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Background There have been concerns about COVID-19 vaccination safety among frail older individuals. We investigated the relationship between COVID-19 mRNA vaccination and mortality among individuals aged ≥ 70 years and whether mortality varies across four groups of health services used. Methods In this nationwide cohort study, we included 688,152 individuals aged ≥ 70 years at the start of the Norwegian vaccination campaign (December 27, 2020). We collected individual-level data from the Norwegian Emergency Preparedness Register for COVID-19. Vaccinated and unvaccinated individuals were matched (1:1 ratio) on the date of vaccination based on sociodemographic and clinical characteristics. The main outcome was all-cause mortality during 21 days after first dose of COVID-19 mRNA vaccination. Kaplan-Meier survival functions were estimated for the vaccinated and unvaccinated groups. We used Cox proportional-hazards regression to estimate hazard ratios (HRs) of death between vaccinated and unvaccinated individuals, with associated 95% confidence intervals (CIs), overall and by use of health services (none, home-based, short- and long-term nursing homes) and age group. Results Between December 27, 2020, and March 31, 2021, 420,771 older individuals (61.1%) were vaccinated against COVID-19. The Kaplan-Meier estimates based on the matched study sample showed a small absolute risk difference in all-cause mortality between vaccinated and unvaccinated individuals, with a lower mortality in the vaccinated group (overall HR 0.28 [95% CI: 0.24–0.31]). Similar results were obtained in analyses stratified by use of health services and age group. Conclusion We found no evidence of increased short-term mortality among vaccinated individuals in the older population after matching on sociodemographic and clinical characteristics affecting vaccination and mortality. publishedVersion

Abstract 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.

Purpose/Background Pharmacokinetics may be of relevance for the risk of clozapine discontinuation. We compared metabolite profiles, accounting for smoking habits, in patients switching versus maintaining clozapine treatment at therapeutic concentrations. Methods/Procedures Adult patients with clozapine serum levels above 1070 nmol/L (350 ng/mL) were retrospectively included from a Norwegian therapeutic drug monitoring service during 2018–2020. Inclusion criteria were (1) known smoking habits, (2) blood sample drawn within 10 to 30 hours after last clozapine intake, and (3) detectable levels of N-desmethylclozapine, clozapine-N-oxide, clozapine-5N-glucuronide, or clozapine-N+-glucuronide. Patients comedicated with cytochrome P450 enzyme inducers, inhibitors, or valproic acid were excluded. The high-resolution mass spectrometry assay enabled detection of 21 clozapine metabolites. Metabolite profiles were compared between patients switching treatment (switchers), measured as clozapine being replaced by another antipsychotic drug in blood samples, versus maintaining clozapine treatment (nonswitchers) during the study period. Findings/Results Of the 84 patients fulfilling the study criteria, 7 patients (8.3%) were identified as clozapine switchers. After correcting for smoking habits, the clozapine-5N-glucuronide/clozapine ratio was 69% lower (P < 0.001), while the clozapine-N+-glucuronide/clozapine-5N-glucuronide ratio was 143% higher (P = 0.026), respectively, in switchers versus nonswitchers. The other metabolite ratios did not significantly differ between switchers and nonswitchers. Implications/Conclusions The present study found a significantly reduced 5N-glucuronidation phenotype in patients switching from clozapine at therapeutic serum concentrations (>1070 nmol/L) to other antipsychotic drugs. This may indicate that glucuronidation, as a potential detoxification mechanism, is related to clozapine tolerability. However, the causality of this observation needs to be investigated in future studies with larger patient populations.

Background: Whether the SARS-CoV-2 mRNA vaccines may cause a transient increased stroke risk is uncertain. Methods: In a registry-based cohort of all adult residents at December 27, 2020, in Norway, we linked individual-level data on COVID-19 vaccination, positive SARS-CoV-2 test, hospital admissions, cause of death, health care worker status, and nursing home resident status extracted from the Emergency Preparedness Register for COVID-19 in Norway. The cohort was followed for incident intracerebral bleeding, ischemic stroke, and subarachnoid hemorrhage within the first 28 days after the first/second or third dose of mRNA vaccination until January 24, 2022. Stroke risk after vaccination relative to time not exposed to vaccination was assessed by Cox proportional hazard ratio, adjusted for age, sex, risk groups, health care personnel, and nursing home resident. Results: The cohort included 4 139 888 people, 49.8% women, and 6.7% were ≥80 years of age. During the first 28 days after an mRNA vaccine, 2104 people experienced a stroke (82% ischemic stroke, 13% intracerebral hemorrhage, and 5% subarachnoid hemorrhage). Adjusted hazard ratios (95% CI) after the first/second and after the third mRNA vaccine doses were 0.92 (0.85–1.00) and 0.89 (0.73–1.08) for ischemic stroke, 0.81 (0.67–0.98) and 1.05 (0.64–1.71) for intracerebral hemorrhage, and 0.64 (0.46–0.87) and 1.12 (0.57–2.19) for subarachnoid hemorrhage, respectively. Conclusions: We did not find increased risk of stroke during the first 28 days after an mRNA SARS-CoV-2 vaccine.

IntroductionSafe and effective pharmacological treatment is of paramount importance for treating severe psoriasis. Brodalumab, a monoclonal antibody against interleukin (IL) 17 receptor A, was granted marketing authorisation in the EU in 2017. The European Medicines Agency requested a postauthorisation safety study of brodalumab to address potential safety issues raised during drug development regarding major adverse cardiovascular events, suicidal conduct, cancer and serious infections.Methods and analysisBRodalumab Assessment of Hazards: A Multinational Safety is a multicentre observational safety study of brodalumab running from 2017 to 2029 using population-based healthcare databases from Denmark, Sweden, Norway, Netherlands, Germany and three different centres in Italy. A distributed database network approach is used, such that only aggregate data are exchanged between sites.Two types of designs are used: a case-time-control design to study acute effects of transient treatment and a variation of the new user active comparator design to study the effects of transient or chronic treatment. As comparators, inhibitors of TNF-α, inhibitors of IL-12 and IL-23, and other inhibitors of cytokine IL-17A are included.In the self-controlled case-time-control design, the risk of developing the outcome of interest during periods of brodalumab use is compared within individuals to the risk in periods without use.In the active comparator cohort design, new users of brodalumab are identified and matched to new users of active comparators. Potential baseline confounders are adjusted for by using propensity score modelling. For outcomes that potentially require large cumulative exposure, an adapted active comparator design has been developed.Ethics and disseminationThe study is approved by relevant authorities in Denmark, Norway, Sweden, the Netherlands, Germany and Italy in line with the relevant legislation at each site. Data confidentiality is secured by the distributed network approach. Results will be published in peer-reviewed journals.Trial registration numberEUPAS30280.

BackgroundAntipsychotics are increasingly used among women of childbearing age and during pregnancy.ObjectiveTo determine whether children exposed to antipsychotics in utero are at increased risk of attention-deficit/hyperactivity disorder (ADHD) or autism spectrum disorder (ASD), accounting for maternal diagnoses of bipolar, psychotic and other psychiatric disorders.DesignPopulation-based cohort study, including a sibling analysis.SettingNationwide data on all pregnant women and their live-born singletons in Denmark (1997-2017), Finland (1996-2016), Iceland (2004-2017), Norway (2004-2017), and Sweden (2006-2016).Participants4 324 086 children were eligible for inclusion to the study cohort.InterventionAntipsychotic exposure in utero, assessed by pregnancy trimester, type of antipsychotic, and varying patterns of use.Main outcome measuresNon-mutually exclusive diagnoses of ADHD and ASD. We used Cox proportional hazard models to calculate hazard ratios (HRs) controlling for maternal psychiatric disorders and other potential confounding factors.FindingsAmong 4 324 086 singleton births, 15 466 (0.4%) were exposed to antipsychotics in utero. During a median follow-up of 10 years, we identified 72 257 children with ADHD and 38 674 children with ASD. Unadjusted HRs were raised for both outcomes but shifted substantially towards the null after adjustment; 1.10 (95%CI 1.00 to 1.27) for ADHD and 1.12 (0.97 to 1.29) for ASD. Adjusted HRs remained consistent by trimester of exposure and type of antipsychotic. Comparing in utero exposure with pre-pregnancy use yielded HRs of 0.74 (0.62 to 0.87) for ADHD and 0.88 (0.70 to 1.10) for ASD. Sibling analyses yielded HRs of 1.14 (0.79 to 1.64) for ADHD and 1.34 (0.75 to 2.39) for ASD.DiscussionOur findings suggest little or no increased risk of child ADHD or ASD after in utero exposure to antipsychotics.Clinical implicationsResults regarding child neurodevelopment are reassuring for women who need antipsychotics during pregnancy.

ImportanceThe SARS-CoV-2 mRNA vaccines are associated with an increased risk of myocarditis. This association appears to be strongest in male adolescents and younger males and after the second dose. Few studies have evaluated the association after booster doses.ObjectiveTo evaluate the risk of myocarditis following SARS-CoV-2 mRNA booster vaccination in 12-to-39-year-olds.DesignA multinational cohort study using nationwide register data.SettingDenmark, Finland, Norway, and Sweden.ParticipantsCohorts comprising all 8.9 million individuals residing in each of the four countries, born 1982-2009, and alive at start of study on December 27, 2020, without a previous diagnosis of myocarditis or pericarditis or laboratory-confirmed SARS-CoV-2 infection.ExposuresThe 28-day acute risk periods following the second and third dose of BNT162b2 and mRNA-1273, respectively, in a homologous schedule defines the exposures of interest.Main Outcomes and MeasuresCohort participants were followed until an inpatient diagnosis of myocarditis, loss to follow-up, or end of study (latest data availability in each country), whichever occurred first. In each of the four countries, Poisson regression was used to estimate adjusted incidence rate ratios (IRRs) of myocarditis, with associated 95% confidence intervals (CIs), according to vaccination status. Country-specific results were combined in meta-analyses.ResultsA total of 8.9 million residents were followed for 12,271,861 person-years. We identified 1533 cases of myocarditis. In 12-to-39-year-old males, the 28-day acute risk period following the third dose of BNT162b2 or mRNA-1273 was associated with an increased incidence rate of myocarditis compared to the post-acute risk period 28 days or more after a second homologous dose (IRR, 2.08 [95% CI, 1.31 to 3.33] and 8.89 [95% CI, 2.26 to 35.03], respectively). The corresponding incidence rates following the third dose of BNT162b2 and mRNA-1273 were 0.86 and 1.95, respectively, within 28 days of follow-up among 100,000 individuals.Conclusions and RelevanceOur results suggest that a booster dose is associated with increased myocarditis risk in male adolescents and young male adults.KEY POINTSQuestionIs a first booster dose of SARS-CoV-2 messenger RNA (mRNA) vaccine associated with increased risk of myocarditis in male adolescents and young male adults?FindingsIn a cohort study of 8.9 million residents in Denmark, Finland, Norway, and Sweden, a booster dose of BNT162b2 or mRNA-1273 vaccine was associated with increased risk of myocarditis in 12-to-39-year-old males, with incidence rates 0.86 and 1.95, respectively, within 28 days of follow-up per 100,000 vaccinated individuals.MeaningA booster dose with a SARS-CoV-2 mRNA vaccine is associated with increased myocarditis risk in male adolescents and young male adults. Compared to after a primary course, the risk appears attenuated.

Purpose Cutaneous melanoma is among the fastest growing malignancies in Norway and ultraviolet radiation (UVR) exposure is the primary environmental risk factor. Immunomodulating drugs can increase skin photosensitivity and suppress immune responses, and by such mechanisms influence melanoma risk. We, therefore, aimed to examine the associations between use of immunomodulating drugs and melanoma risk, at a nationwide population level. Patients and methods In the Cancer Registry of Norway, we identified all cases aged 18-85 with a first primary cutaneous melanoma diagnosed in 2007-2015 (n=12,106). These were matched to population controls from the Norwegian National Registry 1:10 (n=118,564), on sex and year of birth using risk set sampling. Information on prescribed drugs (2004-2015) was obtained by linkage to the Norwegian Prescription Database (NorPD). Conditional logistic regression was used to estimate rate ratios (RRs) and 95% confidence intervals (CIs) for associations between use of immunomodulating drugs (immunosuppressants and corticosteroids) and melanoma risk, adjusted for ambient UVR and other drug use. Results Compared with ≤1 prescription, use of ≥8 prescriptions of immunosuppressants was associated with increased risk of melanoma (RR 1.50, 95% CI 1.27, 1.77). Similar associations were found for subgroups of immunosuppressants: drugs typically prescribed to organ transplant recipients (OTRs) (RR 2.02, 95% CI 1.35, 3.03) and methotrexate (RR 1.27, 95% CI 1.04, 1.55). Similar results were found for high levels of cumulative doses and across all histological subtypes. Use of corticosteroids was not associated with melanoma risk. Conclusion We found a positive association between use of immunosuppressants and melanoma risk, with the highest risk seen for drugs prescribed to OTRs. Knowledge about this risk increase is important for physicians and users of these drugs, for intensified surveillance, awareness and cautious sun exposure.

Background Less smoking should lead to fewer COPD cases. We aimed at estimating time trends in the prevalence and burden of COPD in Norway from 2001 to 2017. Methods We used pre-bronchodilator spirometry and other health data from persons aged 40-84 years in three surveys of the Tromso Study, 2001-2002, 2007-2008 and 2015-2016. We applied spirometry lower limits of normal (LLN) according to Global Lung Initiative 2012. Age-standardized prevalence was determined. We defined COPD as FEV1/FVC

Background Most antihypertensives can induce dermal photosensitivity, which may increase melanoma risk. However, corroborating evidence is limited. We examined the associations between use of antihypertensives and melanoma risk. Methods A nationwide nested case-control study was conducted using data from the Cancer Registry of Norway, the National Registry and the Norwegian Prescription Database in 2004–15. Ten controls were randomly selected for each melanoma case, matched on sex and birth year. The study included 12 048 cases and 117 895 controls. We estimated rate ratios (RRs) with 95% confidence intervals (CIs). All analyses were adjusted for ambient ultraviolet radiation (UVR). We additionally performed active comparator analyses, and sensitivity analyses by only including new users, distinguishing between exclusive and mixed users, allowing for different latency periods, and subgroup analyses by melanoma subtype and clinical stage. Results Compared with non-use, we observed a slightly increased melanoma risk in users of diuretics (RR 1.08, CI 1.01–1.15), calcium-channel blockers (RR 1.10, CI 1.04–1.18) and drugs affecting the renin-angiotensin system (RR 1.10, CI 1.04–1.16), but not for beta blockers (RR 0.97, CI 0.92–1.03). We found no heterogeneity of associations by melanoma subtype or clinical stage and no dose-response relationship between the cumulative defined daily doses (DDDs) and melanoma. No interaction was found between cumulative DDDs and ambient UVR. Conclusions Weak associations, with lack of a dose-response relationship and lack of interactions with ambient UVR, in the DDD analysis in this nationwide study do not support a causal relationship between antihypertensives and melanoma risk.

Maternal antibiotic use during pregnancy has been linked to asthma risk in children, but the role of underlying infections remains unclear. We investigated the association of maternal antibiotic use and infections during pregnancy with offspring risk of asthma. We used two population-based cohorts: the Norwegian Mother, Father and Child Cohort Study (MoBa) (n = 53 417) and a register-based cohort (n = 417 548). Asthma was defined based on dispensed asthma medications at 7 and 13 years from the Norwegian Prescription Database. Self-reported information on antibiotic use and infections during pregnancy was available in MoBa, while registrations of dispensed prescriptions were used to classify use of antibiotics in the register-based cohort. Maternal antibiotic use during pregnancy was associated with asthma at 7 in both cohorts (adjusted risk ratio (aRR) 1.23, 95% CI 1.11–1.37 in MoBa and 1.21, 1.16–1.25 in the register cohort) and asthma at 13 in the register cohort (1.13, 1.03–1.23) after adjusting for maternal characteristics. In MoBa, the estimate was attenuated after adjusting for infections during pregnancy. Maternal lower and upper respiratory tract infections (aRR 1.30, 95% CI 1.07–1.57 and 1.19, 1.09–1.30, respectively) and urinary tract infections (1.26, 1.11–1.42) showed associations with asthma at 7. Register cohort also showed an increased risk of asthma in relation to maternal antibiotics before and after pregnancy. Our findings suggest that both maternal antibiotics and infections during pregnancy have a role in the risk of offspring asthma. However, results from the register cohort suggest that the effect of antibiotics may reflect the shared underlying susceptibility.

Importance: Reports of myocarditis after SARS-CoV-2 messenger RNA (mRNA) vaccination have emerged. Objective: To evaluate the risks of myocarditis and pericarditis following SARS-CoV-2 vaccination by vaccine product, vaccination dose number, sex, and age. Design, Setting, and Participants: Four cohort studies were conducted according to a common protocol, and the results were combined using meta-analysis. Participants were 23122522 residents aged 12 years or older. They were followed up from December 27, 2020, until incident myocarditis or pericarditis, censoring, or study end (October 5, 2021). Data on SARS-CoV-2 vaccinations, hospital diagnoses of myocarditis or pericarditis, and covariates for the participants were obtained from linked nationwide health registers in Denmark, Finland, Norway, and Sweden. Exposures: The 28-day risk periods after administration date of the first and second doses of a SARS-CoV-2 vaccine, including BNT162b2, mRNA-1273, and AZD1222 or combinations thereof. A homologous schedule was defined as receiving the same vaccine type for doses 1 and 2. Main Outcomes and Measures: Incident outcome events were defined as the date of first inpatient hospital admission based on primary or secondary discharge diagnosis for myocarditis or pericarditis from December 27, 2020, onward. Secondary outcome was myocarditis or pericarditis combined from either inpatient or outpatient hospital care. Poisson regression yielded adjusted incidence rate ratios (IRRs) and excess rates with 95% CIs, comparing rates of myocarditis or pericarditis in the 28-day period following vaccination with rates among unvaccinated individuals. Results: Among 23122522 Nordic residents (81% vaccinated by study end; 50.2% female), 1077 incident myocarditis events and 1149 incident pericarditis events were identified. Within the 28-day period, for males and females 12 years or older combined who received a homologous schedule, the second dose was associated with higher risk of myocarditis, with adjusted IRRs of 1.75 (95% CI, 1.43-2.14) for BNT162b2 and 6.57 (95% CI, 4.64-9.28) for mRNA-1273. Among males 16 to 24 years of age, adjusted IRRs were 5.31 (95% CI, 3.68-7.68) for a second dose of BNT162b2 and 13.83 (95% CI, 8.08-23.68) for a second dose of mRNA-1273, and numbers of excess events were 5.55 (95% CI, 3.70-7.39) events per 100000 vaccinees after the second dose of BNT162b2 and 18.39 (9.05-27.72) events per 100000 vaccinees after the second dose of mRNA-1273. Estimates for pericarditis were similar. Conclusions and Relevance: Results of this large cohort study indicated that both first and second doses of mRNA vaccines were associated with increased risk of myocarditis and pericarditis. For individuals receiving 2 doses of the same vaccine, risk of myocarditis was highest among young males (aged 16-24 years) after the second dose. These findings are compatible with between 4 and 7 excess events in 28 days per 100000 vaccinees after BNT162b2, and between 9 and 28 excess events per 100000 vaccinees after mRNA-1273. This risk should be balanced against the benefits of protecting against severe COVID-19 disease.

ObjectivesPatients with hip fracture are typically characterised by extensive comorbidities and excess mortality. Methods that account for a wide range of comorbidities are needed when attempting to identify causal associations in registry-based studies. We aimed to study the association between the prescription-based Rx-Risk Comorbidity Index (abbreviated Rx-Risk) and mortality by history of hip fracture, and to quantify the contribution of Rx-Risk in explaining the excess mortality after hip fracture.SettingIn this prospective study, we used nationwide registry data from outpatient care. Rx-Risk was based on filled prescriptions recorded in the Norwegian Prescription Database. Medications were mapped to 46 comorbidity categories by Anatomical Therapeutic Chemical code. Information on hip fractures during 1994–2013 was available from the Norwegian Epidemiologic Osteoporosis Studies hip fracture database, and year of death was obtained from Statistics Norway. We estimated 1-year mortality risk (January through December 2014) according to Rx-Risk score based on dispensed prescriptions in 2013, history of hip fracture, age and sex using Poisson regression.ParticipantsAll individuals aged 65 years and older who were alive by the end of 2013 and had filled at least one prescription in an outpatient pharmacy in Norway in 2013 (n=735 968).ResultsMortality increased exponentially with increasing Rx-Risk scores, and it was highest in persons with a history of hip fracture across the major range of Rx-Risk scores. Age- and sex-adjusted mortality risk difference according to history of hip fracture (yes vs no) was 4.4 percentage points (7.8% vs 3.4%). Adjustment for Rx-Risk score further attenuated this risk difference to 3.3 percentage points.ConclusionsHistory of hip fracture and comorbidity assessed by Rx-Risk are independent risk factors for mortality in the community-dwelling older population in Norway. Comorbidity explained a quarter of the excess mortality in persons with a history of hip fracture.

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.

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.

Aim: Our aim was to study hormonal contraceptive use among women in Norway during 2006-2020 according to age groups and geography, including choice of contraceptive method, type of prescriber for long-acting reversible contraceptives, and prescriber’s adherence to the national health authority recommendations.Material and methods: We conducted a nationwide drug utilization study including all women aged 16-49 years in Norway during 2006-2020. The Norwegian Prescription Database (NorPD) includes detailed information about all dispensed prescription medications from Norwegian pharmacies to individuals in ambulatory care, including year of dispensing, patient’s year of birth and county of residence, and the prescriber’s profession.Results: This study shows a slight increase in overall use of hormonal contraceptives among 16-49-year-olds during 2006-2018, increasing from 36% of the population to 40%. Combined oral contraceptives (COCs) was the most commonly used hormonal contraceptive method in all age groups. The use of COCs decreased during the period and the decline was greatest in those below 25 years. From 2016 80% of all new users of COCs received the recommended COC containing levonorgestrel. Use of estrogen-free contraceptives, long-acting reversible contraceptives (LARCs) and gestagen pills, has increased. After 2014 the use of LARCs, especially subdermal implant, increased steeply among younger women. Oslo had the lowest proportion of users of hormonal contraceptives among teenagers and young adults during the whole period, while among 30-49-yearolds Oslo was more in line with the other counties.Conclusion: Combined oral contraceptives (COC) was the most used hormonal contraceptive method in all age groups. However, the use of COCs decreased during the period, especially in those < 25 years, where a corresponding increase in the use of LARC has taken place, mainly from 2014 onwards. Four out of five women who initiated COC received the recommended COC type and the steep increase in use of estrogen-free LARCs in recent years implies that Norwegian prescribers have high compliance with the recommendations from the health authorities.

It is necessary to carry out large observational studies to generate robust evidence about the safety of drugs used during pregnancy. In the Nordic countries, nationwide population-based health registers that document all births and dispensed prescribed drugs are valuable resources for such studies. A common data model (CDM) is a data harmonization and structuring tool that enables a unified and streamlined analytic approach for studies including data from multiple countries or databases. We describe a CDM developed for the Nordic Pregnancy Drug Safety Studies (NorPreSS), including details on data sources and structure of the data tables. We also provide an overview of the advantages and disadvantages of the approach (e.g. sharing of data analysis programs versus extra initial work to create CDM datasets from raw data).

Objective To assess rates of cardiovascular and haemostatic events in the first 28 days after vaccination with the Oxford-AstraZeneca vaccine ChAdOx1-S in Denmark and Norway and to compare them with rates observed in the general populations. Design Population based cohort study. Setting Nationwide healthcare registers in Denmark and Norway. Participants All people aged 18-65 years who received a first vaccination with ChAdOx1-S from 9 February 2021 to 11 March 2021. The general populations of Denmark (2016-18) and Norway (2018-19) served as comparator cohorts. Main outcome measures Observed 28 day rates of hospital contacts for incident arterial events, venous thromboembolism, thrombocytopenia/coagulation disorders, and bleeding among vaccinated people compared with expected rates, based on national age and sex specific background rates from the general populations of the two countries. Results The vaccinated cohorts comprised 148 792 people in Denmark (median age 45 years, 80% women) and 132 472 in Norway (median age 44 years, 78% women), who received their first dose of ChAdOx1-S. Among 281 264 people who received ChAdOx1-S, the standardised morbidity ratio for arterial events was 0.97 (95% confidence interval 0.77 to 1.20). 59 venous thromboembolic events were observed in the vaccinated cohort compared with 30 expected based on the incidence rates in the general population, corresponding to a standardised morbidity ratio of 1.97 (1.50 to 2.54) and 11 (5.6 to 17.0) excess events per 100 000 vaccinations. A higher than expected rate of cerebral venous thrombosis was observed: standardised morbidity ratio 20.25 (8.14 to 41.73); an excess of 2.5 (0.9 to 5.2) events per 100 000 vaccinations. The standardised morbidity ratio for any thrombocytopenia/coagulation disorders was 1.52 (0.97 to 2.25) and for any bleeding was 1.23 (0.97 to 1.55). 15 deaths were observed in the vaccine cohort compared with 44 expected. Conclusions Among recipients of ChAdOx1-S, increased rates of venous thromboembolic events, including cerebral venous thrombosis, were observed. For the remaining safety outcomes, results were largely reassuring, with slightly higher rates of thrombocytopenia/coagulation disorders and bleeding, which could be influenced by increased surveillance of vaccine recipients. The absolute risks of venous thromboembolic events were, however, small, and the findings should be interpreted in the light of the proven beneficial effects of the vaccine, the context of the given country, and the limitations to the generalisability of the study findings.

Aims To assess persistence and adherence to non-vitamin K antagonist oral anticoagulant (NOAC) treatment in patients with atrial fibrillation (AF) in five Western European healthcare settings. Methods and results We conducted a multi-country observational cohort study, including 559 445 AF patients initiating NOAC therapy from Stockholm (Sweden), Denmark, Scotland, Norway, and Germany between 2011 and 2018. Patients were followed from their first prescription until they switched to a vitamin K antagonist, emigrated, died, or the end of follow-up. We measured persistence and adherence over time and defined adequate adherence as medication possession rate ≥90% among persistent patients only. Results Overall, persistence declined to 82% after 1 year and to 63% after 5 years. When including restarters of NOAC treatment, 85% of the patients were treated with NOACs after 5 years. The proportion of patients with adequate adherence remained above 80% throughout follow-up. Persistence and adherence were similar between countries and was higher in patients starting treatment in later years. Both first year persistence and adherence were lower with dabigatran (persistence: 77%, adherence: 65%) compared with apixaban (86% and 75%) and rivaroxaban (83% and 75%) and were statistically lower after adjusting for patient characteristics. Adherence and persistence with dabigatran remained lower throughout follow-up. Conclusion Persistence and adherence were high among NOAC users in five Western European healthcare settings and increased in later years. Dabigatran use was associated with slightly lower persistence and adherence compared with apixaban and rivaroxaban.

The Norwegian Society for Pharmacoepidemiology (NFFE) is a multidisciplinary, nation-wide network of professionals involved in the field of pharmacoepidemiology. Pharmacoepidemiology is the science that bridges epidemiologic methodology with clinical pharmacology and clinical pharmacy, for studying the use, effectiveness, value and safety of pharmaceuticals1 . The foundation of NFFE took into account the growing value of real-world data in assessing potential benefits and risks of medication use, and capitalized on the growing availability of linkable, nation-wide health registries and large population-based cohorts in Norway. In this short commentary, we briefly describe the history and mission of the society, and our current and future activities to foster high-quality research and education at national and international level.

Cardiovascular diseases, cancer, type-2 diabetes and chronic obstructive pulmonary disease (COPD) were initially noted as the most common diseases among individuals who were hospitalised for COVID-19. However, the evidence base is weak. The objective of this study is to describe how selected diseases were distributed among adults with confirmed COVID-19 (COVID-19 positive tests) and among those hospitalised for COVID-19 compared to the general population.We used data from the Norwegian Patient Registry, the Norwegian Registry for Primary Health Care and the Norwegian Surveillance System for Communicable Diseases for adults from the age of 20 and older for the period 1 March 2020-13 May 2020.Of all those who tested positive for COVID-19, 7 632 (94 %) were aged 20 years or older, and 1 025 (13.4 %) of these had been hospitalised. Among those hospitalised with COVID-19, there was a higher proportion of individuals with cardiovascular diseases (18.3 % versus 15.6 %), cancer (6.9 % versus 5.4 %), type-2 diabetes (8.6 % versus 5.2 %) and COPD (3.8 % versus 2.7 %) than in the general population as a whole after adjusting for age. The proportion of hospitalised patients with asthma, other chronic respiratory disease, cardiovascular disease, ongoing cancer treatment, complications related to hypertension, obesity and overweight, neurological disorders and cardiac and renal failure was also higher than in the general population. There were few differences between persons who had tested positive for COVID-19 and the general population in terms of underlying conditions.Among those hospitalised for COVID-19, there was a higher proportion of patients with underlying illnesses than in the general population. This may indicate that these patients tend to have a more severe course of disease or that they are more likely to be hospitalised compared to healthy individuals. The results must be interpreted with caution, since the sample of COVID-19 individuals is non-random.

Introduction: Previous studies have suggested that maternal antibiotic use during pregnancy increases the risk of offspring asthma, but the potential role of confounding by indication (infections) is unclear. Objectives: To investigate the association of maternal use of antibiotics and experience of infections during pregnancy on the risk of offspring asthma at 7 years of age. Methods: We used information from the Norwegian Mother, Father and Child Cohort Study (MoBa) conducted by The Norwegian Institute of Public health. Definition of asthma was based on information on dispensed asthma medication at 7 years from the Norwegian Prescription Database. Results: Maternal antibiotic use during pregnancy was associated with child asthma at 7 years (adjusted risk ratio (aRR) per course 1.14; 95% confidence interval (CI) 1.06-1.23). We adjusted for maternal and child characteristics, such as maternal asthma, smoking, education and preterm birth as well as urinary tract infections (UTIs) and respiratory tract infections (RTIs) during pregnancy and child early antibiotic use and infections, which suggests that mother antibiotic use was independently associated with child risk of asthma. Maternal experience of UTIs (aRR 1.23; 95% CI 1.03-1.46) and RTIs (aRR 1.23; 95% CI 1.09-1.39) alone during pregnancy and together with antibiotic use for that indication (aRR 1.27; 1.08-1.49 and aRR 1.41; 1.20-1.67, respectively), compared to no such infections or antibiotic use for any reason, tended also to be associated with child asthma. Conclusion: The results suggest that both maternal antibiotic use and infections during pregnancy, in addition to childhood exposures, have an independent role in the risk of offspring asthma.

Purpose Cutaneous melanoma is among the fastest growing malignancies in Norway and ultraviolet radiation (UVR) exposure is the primary environmental risk factor. Immunomodulating drugs can increase skin photosensitivity and suppress immune responses, and by such mechanisms influence melanoma risk. We, therefore, aimed to examine the associations between use of immunomodulating drugs and melanoma risk, at a nationwide population level. Patients and Methods In the Cancer Registry of Norway, we identified all cases aged 18–85 with a first primary cutaneous melanoma diagnosed in 2007–2015 (n=12,106). These were matched to population controls from the Norwegian National Registry 1:10 (n=118,564), on sex and year of birth using risk set sampling. Information on prescribed drugs (2004–2015) was obtained by linkage to the Norwegian Prescription Database (NorPD). Conditional logistic regression was used to estimate rate ratios (RRs) and 95% confidence intervals (CIs) for associations between use of immunomodulating drugs (immunosuppressants and corticosteroids) and melanoma risk, adjusted for ambient UVR and other drug use. Results Compared with ≤1 prescription, use of ≥8 prescriptions of immunosuppressants was associated with increased risk of melanoma (RR 1.50, 95% CI 1.27, 1.77). Similar associations were found for subgroups of immunosuppressants: drugs typically prescribed to organ transplant recipients (OTRs) (RR 2.02, 95% CI 1.35, 3.03) and methotrexate (RR 1.27, 95% CI 1.04, 1.55). Similar results were found for high levels of cumulative doses and across all histological subtypes. Use of corticosteroids was not associated with melanoma risk. Conclusion We found a positive association between use of immunosuppressants and melanoma risk, with the highest risk seen for drugs prescribed to OTRs. Knowledge about this risk increase is important for physicians and users of these drugs, for intensified surveillance, awareness and cautious sun exposure.

Adequate antipsychotic treatment intensity is required for defining treatment-resistant schizophrenia (TRS) and justifying clozapine treatment. We investigated the occurrence of undetectable or subtherapeutic serum levels of oral antipsychotics preceding switch to clozapine as an endpoint of TRS. For patients starting clozapine, 12-month retrospective reviews of antipsychotic serum concentration measurements were performed in a Norwegian therapeutic drug monitoring (TDM) database from 2005 to 2017. Undetectable levels in high-sensitive analytical assays defined ‘no drug use’, while levels

Background Cardiovascular diseases, cancer, type-2 diabetes and chronic obstructive pulmonary disease (COPD) were initially noted as the most common diseases among individuals who were hospitalised for COVID-19. However, the evidence base is weak. The objective of this study is to describe how selected diseases were distributed among adults with confirmed COVID-19 (COVID-19 positive tests) and among those hospitalised for COVID-19 compared to the general population. Material and method We used data from the Norwegian Patient Registry, the Norwegian Registry for Primary Health Care and the Norwegian Surveillance System for Communicable Diseases for adults from the age of 20 and older for the period 1 March 2020-13 May 2020. Results Of all those who tested positive for COVID-19, 7 632 (94 %) were aged 20 years or older, and 1 025 (13.4 %) of these had been hospitalised. Among those hospitalised with COVID-19, there was a higher proportion of individuals with cardiovascular diseases (18.3 % versus 15.6 %), cancer (6.9 % versus 5.4 %), type-2 diabetes (8.6 % versus 5.2 %) and COPD (3.8 % versus 2.7 %) than in the general population as a whole after adjusting for age. The proportion of hospitalised patients with asthma, other chronic respiratory disease, cardiovascular disease, ongoing cancer treatment, complications related to hypertension, obesity and overweight, neurological disorders and cardiac and renal failure was also higher than in the general population. There were few differences between persons who had tested positive for COVID-19 and the general population in terms of underlying conditions. Interpretation Among those hospitalised for COVID-19, there was a higher proportion of patients with underlying illnesses than in the general population. This may indicate that these patients tend to have a more severe course of disease or that they are more likely to be hospitalised compared to healthy individuals. The results must be interpreted with caution, since the sample of COVID-19 individuals is non-random.

Supplemental Digital Content is available in the text., Background: Previous studies of early day care attendance and asthma development are inconsistent, which may be explained by inadequate control of confounding and effect modification. We examined the effect of early day care on the risk of asthma taking into account the underlying susceptibility to asthma. Methods: The study included 55,404 children participating in the Norwegian Mother, Father and Child Cohort Study. Asthma at age 7 was defined by dispensed asthma medications in the Norwegian Prescription Database. We defined a disease risk score (DRS) to account for an underlying susceptibility to asthma including a range of hereditary and nonhereditary predictors of asthma. We assessed confounding and modifying effects of DRS on the association between day care and asthma. Results: Day care before 18 months was associated with a lower risk of asthma by age 7 (adjusted risk ratio [RR] = 0.85; 95% confidence interval [CI] = 0.78, 0.92) when compared with home care. DRS modified the estimated effect of day care on asthma risk. Among the 80% of children with DRS between 0.03 and 0.16, day care was associated with a reduced asthma risk (RRs between 0.79 and 0.87), whereas among 0.5% of children with a high DRS (above 0.28), estimated effect of day care on asthma increased gradually (RR for the highest DRS 2.2; 1.0–4.9). Conclusions: In our study, among most children, early day care was associated with reduced asthma risk at 7 years, and increased risk in a small group of children with very high underlying susceptibility to asthma.

Background: it remains unclear what underlies the greater risk of asthma reported among children conceived by assisted reproductive technologies (art). Objective: Our aim was to clarify the role of parental subfertility and unmeasured confounding on the association between art and childhood asthma, and to examine the possibility for common mechanisms underlying parental subfertility and miscarriages influencing asthma pathogenesis. Methods: We used data from national norwegian health registries (n=474 402) and the norwegian Mother and child cohort Study (MoBa) (n=75 797). We used log-linear regression to estimate overall associations, and fixed-effects logistic regression to estimate associations within siblings. Results: ART offspring had greater asthma risk, the adjusted relative risk (arr) was 1.20 (95% ci 1.09 to 1.32) in the registry-based cohort, and 1.42 (95% ci 1.14 to 1.76) in MoBa. the sibling analysis yielded similar associations, although the ci included the null value. the elevated asthma risk among art offspring was attenuated when they were compared with spontaneously conceived offspring with time to conception >12 months, arr 1.22 (95% ci 0.95 to 1.57). asthma risk also increased with maternal history of early miscarriages (≤12 weeks), with an arr of 1.07 (95% ci 1.03 to 1.11) for one, arr 1.18 (95% ci 1.10 to 1.26) for two and arr 1.24 (95% ci 1.12 to 1.37) for three or more. Conclusion: Our findings indicate that both parental subfertility and characteristics related to the art procedure itself might increase offspring asthma risk, although this needs to be confirmed in future studies, and further suggest that common mechanisms underlying parental subfertility and recurrent miscarriages might influence offspring asthma pathogenesis. The data collection in the Norwegian Mother and Child Cohort Study is supported by the National Institutes of Health (National Institute of Environmental Health Sciences contract number n01-eS-75558, National Institute of Neurological Disorders and Stroke grant no. 1 UO1 nS 047537-01 and grant no. 2 UO1 nS 047537-06a1) and the Norwegian Research Council (grant number 151918/S10). MCM works at the MRC Integrative Epidemiology Unit at the University of Bristol, which receives infrastructure funding from UK Medical Research Council (Mc/ UU/12013/5), and she is also supported by the fellowship from the UK Medical Research Council (Mr/M009351/1). AJW and SJl are both supported in part by the intramural Program of the National Institute of Environmental Health Sciences, NIH. this work was also supported by the Norwegian Research Council (grant no. 221919 to WN), and the Research Council of Norway Centres of Excellence funding scheme (project number 262700).

Summary Background The use of medications to treat attention deficit hyperactivity disorder (ADHD) has increased, but the prevalence of ADHD medication use across different world regions is not known. Our objective was to determine regional and national prevalences of ADHD medication use in children and adults, with a specific focus on time trends in ADHD medication prevalence. Methods We did a retrospective, observational study using population-based databases from 13 countries and one Special Administrative Region (SAR): four in Asia and Australia, two in North America, five in northern Europe, and three in western Europe. We used a common protocol approach to define study populations and parameters similarly across countries and the SAR. Study populations consisted of all individuals aged 3 years or older between Jan 1, 2001, and Dec 31, 2015 (dependent on data availability). We estimated annual prevalence of ADHD medication use with 95% CI during the study period, by country and region and stratified by age and sex. We reported annual absolute and relative percentage changes to describe time trends. Findings 154·5 million individuals were included in the study. ADHD medication use prevalence in 2010 (in children aged 3–18 years) varied between 0·27% and 6·69% in the countries and SAR assessed (0·95% in Asia and Australia, 4·48% in North America, 1·95% in northern Europe, and 0·70% in western Europe). The prevalence of ADHD medication use among children increased over time in all countries and regions, and the absolute increase per year ranged from 0·02% to 0·26%. Among adults aged 19 years or older, the prevalence of any ADHD medication use in 2010 varied between 0·003% and 1·48% (0·05% in Asia and Australia, 1·42% in North America, 0·47% in northern Europe, and 0·03% in western Europe). The absolute increase in ADHD medication use prevalence per year ranged from 0·0006% to 0·12%. Methylphenidate was the most commonly used ADHD medication in most countries. Interpretation Using a common protocol and data from 13 countries and one SAR, these results show increases over time but large variations in ADHD medication use in multiple regions. The recommendations of evidence-based guidelines need to be followed consistently in clinical practice. Further research is warranted to describe the safety and effectiveness of ADHD medication in the short and long term, and to inform evidence-based guidelines, particularly in adults. Funding None

Background Western diets may provide excess vitamin A, which is potentially toxic and could adversely affect respiratory health and counteract benefits from vitamin D. Objective The aim of this study was to examine child asthma at age 7 y in relation to maternal intake of vitamins A and D during pregnancy, infant supplementation with these vitamins, and their potential interaction. Design We studied 61,676 school-age children (born during 2002–2007) from the Norwegian Mother and Child Cohort with data on maternal total (food and supplement) nutrient intake in pregnancy (food-frequency questionnaire validated against biomarkers) and infant supplement use at age 6 mo (n = 54,142 children). Linkage with the Norwegian Prescription Database enabled near-complete follow-up (end of second quarter in 2015) for dispensed medications to classify asthma. We used log-binomial regression to calculate adjusted RRs (aRRs) for asthma with 95% CIs. Results Asthma increased according to maternal intake of total vitamin A [retinol activity equivalents (RAEs)] in the highest (≥2031 RAEs/d) compared with the lowest (≤779 RAEs/d) quintile (aRR: 1.21; 95% CI: 1.05, 1.40) and decreased for total vitamin D in the highest (≥13.6 µg/d) compared with the lowest (≤3.5 µg/d) quintile (aRR: 0.81; 95% CI: 0.67, 0.97) during pregnancy. No association was observed for maternal intake in the highest quintiles of both nutrients (aRR: 0.99; 95% CI: 0.83, 1.18) and infant supplementation with vitamin D or cod liver oil. Conclusions Excess vitamin A (≥2.5 times the recommended intake) during pregnancy was associated with increased risk, whereas vitamin D intake close to recommendations was associated with a reduced risk of asthma in school-age children. No association for high intakes of both nutrients suggests antagonistic effects of vitamins A and D. This trial was registered at http://www.clinicaltrials.gov as NCT03197233. © 2018 American Society for Nutrition. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Importance: Given the rapidly increasing use of stimulant medications during pregnancy and among women of reproductive age who may become pregnant inadvertently, there is a need to better understand their safety.Objective: To examine the risk of congenital malformations associated with intrauterine exposure to stimulants.Design, Setting, and Participants: Cohort study of the Medicaid-insured population in the United States nested in the 2000-2013 US Medicaid Analytic eXtract, with follow-up of safety signals detected in the Medicaid Analytic eXtract data using the Nordic Health registries (2003-2013) (Denmark, Finland, Iceland, Norway, and Sweden). A total of 1 813 894 publicly insured pregnancies in the United States and 2 560 069 singleton pregnancies in the 5 Nordic countries ending in live births were included. Relative risks were estimated accounting for underlying psychiatric disorders and other potential confounders. Relative risk estimates for the US and Nordic data were pooled using a fixed-effects meta-analytic approach. The study was conducted from July 1, 2015, to March 31, 2017.Exposures: Methylphenidate and amphetamines dispensed during the first trimester.Main Outcomes and Measures: Major congenital malformations and subgroup of cardiac malformations.Results: In the US data, of the 1 813 894 pregnancies evaluated, 35.0 per 1000 infants not exposed to stimulants were diagnosed as having congenital malformations, compared with 45.9 per 1000 infants for methylphenidate and 45.4 for amphetamines. For cardiac malformations, the risks were 12.7 (95% CI, 12.6-12.9), 18.8 (95% CI, 13.8-25.6), and 15.4 (95% CI, 12.5-19.0) per 1000 infants, respectively. The adjusted relative risks for methylphenidate were 1.11 (95% CI, 0.91-1.35) for any malformation and 1.28 (95% CI, 0.94-1.74) for cardiac malformations. No increased risks were observed for amphetamines: 1.05 (95% CI, 0.93-1.19) for any malformations and 0.96 (95% CI, 0.78-1.19) for cardiac malformations. Findings were confirmed in sensitivity analyses accounting for proxies of unmeasured confounders and increasing the specificity of the exposure and outcome definitions. Replication of the analyses for methylphenidate using the Nordic data including 2 560 069 pregnancies yielded a relative risk of 1.28 (95% CI, 0.83-1.97) for cardiac malformations, resulting in a pooled estimate of 1.28 (95% CI, 1.00-1.64).Conclusions and Relevance: These findings suggest a small increase in the risk of cardiac malformations associated with intrauterine exposure to methylphenidate but not to amphetamines. This information is important when weighing the risks and benefits of alternative treatment strategies for attention-deficit/hyperactivity disorder in women of reproductive age and during early pregnancy.

Prenatal maternal psychosocial stress might influence the development of childhood asthma. Evaluating paternal psychosocial stress and conducting a sibling comparison could provide further insight into the role of unmeasured confounding. We examined the associations of parental psychosocial stress during and after pregnancy with asthma at age 7 years in the Norwegian Mother and Child Cohort Study (n = 63,626; children born in 2000–2007). Measures of psychosocial stress included lifetime major depressive symptoms, current anxiety/depression symptoms, use of antidepressants, anxiolytics, and/or hypnotics, life satisfaction, relationship satisfaction, work stress, and social support. Childhood asthma was associated with maternal lifetime major depressive symptoms (adjusted relative risk (aRR) = 1.19, 95% confidence interval (CI): 1.09, 1.30), in addition to symptoms of anxiety/depression during pregnancy (aRR = 1.17, 95% CI: 1.06, 1.29) and 6 months after delivery (aRR = 1.17, 95% CI: 1.07, 1.28). Maternal negative life events during pregnancy (aRR = 1.10, 95% CI: 1.06, 1.13) and 6 months after delivery (aRR = 1.14, 95% CI: 1.11, 1.18) were also associated with asthma. These associations were not replicated when evaluated within sibling groups. There were no associations with paternal psychosocial stress. In conclusion, maternal anxiety/depression and negative life events were associated with offspring asthma, but this might be explained by unmeasured maternal background characteristics that remain stable across deliveries.

Background: Studies from several countries have reported that children youngest in grade are at higher risk of attention-deficit/hyperactivity disorder (ADHD) diagnosis and treatment. Norwegian children start school the year they turn six, making children born in December youngest in their grade. We used data on medication, specialist healthcare diagnoses, and primary healthcare diagnoses from national registers to investigate associations between birth month and ADHD. Methods: All children born in Norway between 1998 and 2006 ( N=509,827) were followed from age six until 31 December 2014. We estimated hazard ratios for ADHD medication and diagnoses by birth month in Cox proportional-hazards models. We compared risk among siblings to control for potentially confounding socioeconomic factors, and assessed risk of receiving ADHD medication by birth month while attending different grades in cross-sectional time-series analyses. Results: At end of follow-up, 5.3% of boys born in October–December had received ADHD medication, compared with 3.7% of boys born in January–March. Corresponding numbers for girls were 2.2% and 1.3%, respectively. The adjusted hazard ratio for ADHD medication for children born in October–December (reference: January–March) was 1.4 (95% confidence interval: 1.4–1.5) for boys and 1.8 (1.7–2.0) for girls. Analyses with diagnoses as outcome showed consistent results, and analyses restricted to siblings within the study population also supported the findings. Analysis by grade revealed an increased risk for children born late in the year from grade 3 onwards, with most marked differences in higher grades. Conclusions: Children youngest in grade had the highest risk of receiving ADHD treatment. Differences were most marked among older children.

Survivors of cancer may experience higher rates of psychological problems requiring pharmacological interventions than age-matched controls from the general population. This study compares prescription rates of antidepressants in survivors of cancer, diagnosed in childhood, adolescence, or early adulthood, to the rate in age- and gender-matched controls from the Norwegian population.Antidepressants prescribed to 5341 cancer survivors, diagnosed ≤25 years during 1965-2000, were studied in a population-based cohort by linking data from the following nationwide registries: the Population Registry of Norway, the Cancer Registry of Norway, and the Norwegian Prescription Database. For each survivor, three age- and gender-matched controls were randomly selected from the population. A Cox proportional hazard model was applied to estimate hazard ratios (HRs) of antidepressant prescriptions during 2004-2012 to the survivors with controls as referents.Survivors had an increased risk of being prescribed antidepressants with crude rates of 26.9/1000 person-years compared with 22.5/1000 person-years in controls (HR 1.19; 95% confidence interval [CI] 1.12-1.28). The relative risk was highest for survivors of central nervous system tumors (HR 1.30; 95% CI 1.04-1.63), leukemias (HR 1.29; 95% CI 1.03-1.63), testicular tumors (HR 1.27; 95% CI 1.04-1.55), and "other tumors" (HR 1.42; 95% CI 1.10-1.84). No effect of age at cancer diagnosis was found.Certain groups of survivors of cancer in childhood, adolescence, or young adulthood have a slightly increased risk for being prescribed antidepressants than their peers. The results may indicate an increased prevalence of depression among these survivors, but diagnostic reasons for prescriptions need to be confirmed in clinical studies.

RATIONALE: A potential adverse effect of high folate intake during pregnancy on children's asthma development remains controversial.OBJECTIVES: To prospectively investigate folate intake from both food and supplements during pregnancy and asthma at age seven years when the diagnosis is more reliable than at preschool age.METHODS: This study included eligible children born 2002-2006 from the Norwegian Mother and Child Cohort Study, a population-based pregnancy cohort, linked to the Norwegian Prescription Database. Current asthma at age seven was defined by asthma medications dispensed at least twice in the year (1,901 cases, n=39,846) or by maternal questionnaire report (1,624 cases, n=28,872). Maternal folate intake was assessed with a food frequency questionnaire validated against plasma folate. We used log-binomial and multinomial regression to calculate adjusted relative risks with 95% confidence intervals.MEASUREMENTS AND MAIN RESULTS: Risk of asthma was increased in the highest vs. lowest quintile of total folate intake with an adjusted relative risk of 1.23 (95% confidence interval 1.06 to 1.44) that was similar for maternally reported asthma. Mothers in the highest quintile had a relatively high intake of food folate (median 308, interquartile range 241-366 μg/day) and nearly all took at least 400 μg/day of supplemental folic acid (median 500, interquartile range 400-600).CONCLUSIONS: In this large prospective population based cohort with essentially complete follow-up, pregnant women taking supplemental folic-acid at or above the recommended dose, combined with a diet rich in folate, reach a total folate intake level that may slightly increase risk of asthma in children.

Publisher's version (útgefin grein), Purpose: To describe recent international trends in antiepileptic drug (AED) use during pregnancy and individual patterns of use including discontinuation and switching. Methods: We studied pregnancies from 2006 to 2016 within linked population-based registers for births and dispensed prescription drugs from Denmark, Finland, Iceland, Norway, Sweden, and New South Wales, Australia and claims data for public and private insurance enrollees in the United States. We examined the prevalence of AED use: the proportion of pregnancies with ≥1 prescription filled from 3 months before pregnancy until birth, and individual patterns of use by trimester. Results: Prevalence of AED use in almost five million pregnancies was 15.3 per 1000 (n = 75 249) and varied from 6.4 in Sweden to 34.5 per 1000 in the publicly-insured US population. AED use increased in all countries in 2006-2012 ranging from an increase of 22% in Australia to 104% in Sweden, and continued to rise or stabilized in the countries in which more recent data were available. Lamotrigine, clonazepam, and valproate were the most commonly used AEDs in the Nordic countries, United States, and Australia, respectively. Among AED users, 31% only filled a prescription in the 3 months before pregnancy. Most filled a prescription in the first trimester (59%) but few filled prescriptions in every trimester (22%). Conclusions: Use of AEDs in pregnancy rose from 2006 to 2016. Trends and patterns of use of valproate and lamotrigine reflected the safety data available during this period. Many women discontinued AEDs during pregnancy while some switched to another AED., This study was funded by NordForsk as part of the Nordic Pregnancy Drug Safety Studies (NorPreSS) (Project No: 83539) and the Research Council of Norway as part of the International Pregnancy Drug Safety Studies (InPreSS) (Project No: 273366). Linkage of Danish data was supported by the Danish Council for Independent Research (Project No: DFF‐6110‐00019) and Karen Elise Jensens Fond (2016), and grant NNF18OC0052029 from Novo Nordisk Fonden (Li). Linkage of the Australian data was supported by an Australian National Health and Medical Research Council Project grant (No. 1028543). We thank Anders Engeland (Norwegian Institute of Public Health, University of Bergen, Norway), Anna Heino (National Institute for Health and Welfare, Finland), Mette Nørgaard (Aarhus University, Denmark), Pär Karlsson (Karolinska Institutet, Sweden), Jennifer Yland (Harvard T.H. Chan School of Public Health, USA), Gregory Brill and Helen Mogun (Brigham and Women's Hospital & Harvard Medical School, USA) for providing assistance with analyses. The authors would like to thank the NSW Ministry of Health, the Australian Government Department of Health and Ageing and the Department of Human Services for providing data. The authors also thank the Centre for Health Record Linkage (CHeReL) and the Australian Institute for Health and Welfare for conducting the linkage of records.

Diagnosing asthma and deciding treatment are difficult in young children. An inappropriate and too high prescription rate of inhaled corticosteroids (ICS) is suggested, but how airway symptoms are associated with prescriptions of asthma medication is less known. We studied how strongly wheeze, lower respiratory tract infections (LRTI), and atopic diseases are associated with dispensing of asthma medications during early childhood. We used data from the Norwegian Mother and Child Cohort Study and the Norwegian Prescription Database at four age‐intervals (0‐6, 6‐18, 18‐36 months, and 3‐7 years). Primary outcomes were dispensed asthma medications (no medication, short‐acting β‐2 agonist, or ICS). Relative risks (RRs) and average attributable fractions (AAFs) were estimated. Both wheeze and LRTI were positively associated with both medication groups (0‐6 months: no data on wheeze). The RRs and AAFs were higher for wheeze than LRTI. For ICS, the AAFs (95% CI) for wheeze vs LRTI were: 6 to 18 months: 69.2 (67.2, 71.2)% vs 10.4 (9.0, 11.8)%, 18 to 36 months: 33.0 (30.5, 35.5)% vs 10.0 (8.0, 12.0)%, and 3 to 7 years: 33.7 (31.0, 36.5)% vs 1.2 (0.5, 1.9)%. Except at 3 to 7 years of age, the AAFs were lower for atopic diseases than for LRTI and wheeze. Atopic diseases modified the associations between wheeze and ICS at 18 to 36 months and between LRTI or wheeze and ICS at 3 to 7 years. In conclusion, both wheeze and LRTI were associated with prescriptions of asthma medications in young children, with the strongest associations seen for wheeze. Atopic diseases contributed to these associations only in the oldest age groups. publishedVersion

IntroductionSurveillance of unintended effects of pharmaceuticals (pharmacovigilance or drug safety) is crucial, as knowledge of rare or late side effects is limited at the time of the introduction of new medications into the market. Side effects of drugs may involve increased or decreased risk of cancer, but these typically appear after a long induction period. This fact, together with low incidences of many cancer types, limits the usefulness of traditional pharmacovigilance strategies, primarily based on spontaneous reporting of adverse events, to identify associations between drug use and cancer risk. Postmarketing observational pharmacoepidemiological studies are therefore crucial in the evaluation of drug-cancer associations.Methods and analysisThe main data sources in this project will be the Norwegian Prescription Database and the Cancer Registry of Norway. The underlying statistical model will be based on a multiple nested case–control design including all adult (~200 000) incident cancer cases within the age-range 18–85 years from 2007 through 2015 in Norway as cases. 10 cancer-free population controls will be individually matched to these cases with respect to birth year, sex and index date (date of cancer diagnosis). Drug exposure will be modelled as chronic user/non-user by counting prescriptions, and cumulative use by summarising all dispensions’ daily defined doses over time. Conditional logistic regression models adjusted for comorbidity (National Patient Register), socioeconomic parameters (Statistics Norway), concomitant drug use and, for female cancers, reproduction data (Medical Birth Registry), will be applied to identify drug-use–cancer-risk associations.Ethics and disseminationThe study is approved by the regional ethical committee and the Norwegian data protection authority. Results of the initial screening step and analysis pipeline will be described in a key paper. Subsequent papers will report the evaluation of identified signals in replication studies. Results will be published in peer-reviewed journals, at scientific conferences and through press releases.

STUDY OBJECTIVE: Evidence on the cardiotoxicity of nonaspirin nonsteroidal antiinflammatory drugs (NSAIDs)-particularly diclofenac and the newer selective cyclooxygenase (COX)-2 inhibitors-has accumulated over the last decade. Our objective was to examine whether the use of NSAIDs in the Nordic countries changed with the emerging evidence, regulatory statements, and clinical guidelines advocating caution for use of specific NSAIDs.DESIGN: Drug utilization study.DATA SOURCES: Nationwide wholesale statistics and prescription registries in Denmark, Finland, Iceland, Norway, and Sweden (2000-2016).MEASUREMENTS AND MAIN RESULTS: Our main outcome measures were yearly total sales, expressed as number of sold defined daily doses (DDD)/1000 inhabitants/day, and yearly prevalence of prescription use, expressed as number of prescription users per 1000 inhabitants. The DDD is the assumed average maintenance dose per day for a drug used for its main indication in adults. Total sales of NSAIDs increased in all countries and were highest in Iceland, with 74.3 DDDs/1000 inhabitants/day sold in 2016, followed by Finland (73.9), Sweden (54.4), Norway (43.8), and Denmark (31.8). Diclofenac use declined after 2008 in all countries but remained the most widely prescribed NSAID in Norway, with 63 prescription users/1000 inhabitants in 2016. Diclofenac sales also remained high in Iceland (12.7 DDD/1000 inhabitants/day), Norway (8.1), and Sweden (7.8). Since its introduction in 2003, the use of etoricoxib, a newer selective COX-2 inhibitor, increased in all countries except Denmark, with highest sales in Finland (6.7 DDD/1000 inhabitants/day in 2016).CONCLUSION: Sales and prescription patterns of NSAIDs in the Nordic countries has changed along with the accumulating evidence for the cardiovascular risks of specific NSAIDs. However, given existing evidence on the cardiovascular risks associated with use of diclofenac and etoricoxib, the persistent high use of diclofenac in Iceland, Norway, and Sweden, the persistent over-the-counter availability of diclofenac in Norway and Sweden, and the increasing use of etoricoxib in most of the Nordic countries pose a cardiovascular health concern. This article is protected by copyright. All rights reserved.