Using the Norwegian Mother and Child Cohort Study to determine risk factors for delayed development and neuro-psychiatric symptoms in the offspring of parents with epilepsy

Introduction: Antiepileptic drug (AED) teratogenicity is suspected to be the main cause of impaired development in children of women with epilepsy. However, many factors may confound the reported risks. The purpose of this review is to characterize the epilepsy cohort in the Norwegian Mother and Child Cohort Study (MoBa) and show how it can be used to detangle various risk factors for adverse outcome in children of mothers with epilepsy. Methods: MoBa is a large, long-term prospective, family-based cohort study. The database is linked to the Medical Birth Registry of Norway. The epilepsy cohort consists of mothers and their children representing more than 700 pregnancies. Blood samples were obtained from the mother during pregnancy and from the umbilical cord after delivery, and AED concentrations were measured. Validated screening tools determined the frequency of maternal confounding risk factors and adverse offspring outcomes. Risk estimates were reported as adjusted odds ratios with confidence intervals using the remaining MoBa cohort as a reference (n=107,597). Outcome in offspring of women with epilepsy without AED treatment in pregnancy and of fathers with epilepsy were used to separate the effect of epilepsy from the effect of in utero exposure to AEDs. Results: Socioeconomic and psychiatric risk factors for adverse offspring outcomes were more frequent in mothers with epilepsy. The frequency of adverse offspring outcome was increased at 6, 18 and 36 months for verbal, motor and social development. Children of women with epilepsy without AED treatment and of fathers with epilepsy were generally similar to children of women without epilepsy. Conclusion: Children of mothers with epilepsy are at risk of adverse outcomes. AED exposure emerges as the most important risk factor.publishedVersio

Prevalence of self-reported emotional, physical, and sexual abuse and association with fear of childbirth in pregnant women with epilepsy: The Norwegian Mother, Father, and Child Cohort Study

Objective This study was undertaken to examine the prevalence of self-reported experiences with abuse in pregnant women with epilepsy and the association between having experienced abuse and childbirth expectations, particularly the fear of childbirth. Methods We performed a cross-sectional study of women with and without epilepsy enrolled in the Norwegian Mother, Father, and Child Cohort Study 1999–2008. Data on epilepsy diagnosis; antiseizure medication (ASM) use; emotional, physical, and sexual abuse; and childbirth expectations were collected from questionnaires completed during gestational Weeks 17–19 and 30. Results Our study population included 295 women with ASM-treated epilepsy, 318 women with ASM-untreated epilepsy, and 93 949 women without epilepsy. A total of 115 women (47%) with ASM-treated and 132 women (57%) with ASM-untreated epilepsy reported any emotional, physical, or sexual abuse, compared to 25 100 women (32%) without epilepsy. The adjusted odds ratios (aORs) for having experienced any abuse were 1.8 (95% confidence interval [CI] = 1.4–2.3) and 1.8 (95% CI = 1.4–2.2) for ASM-treated and ASM-untreated epilepsy, respectively. A total of 29 women (11%) with ASM-treated and 34 women (11%) with ASM-untreated epilepsy reported having been raped, compared to 3088 women (4%) without epilepsy (aORs = 2.8 [95% CI = 1.8–4.1] and 2.9 [95% CI = 2.0–4.2], respectively). In nulliparous women with ASM-untreated epilepsy, having experienced abuse was associated with fear of childbirth; 22 women (31%) with abuse experiences reported fear of childbirth compared to five women (7%) with no experience of abuse (aOR = 5.4 [95% CI = 1.7–17.2]). This association was not seen in multiparous women or in women with ASM-treated epilepsy. Significance More women with epilepsy reported emotional, physical, and sexual abuse than women without epilepsy. Such experiences may be associated with childbirth expectations.publishedVersio

Language impairment in children aged 5 and 8 years after antiepileptic drug exposure in utero – the Norwegian Mother and Child Cohort Study

Background and purpose: The purpose was to examine the consequences of antiepileptic drug (AED) exposure during pregnancy on language abilities in children aged 5 and 8 years of mothers with epilepsy. Methods: The study population included children of mothers with and without epilepsy enrolled in the Norwegian Mother and Child Cohort Study 1999–2008. Mothers prospectively provided information on epilepsy diagnosis, AED use during pregnancy and the child’s language abilities at age 5 and 8 years, in questionnaires with validated language screening tools. AED concentrations in gestation week 17–19 and in the umbilical cord were measured. Results: The study population included 346 AED‐exposed and 388 AED‐unexposed children of mothers with epilepsy, and 113 674 children of mothers without epilepsy. Mothers of 117 and 121 AED‐exposed children responded to the questionnaires at age 5 and 8 years, respectively. For AED‐exposed children, the adjusted odds ratio for language impairment was 1.6 [confidence interval (CI) 1.1–2.5, P = 0.03] at age 5 years and 2.0 (CI 1.4–3.0, P < 0.001) at age 8 years, compared to children of mothers without epilepsy. Children exposed to carbamazepine monotherapy had a significantly increased risk of language impairment compared to control children at age 8 years (adjusted odds ratio 3.8, CI 1.6–9.0, P = 0.002). Higher maternal valproate concentrations correlated with language impairment at age 5 years. Periconceptional folic acid supplement use protected against AED‐associated language impairment. Conclusion: Foetal AED exposure in utero is associated with an increased risk of language impairment in children aged 5 and 8 years of mothers with epilepsy. Periconceptional folic acid use had a protective effect on AED‐associated language impairment.publishedVersio

Fluctuations of sensorimotor processing in migraine: A controlled longitudinal study of beta event related desynchronization

Background: The migraine brain seems to undergo cyclic fluctuations of sensory processing. For instance, during the preictal phase, migraineurs experience symptoms and signs of altered pain perception as well as other well-known premonitory CNS-symptoms. In the present study we measured EEG-activation to non-painful motor and sensorimotor tasks in the different phases of the migraine cycle by longitudinal measurements of beta event related desynchronization (beta-ERD). Methods: We recorded electroencephalography (EEG) of 41 migraine patients and 31 healthy controls. Each subject underwent three EEG recordings on three different days with classification of each EEG recording according to the actual migraine phase. During each recording, subjects performed one motor and one sensorimotor task with the flexion-extension movement of the right wrist. Results: Migraine patients had significantly increased beta-ERD and higher baseline beta power at the contralateral C3 electrode overlying the primary sensorimotor cortex in the preictal phase compared to the interictal phase. We found no significant differences in beta-ERD or baseline beta power between interictal migraineurs and controls. Conclusion: Increased preictal baseline beta activity may reflect a decrease in pre-activation in the sensorimotor cortex. Altered pre-activation may lead to changes in thresholds for inhibitory responses and increased beta-ERD response, possibly reflecting a generally increased preictal cortical responsivity in migraine. Cyclic fluctuations in the activity of second- and third-order afferent somatosensory neurons, and their associated cortical and/or thalamic interneurons, may accordingly also be a central part of the migraine pathophysiology.publishedVersio

Effects of insufficient sleep on sensorimotor processing in migraine. A randomised, blinded crossover study of event related beta oscillations

Background Migraine has a largely unexplained connection with sleep and is possibly related to a dysfunction of thalamocortical systems and cortical inhibition. In this study we investigate the effect of insufficient sleep on cortical sensorimotor processing in migraine. Methods We recorded electroencephalography during a sensorimotor task from 46 interictal migraineurs and 28 controls after two nights of eight-hour habitual sleep and after two nights of four-hour restricted sleep. We compared changes in beta oscillations of the sensorimotor cortex after the two sleep conditions between migraineurs, controls and subgroups differentiating migraine subjects usually having attacks starting during sleep and not during sleep. We included preictal and postictal recordings in a secondary analysis of temporal changes in relation to attacks. Results Interictally, we discovered lower beta synchronisation after sleep restriction in sleep related migraine compared to non-sleep related migraine (p=0.006) and controls (p=0.01). No differences were seen between controls and the total migraine group in the interictal phase. After migraine attacks, we observed lower beta synchronisation (p<0.001) and higher beta desynchronisation (p=0.002) after sleep restriction closer to the end of the attack compared to later after the attack. Conclusion The subgroup with sleep related migraine had lower sensorimotor beta synchronisation after sleep restriction, possibly related to dysfunctional GABAergic inhibitory systems. Sufficient sleep during or immediately after migraine attacks may be of importance for maintaining normal cortical excitability.publishedVersio

Young people with epilepsy have an increased risk of eating disorder and poor quality diet

Objective: To investigate whether adolescents with epilepsy are at increased risk of having self‐reported eating disorder symptoms and poor quality diet compared to young people from the general population. Methods: We used data from the Health Profile for Children and Youth in Akershus Study, a cross‐sectional population‐based study based on a voluntary self‐reported questionnaire. There were 19,995 participants (response rate 85%) aged 13–19 years; 247 (1.2%) reported a lifetime diagnosis of epilepsy. Odds ratios (OR) and 95% confidence intervals (CI) for eating disorders, unhealthy diet, dieting, satisfaction with looks, and participation in sports were estimated by using a logistic regression model. All estimates were adjusted for single parents and poor family economy. Results: Children and adolescents with epilepsy had more eating disorders than their peers (OR 1.8, CI 1.0–3.0, p = 0.03). They were less satisfied with their own appearance (OR 0.7, CI 0.5–0.9, p = 0.02), and they eat more unhealthily (OR 1.7, CI 1.3–2.2, p = 0.001). Males with epilepsy were more likely to have been dieting (OR 3.1, CI 1.2–7.9, p = 0.02) and less satisfied with their own appearance (OR 0.4, CI 0.3–0.7, p < 0.001). Females with epilepsy were more likely to eat unhealthily (OR 1.7, CI 1.1–2.5, p = 0.01). Significance: Adolescents with epilepsy are at increased risk of having eating disorder symptoms. They eat less healthily and are less satisfied with their looks. Health workers should be aware of this and bring diet and lifestyle into the dialogue with young people with epilepsy.publishedVersio

Plasma unmetabolized folic acid in pregnancy and risk of autistic traits and language impairment in antiseizure medication-exposed children of women with epilepsy

Background: Fetal exposure to unmetabolized folic acid (UMFA) during pregnancy may be associated with adverse neurodevelopment. Antiseizure medication (ASM) may interact with folate metabolism. Women with epilepsy using ASM are often recommended high-dose folic acid supplement use during pregnancy. Objectives: The aim was to determine the association between UMFA concentrations in pregnant women with epilepsy using ASM and risk of autistic traits or language impairment in their children aged 1.5–8 y. Methods: We included children of women with epilepsy using ASM and with plasma UMFA measurement enrolled in the Norwegian Mother, Father, and Child Cohort Study (MoBa). Data on ASM use, folic acid supplement use, autistic traits, and language impairment were obtained from parent-reported questionnaires during pregnancy and when the child was 1.5, 3, 5, and 8 y old. Plasma UMFA concentrations were measured during gestational weeks 17–19. Results: A total of 227 ASM-exposed children of 203 women with epilepsy were included. Response rates at ages 1.5, 3, 5, and 8 y were 67% (n = 151), 54% (n = 122), 36% (n = 82), and 37% (n = 85), respectively. For 208 (94%) children, the mother reported intake of folic acid supplement. There was no association between UMFA concentrations and autistic traits score in the adjusted multiple regression analyses at age 3 y (unstandardized B: −0.01; 95% CI: −0.03, 0.004) or 8 y (unstandardized B: 0.01; 95% CI: −0.02, 0.03). Children exposed to UMFA had no increased risk of autistic traits at age 3 y [adjusted OR (aOR): 0.98; 95% CI: 0.2, 4.2] or 8 y (aOR: 0.1; 95% CI: 0.01, 1.4) compared with unexposed children. We found no association between UMFA concentrations and language impairment in children aged 1.5–8 y. Conclusions: Our findings do not support any adverse neurodevelopmental effects of UMFA exposure in utero in children of women with epilepsy using ASM.publishedVersio

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

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

Comparative retention and effectiveness of migraine preventive treatments: A nationwide registry-based cohort study

Background and purpose Little is known about the comparative effects of migraine preventive drugs. We aimed to estimate treatment retention and effectiveness of migraine preventive drugs in a nationwide registry-based cohort study in Norway between 2010 and 2020. Methods We assessed retention, defined as the number of uninterrupted treatment days, and effectiveness, defined as the reduction in filled triptan prescriptions during four 90-day periods after the first preventive prescription, compared to a 90-day baseline period. We compared retention and efficacy for different drugs against beta blockers. Comparative retention was estimated with hazard ratios (HRs), adjusted for covariates, using Cox regression, and effectiveness as odds ratios (ORs) using logistic regression, with propensity-weighted adjustment for covariates. Results We identified 104,072 migraine patients, 81,890 of whom were female (78.69%) and whose mean (standard deviation) age was 44.60 (15.61) years. Compared to beta blockers, botulinum toxin (HR 0.43, 95% confidence interval [CI] 0.42–0.44) and calcitonin gene-related peptide pathway antibodies (CGRPabs; HR 0.63, 95% CI 0.59–0.66) were the least likely to be discontinued, while clonidine (HR 2.95, 95% CI 2.88–3.02) and topiramate (HR 1.34, 95% CI 1.31–1.37) were the most likely to be discontinued. Patients on simvastatin, CGRPabs, and amitriptyline were more likely to achieve a clinically significant reduction in triptan use during the first 90 days of treatment, with propensity score-adjusted ORs of 1.28 (95% CI 1.19–1.38), 1.23 (95% CI 0.79–1.90), and 1.13 (95% CI 1.08–1.17), respectively. Conclusions We found a favorable effect of CGRPabs, amitriptyline, and simvastatin compared with beta blockers, while topiramate and clonidine were associated with poorer outcomes.publishedVersio

Continuous positive airway pressure in cluster headache: A randomized, placebo-controlled, triple-blind, crossover study

Background - Oxygen inhalation aborts cluster headache attacks, and case reports show the effect of continuous positive airway pressure. The aim of this study was to investigate the prophylactic effect of continuous positive airway pressure in chronic cluster headache. Methods - This was a randomized placebo-controlled triple-blind crossover study using active and sham continuous positive airway pressure treatment for chronic cluster headache. Patients entered a one month’s baseline period before randomly being assigned to two months’ active continuous positive airway pressure treatment followed by a four weeks’ washout period and two months’ sham continuous positive airway pressure or vice versa. Primary outcome measure was number of cluster headache attacks/week. Results - Of the 30 included participants (12 males, median age 49.5 years, min-max 20–66 years), 25 completed both treatment/sham cycles (two discontinued, three lost to follow-up). The median number of cluster headache attacks per week was reduced from 8.25 (0.75–89.75) attacks to 6.25 (0–56.00) attacks for active continuous positive airway pressure and to 7.50 (0.50–43.75) attacks for sham continuous positive airway pressure, but there was no difference in active versus sham (p = 0.904). One patient had a serious adverse event during active treatment, none occurred during sham treatment. Conclusions - Continuous positive airway pressure treatment did not reduce the number of cluster headache attacks compared to sham treatment in chronic cluster headache patients