio [RR]= .5, p< .001), and increasing estimated epilepsy risk in offspring (with 5%-10% as referent because it is closest to the true value, RR for 25%: .7, p= .05; RR for 50%-100%: .6, p= .03). Number of offspring was not related to the reported influence of "the chance of having a child with epilepsy" on reproductive decisions. Among participants >45 years of age, the number of offspring did not differ significantly according to GA quartile or estimated offspring epilepsy risk. However, those reporting a strong/very strong influence on their reproductive decisions of "the chance of having a child with epilepsy" had only 60% as many offspring as others. These findings suggest that overestimating the risk of epilepsy in offspring can have important consequences for people with epilepsy. Patient and provider education about recurrence risks and genetic testing options to clarify risks are critical, given their potential influence on reproductive decisions.

Chorioamnionitis and risk of long-term neurodevelopmental disorders in offspring: a population-based cohort study

Evidence indicates that in utero exposure to chorioamnionitis might increase the risk of neurodevelopmental disorders in the offspring. However, findings on this topic have been inconsistent. To examine the association between chorioamnionitis and neurodevelopmental disorders in offspring. This was a retrospective population-based cohort study in Sweden. A total of 2,228,280 singleton live births and stillbirths between 1998 and 2019 were included in our study population. Data on maternal characteristics and neurodevelopmental disorders in offspring were obtained by individual record-linkages of nationwide Swedish registries. Chorioamnionitis was identified using the National Medical Birth Register. Inpatient and outpatient diagnoses were obtained for cerebral palsy, autism, attention deficit hyperactivity disorder, epilepsy, and intellectual disability. Multivariable Cox proportional hazards regression was used to estimate the association between chorioamnionitis and each neurodevelopmental disorder with adjusted hazard ratios and 95% confidence intervals. A causal mediation analysis of the relationship between chorioamnionitis and neurodevelopmental disorders with preterm delivery (<37 weeks) was performed. A total of 5770 (0.26%) offspring were exposed to chorioamnionitis during pregnancy. During the study's follow-up time there were 4752 (0.21%) cases of cerebral palsy, 17,897 (0.80 %) cases of epilepsy, 50,570 (2.27 %) cases of autism, 114,087 (5.12%) cases of attention deficit hyperactivity disorder, and 14,574 (0.65%) cases of intellectual disability. After adjusting for potential confounders, exposure to chorioamnionitis increased the hazard ratios of cerebral palsy (adjusted hazard ratio, 7.43; 95% confidence interval, 5.90-9.37), autism (adjusted hazard ratio, 1.43; 95% confidence interval, 1.21-1.68), attention deficit hyperactivity disorder (adjusted hazard ratio, 1.17; 95% confidence interval, 1.03-1.33), and intellectual disability (adjusted hazard ratio, 1.99; 95% confidence interval, 1.53-2.58), whereas chorioamnionitis was not significantly associated with higher rates of epilepsy in offspring. Mediation analysis revealed that these associations were mainly explained through preterm delivery; however, increased risk was also observed among term infants. Chorioamnionitis increases the risk of neurodevelopmental disorders, particularly cerebral palsy, autism, attention deficit hyperactivity disorder, and intellectual disability. These associations were mainly mediated through preterm delivery. Efforts for timely identification and appropriate interventions to treat infections during pregnancy will have sustained benefits in reducing the burden of neurologic complications in children at the population level.

Association of labour epidural analgesia with neurodevelopmental disorders in offspring: a Danish population-based cohort study

BackgroundWhether labour epidural analgesia impacts risk of neurodevelopmental disorders in offspring is unsettled, raising public and scientific concerns. We explored the association between maternal labour epidural analgesia and autism spectrum disorder, and specific developmental disorder, attention-deficit hyperactivity disorder, intellectual disability, and epilepsy in offspring. MethodsThis nationwide population-based cohort study included 624 952 live-born singletons delivered by women who intended to deliver vaginally (i.e. vaginal and intrapartum Caesarean deliveries) in Denmark from 2005 to 2016. A total of 80 862 siblings discordant for exposure to labour epidural analgesia were analysed in a sibling-matched analysis. Both full-cohort and sibling-matched analyses were performed to estimate hazard ratios (HRs) of offspring risk of autism spectrum disorder, specific developmental disorder, attention-deficit hyperactivity disorder, intellectual disability, and epilepsy, according to exposure to labour epidural analgesia, adjusted for maternal socio-economic, pregnancy, and perinatal covariates. ResultsIn the full cohort, maternal labour epidural analgesia was associated with autism spectrum disorder in offspring (HR 1.11; 95% confidence interval [CI]: 1.04–1.18); however, in the sibling-matched analysis, no association with autism spectrum disorder was found (HR 1.03; 95% CI: 0.84–1.27). The association between labour epidural analgesia and specific developmental disorder (HR 1.12; 95% CI: 1.03–1.22) in the full cohort also disappeared in the sibling-matched analysis (HR 1.01; 95% CI: 0.78–1.31). No association between maternal labour epidural analgesia and the remaining neurodevelopmental disorders was found overall (attention-deficit hyperactivity disorder, HR 0.98; 95% CI: 0.92–1.03; intellectual disability, HR 0.98; 95% CI: 0.85–1.14; epilepsy, HR 0.89; 95% CI: 0.79–1.00) or in the sibling-matched analyses. ConclusionsOur findings did not support an association between maternal attention-deficit hyperactivity disorder and autism spectrum disorder, specific developmental disorder, attention-deficit hyperactivity disorder, intellectual disability, or epilepsy.

Association of Labour Epidural Analgesia with the Risks of Autism Spectrum Disorders and Other Neurodevelopmental Disorders in Offspring: A Population-Based Cohort Study

Background: Recently, concern has been raised regarding the impact of labor epidural analgesia (LEA) on offspring risk of autism spectrum disorders (ASD). We explored the association between exposure to LEA and ASD, as well as specific developmental disorder (SDD), attention deficit hyperactivity disorder (ADHD), intellectual disability (ID), and epilepsy in offspring. Methods: This nationwide population-based cohort study included 671,709 live-born singletons delivered by women who intended to have a vaginal birth (i.e., vaginal and intrapartum cesarean deliveries) in Denmark from 2005 to 2017. A total of 91,627 siblings discordant for exposure to LEA were analyzed in a sibling-matched analysis. Both full-cohort and sibling-matched analyses were performed to estimate hazard ratios[HRs] of neurodevelopmental outcomes according to exposure to LEA. Findings: In the full cohort analysis, we observed a 15% increased risk of ASD in offspring exposed to LEA (HR, 1.15 [95% CI, 1.09-1.22]) regardless of LEA duration. In the sibling-matched analysis, we found no association between maternal LEA and offspring ASD (1.02 [0.84-1.24]). No association was found between LEA and other neurodevelopmental disorders in the full cohort (HR for SDD, 1.06 [0.98-1.15]; HR for ADHD, 1.00 [0.95-1.06]; HR for ID, 0.98 [0.86-1.13]; HR for epilepsy, 0.92 [0.83-1.03]) or in the sibling-matched analyses. Interpretation: The association between maternal LEA and ASD did not persist in the sibling-matched analysis. No association was found between maternal LEA and SDD, ADHD, ID, or epilepsy. Our findings accord with a lack of causal effect of LEA on the risk of neurodevelopmental disorders. Funding Statement: This study was supported by grants from the Danish Council for Independent Research (DFF-6110- 00019B and 9039-00010B), the Nordic Cancer Union (R275-A15770), the Karen Elise Jensens Fond (2016), Novo Nordisk Fonden (NNF18OC0052029 and NNF18OC0054457), the National Nature Science Foundation of China (82073570), and Shanghai Municipal Health Commission (GWV-10.1-XK07 and 2020CXJQ01). Declaration of Interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work. Ethics Approval Statement: The study was approved by the Danish Data Protection Agency (Record No. 2013-41- 2569). By Danish law, no informed consent is required for a registry-based study using anonymized data.

Reproductive decision-making in families containing multiple individuals with epilepsy.

This study evaluated factors influencing reproductive decision-making in families containing multiple individuals with epilepsy. One hundred forty-nine adults with epilepsy and 149 adult biological relatives without epilepsy from families containing multiple affected individuals completed a self-administered questionnaire. Participants answered questions regarding their belief in a genetic cause of epilepsy (genetic attribution) and estimated risk of epilepsy in offspring of an affected person. Participants rated factors for their influence on their reproductive plans, with responses ranging from "much more likely" to "much less likely" to want to have a child. Those with epilepsy were asked, "Do you think you would have wanted more (or any) children if you had not had epilepsy?" Participants with epilepsy had fewer offspring than their unaffected relatives (mean = 1.2 vs. 1.9, p=.002), and this difference persisted among persons who had been married. Estimates of risk of epilepsy in offspring of an affected parent were higher among participants with epilepsy than among relatives without epilepsy (mean = 27.2 vs. 19.6, p=.002). Nineteen percent of participants with epilepsy responded that they would have wanted more children if they had not had epilepsy. Twenty-five percent of participants with epilepsy responded that "the chance of having a child with epilepsy" or "having epilepsy in your family" made them less likely to want to have a child. Having these genetic concerns was significantly associated with greater genetic attribution and estimated risk of epilepsy in offspring of an affected parent. People with epilepsy have fewer children than their biological relatives without epilepsy. Beliefs about genetic causes of epilepsy contribute to concerns and decisions to limit childbearing. These beliefs should be addressed in genetic counseling to ensure that true risks to offspring and reproductive options are well understood.

Maternal rheumatoid arthritis during pregnancy and neurodevelopmental disorders in offspring: a systematic review

Objective: To summarize the available literature on in utero exposure to maternal rheumatoid arthritis (RA) and its influence on the risk of neurodevelopmental disorders (NDDs) in offspring. Method: We conducted a systematic literature review and assessed the internal validity of studies with the Newcastle Ottawa Scale tool. Results: Six studies were included. Three reported on autism spectrum disorders; one cohort study indicated a slightly elevated risk, and two case–control studies reported too few cases for risk assessment. Two large cohort studies reported elevated hazard ratios for epilepsy in offspring, in overlapping populations. One study on attention deficit hyperactivity disorder (ADHD) reported higher odds for maternal RA during pregnancy, among children with ADHD. Conclusion:Few studies were found specifically studying maternal RA during pregnancy and NDDs in offspring. The studies pointed towards a moderately higher risk of these outcomes; however, reporting bias appears to be a problem. Additional studies of appropriate design and power are needed.

Maternal use of hormonal contraception and epilepsy in offspring.

Is maternal use of hormonal contraception associated with the development of epilepsy in the offspring? We found that maternal use of hormonal contraception was associated with a slightly increased risk of epilepsy in the offspring. Foetal exposure to exogenous hormones has been associated with changes in brain development. However, little is known about maternal hormonal contraception use and development of epilepsy in the offspring. A nationwide cohort of all live born children born in Denmark between 1 January 1998 and 31 December 2014, was followed from day 29 after birth for epilepsy (first diagnosis of epilepsy or first redeemed prescription for anti-epileptic medication) to censoring (emigration, death) or 31 December 2015, whichever occurred first. Diagnoses of epilepsy were obtained from the National Patient Registry. The Danish National Prescription Registry supplied information on redeemed prescriptions for hormonal contraception and anti-epileptic medication. Maternal hormonal contraception use was categorized as never use (reference group), previous use (prescriptions redeemed >3 months before pregnancy start) and recent use (prescriptions redeemed ≤3 months before or during pregnancy). The data show that 17 585 children developed epilepsy during a median follow-up of 9.2 years (9 732 635 person-years). The hazard ratio (HR) for epilepsy was 1.07 (95% CI 1.02-1.13) in children of mothers who had used any type of hormonal contraception recently, compared with children of mothers who had not used hormonal contraception. The HR was similar for recent use of oral combined products, while the HRs for recent or previous use of non-oral combined products were 1.32 (95% CI 0.98-1.77) and 1.16 (95% CI 1.02-1.32), respectively. For non-oral progestin-only products, the HRs were 1.19 (95% CI 1.04-1.38) and 1.53 (95% CI 1.31-1.80), respectively, for recent and previous use. There may be some misclassification of maternal hormonal contraception use, as some women may not have used the redeemed prescriptions or used them at a different point in time; potentially leading to an attenuation of the estimates. In addition, although we were able to account for known risk factors for epilepsy, unknown or residual confounding cannot be ruled out. Our findings are based on nationwide population-based data and can therefore be applied to other similar populations. However, as this is the first study in this field, further studies are needed to confirm our findings. No specific funding was obtained for this study, which was supported by internal funding at the Unit of Virus, Lifestyle and Genes. All authors report no conflicts of interest. N/A.

Epilepsy risk in offspring of affected parents; a cohort study of the "maternal effect" in epilepsy.

ObjectiveTo assess whether the risk of epilepsy is higher in offspring of mothers with epilepsy than in offspring of fathers with epilepsy.MethodsIn a prospective population‐based register study, we considered all singletons born in Denmark between 1981 and 2016 (N = 1,754,742). From the Danish National Patient Register since 1977, we identified epilepsy diagnoses in all study participants and their family members. Cox regression models were used to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CI), adjusted for relevant confounders.ResultsWe included 1,754,742 individuals contributing > 30 million person‐years of follow‐up. The incidence rate of epilepsy in offspring of unaffected parents was 78.8 (95% CI: 77.8–79.8) per 100,000 person‐years, while the corresponding rate in offspring with an affected father was 172 per 100,000 person‐years (95% CI: 156–187) and in offspring with an affected mother was 260 per 100,000 person‐years (95% CI: 243–277). Having an affected mother was associated with a 1.45‐fold (95% CI: 1.30–1.63) higher risk of epilepsy in the offspring, compared to having an affected father. This maternal effect was found both in male (HR = 1.39, 95% CI: 1.19–1.62) and female offspring (HR = 1.53, 95% CI: 1.30–1.80), and across various ages at onset in the offspring. The maternal effect was also found in familial epilepsies (i.e. where the affected parent had an affected sibling; HR = 1.50, 95% CI: 1.04−2.16).InterpretationWe found a clear maternal effect on offspring risk of epilepsy in this nationwide cohort study.

Prenatal Exposure to Antibiotics and Development of Epilepsy in Children.

We aimed to confirm or reject previous reports on the association of prenatal antibiotic exposure and development of epilepsy in offspring by accounting for known and unidentified confounding factors. In a retrospective cohort investigation, we enrolled children aged 3-18 years born between 1998 and 2012 at a single regional hospital and their mothers. A computerized medication database was linked with hospital records. The exposed group included children whose mothers purchased 1 or more antibiotic medications for use during pregnancy. Epilepsy was defined by epilepsy diagnosis and/or by chronic dispensing of antiepileptic drugs. We analyzed maternal exposure to antibiotics 2 years after delivery (but not during pregnancy and/or the 2 years following delivery) as part of the specificity analysis. We enrolled 88899 children and their 74416 mothers. The group exposed prenatally to antibiotics comprised 36622 children (41.2%). Of them, 326 (0.9%) developed epilepsy compared with 370 of 52277 (0.7%) in the unexposed group (relative risk [RR], 1.24; 95% confidence interval [CI], 1.07-1.44: P = .004). Exposure during the first, second, and third trimesters was characterized by incidence of epilepsy in 0.8% (P = .943), 0.9% (P = .266), and 0.9% (P = .073) of children, respectively, compared with the unexposed group, with an RR of 1.01 (95%CI, 0.83-1.23), 1.12 (95%CI, 0.92-1.36), and 1.19 (95%CI, 0.98-1.45), respectively. Similarly, prenatal exposure by antibiotic class was associated with epilepsy. Nevertheless, the specificity analysis strongly suggested the possibility of confounding by indication. Our findings indicated that pregnant women should receive the indicated antibiotic treatment with no fear of the development of epilepsy in their children.

The "maternal effect" on epilepsy risk: Analysis of familial epilepsies and reassessment of prior evidence.

Previous studies have observed that epilepsy risk is higher among offspring of affected women than offspring of affected men. We tested whether this "maternal effect" was present in familial epilepsies, which are enriched for genetic factors that contribute to epilepsy risk. We assessed evidence of a maternal effect in a cohort of families containing ≥3 persons with epilepsy using 3 methods: (1) "downward-looking" analysis, comparing the rate of epilepsy in offspring of affected women versus men; (2) "upward-looking" analysis, comparing the rate of epilepsy among mothers versus fathers of affected individuals; and (3) lineage analysis, comparing the proportion of affected individuals with family history of epilepsy on the maternal versus paternal side. Downward-looking analysis revealed no difference in epilepsy rates among offspring of affected mothers versus fathers (prevalence ratio = 1.0, 95% confidence interval [CI] = 0.8-1.2). Upward-looking analysis revealed more affected mothers than affected fathers; this effect was similar for affected and unaffected sibships (odds ratio = 0.8, 95% CI = 0.5-1.2) and was explained by a combination of differential fertility and participation rates. Lineage analysis revealed no significant difference in the likelihood of maternal versus paternal family history of epilepsy. We found no evidence of a maternal effect on epilepsy risk in this familial epilepsy cohort. Confounding sex imbalances can create the appearance of a maternal effect in upward-looking analyses and may have impacted prior studies. We discuss possible explanations for the lack of evidence, in familial epilepsies, of the maternal effect observed in population-based studies. ANN NEUROL 2020;87:132-138.

In utero beta‐2‐adrenergic agonists exposure and risk of epilepsy: A Danish nationwide population‐based cohort study

To examine the association between maternal use of beta-2-adrenergic agonists (β2AAs) and the risk of epilepsy in offspring. A nationwide retrospective cohort study was performed based on Danish registries. Children of mothers who used β2AAs during pregnancy were allocated to the exposed group and other children to the unexposed group. The outcome was a diagnosis of epilepsy. Cox regression was performed to estimate the hazard ratios (HRs) of epilepsy after adjusting for parental and children factors. To evaluate confounding by indication, we extended the exposure time window from 2years before pregnancy and stratified the analyses by maternal asthma, in particular analyses by trimesters. The exposed children had a 1.24-fold risk of epilepsy (HR=1.24, 95% confidence interval [CI]: 1.12, 1.38). Compared with no prenatal exposure from 2years before pregnancy through delivery, the HR was 1.11 (95% CI: 1.01, 1.22) in children of mothers with β2AAs use only before pregnancy, 1.28 (95% CI: 1.09, 1.50) only during pregnancy, and 1.23 (95% CI: 1.07, 1.41) both before and during pregnancy. The increased risk was only observed in children of mothers with β2AAs use in the first (HR=1.33, 95% CI: 1.01, 1.75) or second trimesters (HR=1.35, 95% CI: 1.05, 1.74), but not the third trimester. In utero exposure to β2AAs, particularly in the first or second trimesters, may be associated with an increased risk of epilepsy. It may partly be due to the indication of β2AAs use, but a direct effect of β2AAs cannot be ruled out.

Maternal Body Mass Index in Early Pregnancy and Risk of Epilepsy in Offspring

There is growing concern about the long-term neurologic effects of prenatal exposure to maternal overweight and obesity. The causes of epilepsy are poorly understood and, in more than 60% of the patients, no definitive cause can be determined. To investigate the association between early pregnancy body mass index (BMI) and the risk of childhood epilepsy and examine associations between obesity-related pregnancy and neonatal complications and risks of childhood epilepsy. A population-based cohort study of 1 441 623 live single births at 22 or more completed gestational weeks in Sweden from January 1, 1997, to December 31, 2011, was conducted. The diagnosis of epilepsy as well as obesity-related pregnancy and neonatal complications were based on information from the Sweden Medical Birth Register and National Patient Register. Multivariate Cox proportional hazards regression models were used to estimate adjusted hazard ratios (HRs) and 95% CIs after adjusting for maternal age, country of origin, educational level, cohabitation with partner, height, smoking, maternal epilepsy, and year of delivery. Data analysis was conducted from June 1 to December 15, 2016. Risk of childhood epilepsy. Of the 1 421 551 children born between January 1, 1997, and December 31, 2011, with covariate information available, 7592 (0.5%) were diagnosed with epilepsy through December 31, 2012. Of these 3530 (46.5%) were female. The overall incidence of epilepsy in children aged 28 days to 16 years was 6.79 per 10 000 child-years. Compared with offspring of normal-weight mothers (BMI 18.5 to <25.0), adjusted HRs of epilepsy by maternal BMI categories were as follows: overweight (BMI 25.0 to <30.0), 1.11 (95% CI, 1.04-1.17); obesity grade I (BMI 30.0 to <35.0), 1.20 (95% CI, 1.10-1.31); obesity grade II (BMI 35.0 to <40.0), 1.30 (95% CI, 1.12-1.50); and obesity grade III (BMI≥40.0), 1.82 (95% CI, 1.46-2.26). The rates of epilepsy were considerably increased for children with malformations of the nervous system (adjusted HR, 46.4; 95% CI, 42.2-51.0), hypoxic ischemic encephalopathy (adjusted HR, 23.6; 95% CI, 20.6-27.1), and neonatal convulsions (adjusted HR, 33.5; 95% CI, 30.1-37.4). The rates of epilepsy were doubled among children with neonatal hypoglycemia (adjusted HR, 2.10; 95% CI, 1.90-2.33) and respiratory distress syndrome (adjusted HR, 2.43; 2.21-2.66), and neonatal jaundice was associated with more than a 50% increased risk of epilepsy (adjusted HR, 1.47; 95% CI, 1.33-1.63). The elevated risk of epilepsy in children of overweight or obese mothers was not explained by obesity-related pregnancy or neonatal complications. The rates of childhood epilepsy increased with maternal overweight or obesity in a dose-response manner. Given that overweight and obesity are modifiable, prevention of obesity may be an important public health strategy to reduce the incidence of childhood epilepsy.

Maternal immune activation increases seizure susceptibility in juvenile rat offspring.

Epidemiological data suggest a relationship between maternal infection and a high incidence of childhood epilepsy in offspring. However, there is little experimental evidence that links maternal infection with later seizure susceptibility in juvenile offspring. Here, we asked whether maternal immune challenge during pregnancy can alter seizure susceptibility and seizure-associated brain damage in adolescence. Pregnant Sprague-Dawley rats were treated with lipopolysaccharide (LPS) or normal saline (NS) on gestational days 15 and 16. At postnatal day 21, seizure susceptibility to kainic acid (KA) was evaluated in male offspring. Four groups were studied, including normal control (NS-NS), prenatal infection (LPS-NS), juvenile seizure (NS-KA), and "two-hit" (LPS-KA) groups. Our results demonstrated that maternal LPS exposure caused long-term reactive astrogliosis and increased seizure susceptibility in juvenile rat offspring. Compared to the juvenile seizure group, animals in the "two-hit" group showed exaggerated astrogliosis, followed by worsened spatial learning ability in adulthood. In addition, prenatal immune challenge alone led to spatial learning impairment in offspring but had no effect on anxiety. These data suggest that prenatal immune challenge causes a long-term increase in juvenile seizure susceptibility and exacerbates seizure-induced brain injury, possibly by priming astroglia.

Childhood epilepsy and maternal antibodies to microbial and tissue antigens during pregnancy

Several epidemiologic studies show associations between mother's infections during pregnancy and an increased risk of mental and neurological disorders in the offspring. Such associations could be due to the direct or indirect effects of infectious agents, including immune responses to infectious agents that display molecular mimicry with host antigens. We measured a range of antigen-specific maternal IgG antibodies to examine if any were associated with risk for childhood epilepsy in offspring. We used a case-cohort design within the Danish National Birth Cohort (DNBC) to examine maternal IgG antibodies to 25 microbial and tissue antigens during pregnancy and their association with the risk of epilepsy in offspring. The source population of this study was 68,250 live born singletons with up to 10 years of follow up. We randomly identified a sample of 282 children as a subcohort and included 275 children with a verified diagnosis of epilepsy as cases. Maternal antibodies were categorized into 6 groups (<50, 50-59, 60-69, 70-79, 80-89, ≥90 percentile) according to the level in the subcohort. We used a Prentice-weighted Cox regression model to estimate the hazard ratio (HR) and 95% confidence interval (CI) for epilepsy according to measured antibodies. Higher levels of maternal antibodies against herpes simples virus type 1 (anti-HSV1) were associated with a slightly higher risk of childhood epilepsy (HR for trend=1.09, 95% CI: 0.99-1.21), while higher levels of maternal antibodies against pneumococcal polysaccharide 18 (anti-PnPS18) were associated with a lower risk of childhood epilepsy (HR for trend=0.90, 95% CI: 0.81-1.01). Among the subtypes, a significantly higher risk associated with anti-HSV1 antibodies was seen for childhood absence epilepsy (HR for trend=2.08, 95% CI: 1.12-3.85) and for epileptic encephalopathies (HR for trend=1.49, 95% CI: 1.01-2.22). The significantly lower risk associated with anti-PnPS18 antibodies was observed for infantile spasms (HR for trend=0.47, 95% CI: 0.27-0.83). Maternal anti-HSV1and anti-PnPS18 antibodies during pregnancy may be associated with the risk of epilepsy in offspring, but any potential etiologic and preventative implications of these associations warrant further exploration.

Maternal Use of Antibiotics, Hospitalisation for Infection during Pregnancy, and Risk of Childhood Epilepsy: A Population-Based Cohort Study

BackgroundMaternal infection during pregnancy may be a risk factor for epilepsy in offspring. Use of antibiotics is a valid marker of infection.Methodology/Principal FindingsTo examine the relationship between maternal infection during pregnancy and risk of childhood epilepsy we conducted a historical cohort study of singletons born in northern Denmark from 1998 through 2008 who survived ≥29 days. We used population-based medical databases to ascertain maternal use of antibiotics or hospital contacts with infection during pregnancy, as well as first-time hospital contacts with a diagnosis of epilepsy among offspring. We compared incidence rates (IR) of epilepsy among children of mothers with and without infection during pregnancy. We examined the outcome according to trimester of exposure, type of antibiotic, and total number of prescriptions, using Poisson regression to estimate incidence rate ratios (IRRs) while adjusting for covariates. Among 191 383 children in the cohort, 948 (0.5%) were hospitalised or had an outpatient visit for epilepsy during follow-up, yielding an IR of 91 per 100 000 person-years (PY). The five-year cumulative incidence of epilepsy was 4.5 per 1000 children. Among children exposed prenatally to maternal infection, the IR was 117 per 100 000 PY, with an adjusted IRR of 1.40 (95% confidence interval (CI): 1.22–1.61), compared with unexposed children. The association was unaffected by trimester of exposure, antibiotic type, or prescription count.Conclusions/SignificancePrenatal exposure to maternal infection is associated with an increased risk of epilepsy in childhood. The similarity of estimates across types of antibiotics suggests that processes common to all infections underlie this outcome, rather than specific pathogens or drugs.