Comparative Safety of Antiseizure Medication Monotherapy for Major Malformations.

OBJECTIVE: This study was undertaken to examine the comparative safety of antiseizure medication (ASM) monotherapy in pregnancy with respect to risk of major congenital malformations (MCMs), overall and by MCM subtype. METHODS: We conducted a population-based cohort study using national health register data from Denmark, Finland, Iceland, Norway, and Sweden (1996-2020). We compared pregnancies with first trimester exposure to lamotrigine monotherapy to ASM-unexposed, carbamazepine, valproate, oxcarbazepine, levetiracetam, and topiramate to lamotrigine monotherapy, and stratified monotherapy groups by dose. The outcome was nongenetic MCM and specific subtypes. We estimated adjusted risk ratios (aRRs) and 95% confidence intervals (CIs) with log-binomial regression and propensity score weights. RESULTS: There was a higher crude risk of any MCM in pregnancies exposed to lamotrigine monotherapy (n = 8,339) compared to ASM-unexposed pregnancies (n = 4,866,362), but not after confounder adjustment (aRR = 0.97, 95% CI = 0.87-1.08). Compared to lamotrigine, there was an increased risk of malformations associated with valproate (n = 2,031, aRR = 2.05, 95% CI = 1.70-2.46) and topiramate (n = 509, aRR = 1.81, 95% CI = 1.26-2.60), which increased in a dose-dependent manner. We found no differences in malformation risk for carbamazepine (n = 2,674, aRR = 0.91, 95% CI = 0.72-1.15), oxcarbazepine (n = 1,313, aRR = 1.09, 95% CI = 0.83-1.44), or levetiracetam (n = 1,040, aRR = 0.78, 95% CI = 0.53-1.13). Valproate was associated with several malformation subtypes, including nervous system, cardiac, oral clefts, clubfoot, and hypospadias, whereas lamotrigine and carbamazepine were not. INTERPRETATION: Topiramate is associated with an increased risk of MCM similar to that associated with valproate, but lower doses may mitigate the risks for both drugs. Conversely, we found no increased risks for lamotrigine, carbamazepine, oxcarbazepine, or levetiracetam, which is reassuring. ANN NEUROL 2023;93:551-562.

Pharmacological treatment of obesity in adults in Norway 2004-2022.

AIMS: To describe trends in the use of anti-obesity drugs in Norway during the period 2004-2022. MATERIALS AND METHODS: We assessed the annual utilization of any available drug indicated for obesity recorded in the nationwide Norwegian Prescribed Drug Register for adults (age 18-79 years) from 1 January 2004 to 31 December 2022. Prevalence was stratified by sex and age group (18-29 years and 10-year age groups thereafter). Additional analyses were performed in individuals initiating treatment with an anti-obesity drug and on the cost of the anti-obesity drugs since 2017. RESULTS: The prevalence of anti-obesity drug use decreased from 2009, when sibutramine and rimonabant were withdrawn from the market, and increased again after the approval of bupropion-naltrexone in 2017 and liraglutide in 2018. The use of the peripheral-acting anti-obesity drug orlistat decreased from 2004. In 2022, 1.04% of the adult Norwegian population (72.8% women) filled at least one prescription of bupropion-naltrexone, 0.91% used liraglutide (Saxenda; 74.2% women), and semaglutide without reimbursement was used by 0.68% (76.7% women). The prevalence increased with age, peaking in the age group 50 to 59 years, and decreased in older age groups. From 2017 to 2022, 2.8% of the adult residents initiated treatment with an anti-obesity drug. The total sale of those drugs increased from 1.1 million euros in 2017 to 91.8 million euros in 2022. CONCLUSIONS: The use of anti-obesity drugs in Norway has increased substantially in recent years, especially among women aged 40 to 59 years. Changes in availability and reimbursement have influenced the use of these drugs in recent years.

Treatment patterns of antidepressants in children and adolescents in Scandinavia.

The aim of this study was to examine variations in use of antidepressants among children and adolescents in the three Scandinavian countries (Sweden, Norway, and Denmark). We identified new users of antidepressants (5-17 years) during 2007-2018 and described the annual incidence rate, treatment duration, concomitant psychotropic drug use, and the clinical setting of the prescribing physician (in Sweden and Denmark). Incident use of antidepressants increased by a factor 1.9 in Sweden, 1.3 in Norway and decreased by a factor 0.6 in Denmark during the study period. In Sweden, 58% of antidepressant users were covered by a prescription 12 months after initiation compared to 40% in Norway and 49% in Denmark. Also, 34% of Swedish antidepressant users were in continuous treatment after 12 months compared to 26% in Norway and 31% in Denmark. Concomitant use of other psychotropics was more common in Sweden (57%) than in Norway (37%) and Denmark (27%). During 2007-2018, clinicians from psychiatry settings initiated 75% of antidepressant treatments in Sweden, while this was the case for 50% of prescriptions in Denmark, although the proportion increased over time. The number of new antidepressant users is high and still rising in Sweden compared to Norway and Denmark. Swedish antidepressant users are more likely to use other psychotropics and to be covered by an antidepressant prescription after one year. Most antidepressants in Sweden are prescribed by physicians within psychiatric settings suggesting that they are based on specialized psychiatric evaluation.

Incidence and prevalence of drugs used for chronic diseases in survivors of adult-onset gynaecological cancer - A nationwide cohort study.

OBJECTIVES: To evaluate both incidence and prevalence of drugs used for chronic diseases in survivors of adult-onset gynaecological cancer. DESIGN: A prospective study. SETTING: Population-based registries. POPULATION: 1.76 million women, including 17 500 women with gynaecological cancers. METHODS: Data from the Cancer Registry of Norway was linked to the Norwegian Prescription Database and other national databases. MAIN OUTCOME MEASURES: Prevalence ratios (PRs) and hazard ratios (HRs), with 95% confidence intervals (CIs), of dispensed drugs in gynaecological cancer patients (up to 15 years after diagnosis) were estimated by log-binomial and Cox regression, respectively, with cancer-free women as reference. RESULTS: For gynaecological cancer patients, the incidence of drugs used for pain control was higher than in cancer-free women, especially the first 5 years after diagnosis, and the prevalence was high at least 10 years after. The prevalence of sex hormones was high in women with gynaecological cancer at least 10 years after diagnosis (cervical and ovarian cancer PR = 23, 95% CI 18-30 and PR = 29, 95% CI 15-38, respectively), but low in cancer-free women (0.3%). Patients with uterine corpus cancer had a higher prevalence of antidiabetics before and at least 10 years after diagnosis, most pronounced in women diagnosed before age 50 (PR = 10, 95% CI 5.0-21). The prevalence of antidepressants was moderately elevated in women with gynaecological cancers. CONCLUSIONS: Gynaecological cancer survivors, particularly cervical and ovarian cancer survivors, had an increased long-term use of drugs for pain control and sex hormones. Survivors of uterine corpus cancer used antidiabetics more often, both before and after diagnosis.

Prevalence trends and individual patterns of ADHD medication use in pregnancy in Norway and Sweden, 2010-2019.

PURPOSE: This study aimed to describe recent trends in ADHD medication use in pregnancy in Norway and Sweden, including prevalence, individual characteristics, and patterns of use. METHODS: We studied ADHD medication use (amphetamine, dexamphetamine, methylphenidate, atomoxetine, lisdexamfetamine, guanfacine) by year and age in pregnancies from 2010 to 2019 identified from the medical birth registers (gestational age ≥ 22 weeks) linked to prescribed drug registers (Norway, N = 577,116; Sweden, N = 1,118,988). We compared characteristics of those who used any ADHD medication in pregnancy to no use in pregnancy. Discontinuation was defined as no use after first trimester. RESULTS: ADHD medication use increased from 2010 to 2019 by 3.0 users per 1000 pregnancies in Norway (from 2.5 to 5.5/1000) and by 6.3 per 1000 in Sweden (from 1.6 to 7.9/1000), mainly driven by methylphenidate and since 2015 by lisdexamfetamine. Medication use has increased among pregnant individuals of all age groups, with higher use among the youngest. Pregnant individuals who used ADHD medication were less likely to be married/cohabiting, more likely be nulliparous and to smoke. They had particularly high use of co-medication with antidepressants, anxiolytics/hypnotics, and opioids: 42% in Norway and 65% in Sweden used at least one additional class of psychotropic medication. Most individuals discontinued ADHD medication in pregnancy (85% Norway, 78% Sweden). CONCLUSION: ADHD medication use during pregnancy increased in Norway and Sweden in the last decade. However, discontinuation rates during pregnancy were high. Those who used ADHD medication had more risk factors for pregnancy complications including low parity, smoking, and other psychotropic drug use.

Trajectories of ADHD medication use before, during, and after pregnancy: A population-based study from Norway and Sweden.

PURPOSE: To describe ADHD medication use trajectories around pregnancy in Norway and Sweden. METHODS: We identified pregnancies resulting in births using linked data from birth and prescribed drug registers of Norway (2006-2019, N = 813 107) and Sweden (2007-2018, N = 1 269 146). We restricted to women who filled prescriptions for ADHD medication during pregnancy or in the year before or after. We described exposure as use versus no use, and total amount of drug dispensed in defined daily doses (DDDs). Group-based trajectory modeling was used to identify distinct medication use trajectories. RESULTS: In total, 13 286 women (0.64%) filled a prescription for ADHD medication. We identified four trajectory groups: continuers (5.7%), interrupters (23.8%), discontinuers (49.5%), and late initiators (21.0%). Discontinuers were younger, continuers were older on average. More women continued medication in recent years (2014-2019). Most discontinuers (60.7%) were nulliparous; more initiators and continuers had one or multiple previous births, respectively. Continuers were least likely to live with a partner (65.8%). Discontinuers were least likely (24.7%) and continuers most likely (37.6%) to smoke at the beginning of pregnancy. More continuers used amphetamine derivatives and were most likely to use other psychotropics. On modeling continuers, we identified three dose-trajectory groups which suggested that most women reduced medication dose during pregnancy. CONCLUSIONS: Most pregnant women discontinued or interrupted their ADHD medication during pregnancy, but more continued in recent years. Continuers were more likely to have had previous births, less likely to have lived with a partner, and may have had additional comorbidities warranting the use of other psychotropics.

Trends in use of attention deficit hyperactivity disorder medication among children and adolescents in Scandinavia in 2010-2020.

The objective of the study was to compare the use of attention deficit hyperactivity disorder (ADHD) medication among children and adolescents in Scandinavia 2010-2020. Using aggregated prescription data for individuals aged 5-19 years, we calculated annual prevalence proportions of ADHD medication (users/1000 inhabitants) for each country, overall and stratified by age and sex. Overall, use of ADHD medication increased during 2010-2020 in all countries. The increase was pronounced in Sweden reaching 35 users/1000 inhabitants in 2020 (119% increase), whereas it reached 22/1000 in Denmark and Norway (equivalent to a 38% and 16% increase, respectively). Methylphenidate was the most frequently used drug and Sweden had the highest use reaching 25/1000 in 2020 compared to 16/1000 and 18/1000 in Denmark and Norway, respectively. Lisdexamfetamine use increased steadily and was also highest in Sweden (13/1000 in 2020). In 2020, atomoxetine use was higher in Sweden (4.6/1000) and Denmark (4.5/1000) compared to Norway (2.2/1000). From 2015, use of guanfacine increased in Sweden reaching 4.4/1000 in 2020 but remained low in Denmark (0.4/1000) and Norway (0.7/1000). Use of dexamphetamine was low (ranging from 0.47 to 0.75/1000 in 2020) in the three countries. ADHD medication use was highest in Sweden across all age groups. In all countries, the prevalence was higher in males compared to females. In conclusion, use of ADHD medication among children and adolescents in Scandinavia is increasing. The prevalence of use is higher in Sweden for all drug groups compared to Norway and Denmark.

Use of non-insulin antidiabetic drugs in children and young adults - A Scandinavian drug utilization study from 2010-2019.

Knowledge on utilization patterns of non-insulin antidiabetic drugs in childhood and youth is limited. Therefore, we conducted a population-based drug utilization study using publicly available aggregate data on use of non-insulin antidiabetics from 2010 to 2019 in Scandinavia (Denmark, Norway and Sweden) in individuals aged up to 24 years. For each non-insulin antidiabetic drug, we calculated the annual prevalence proportion of users, overall and for specific age groups. From 2010 to 2019, the prevalence of non-insulin antidiabetic users in Scandinavia increased 37% from 0.43 to 0.59/1000 individuals. The prevalence proportions were highest among female adolescents and young adults, but the largest relative increase in use was seen among 10-14-year-olds (78%). Metformin was by far the most widely used non-insulin antidiabetic drug with a prevalence proportion of 0.51/1000 in 2019, followed by glucagon-like peptide-1 (GLP-1) analogues, which, however, showed an eight-fold relative increase during the study period.

Prescribed drugs in 27 000 individuals after diagnosis of colorectal cancer: A population-based cohort study.

BACKGROUND: The prevalence of prescribed drugs in survivors of colorectal cancer (CRC) was evaluated. METHODS: Data from the Cancer Registry of Norway were linked to the Norwegian Prescription Database for a study population of 3.52 million individuals. Prevalence ratios (PRs) with 95% confidence intervals (CIs) of prescribed drugs in CRC-survivors compared to the cancer-free population, were estimated by log-binomial regression, adjusting for age and education. RESULTS: Almost 27 000 individuals, aged 20 to 84, were diagnosed with CRC during 2005 to 2014. The first year after diagnosis, the prevalence of prescribed drugs was higher in CRC-survivors compared with the cancer-free population, especially drugs for anxiety and tension, and steroid-responsive conditions. PRs for several drugs, especially drugs used for mental and behavioural disorders, decreased with time since diagnosis. The prevalence of drugs used for anxiety and tension was elevated 10 years after diagnosis; PRs the first year after diagnosis were 20 (95% CI: 18-22) in males and 17 (16-18) in females. Ten years after diagnosis PRs were 5.0 (3.1-7.9) and 2.0 (1.0-3.8), respectively. In absolute numbers, the largest increase, compared to the cancer-free population, was in drugs used for gastric acid disorders and pain. The prevalence of neuromodulatory drugs was higher in CRC-survivors. CONCLUSIONS: The prevalence of several drugs was higher in CRC-survivors than in the cancer-free population 10 years after diagnosis. The largest absolute excess in prevalence was for gastric acid disorder and pain medications, while the relative prevalence of drugs used for anxiety and tension was high in CRC-survivors. Long persisting neuropathia was indicated.

ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility.

N(6)-methyladenosine (m(6)A) is the most prevalent internal modification of messenger RNA (mRNA) in higher eukaryotes. Here we report ALKBH5 as another mammalian demethylase that oxidatively reverses m(6)A in mRNA in vitro and in vivo. This demethylation activity of ALKBH5 significantly affects mRNA export and RNA metabolism as well as the assembly of mRNA processing factors in nuclear speckles. Alkbh5-deficient male mice have increased m(6)A in mRNA and are characterized by impaired fertility resulting from apoptosis that affects meiotic metaphase-stage spermatocytes. In accordance with this defect, we have identified in mouse testes 1,551 differentially expressed genes that cover broad functional categories and include spermatogenesis-related mRNAs involved in the p53 functional interaction network. The discovery of this RNA demethylase strongly suggests that the reversible m(6)A modification has fundamental and broad functions in mammalian cells.