Randi Selmer

Aims: To examine how consumption of wine, beer, and spirits—both individually and in combination—is associated with mortality. We also assessed the relationship between overall alcohol intake and mortality from cardiovascular disease, ischemic heart disease, cancer, and alcohol-related diseases. Methods: A cohort of 187,294 men and women aged 16–99 years (10th percentile 36 years, 90th percentile 52 years), without cardiovascular disease or cancer, were followed for an average of 21 years, with 15,642 deaths. The participants completed a cardiovascular health survey and a questionnaire reporting their consumption of beer, wine, and spirits over the preceding 14 days. Mortality outcomes were assessed using absolute mortality rates, calculated with the direct method, and hazard ratios, adjusted for major cardiovascular risk factors, estimated with Cox proportional hazards models. Non-drinkers served as the reference group. Results: For all-cause death in men and women combined, the hazard ratio was 0.91 (95% confidence interval: 0.88–0.94) for 1–9 glasses/14 days of alcohol, 1.01 (0.96–1.07) for 10–19 glasses, and 1.44 (1.32–1.57) for 20+ glasses versus non-drinkers. Corresponding hazard ratios for ischemic heart disease death were 0.86 (0.77–0.97), 0.82 (0.68–0.98), and 1.09 (0.83–1.43), and for alcohol-related deaths 1.63 (1.07–2.49), 4.47 (2.85–7.02), and 13.0 (8.11–20.8). Low wine consumption alone, or combined with low beer or spirits consumption, was associated with hazard ratios of 0.84 (0.78–0.89) to 0.90 (0.84–0.97). Combinations without wine showed hazard ratios ranging from 1.00 (0.95–1.06) to1.06 (1.00–1.13). Conclusions: Low wine consumption was associated with lower mortality than no alcohol consumption, irrespective of low beer or spirits consumption .

Background: Smoking is closely linked to socioeconomic status and risk of death. We examined the extent to which educational disparities in mortality can be explained by smoking. Methods: We analysed data from 513,552 men and women aged 25–69 years, excluding individuals with a history of cardiovascular disease, diabetes or cancer. The educational level was lower (less than 10 years), upper (10–12 years) and higher (13 or more years). We employed the direct method to estimate age-adjusted mortality rates and used the Cox proportional hazards model to calculate hazard ratios, using a higher educational level as the reference level. We ran models among non-smokers with interaction terms, educational level and another variable. Based on Akaike information criterion, we performed stratified analyses by marital status among non-smokers. Results: The hazard ratio for lower educational level in men was 1.38 (1.31–1.45) in non-smokers and 1.57 (1.49–1.66) in smokers. The figures for women were almost identical. Among non-smoking men, the hazard ratio for lower educational level was 1.28 (1.21–1.35) for the ever married and 2.20 (1.93–2.52) for the unmarried men. In women the figures were the same. For non-smoking men and women combined, the population attributable risk ascribed to upper or lower educational level was 17% for the ever married and 35% for the unmarried. Conclusions: An educational gradient in mortality persists in the absence of smoking and is more pronounced among the unmarried. Marital status appears to modify the relationship between education and mortality, underscoring the need to consider social and relational factors in health inequality research.

Valproate should be avoided in pregnancy, but it is the most effective drug for generalized epilepsies. Alternative treatment may require combinations of other drugs. Our objectives were to describe first trimester use of antiseizure medication (ASM) combinations that are relevant alternatives to valproate and determine whether specific combinations were associated with a lower risk of major congenital malformations (MCM) compared with valproate monotherapy. We conducted a population-based cohort study using linked national registers from Denmark, Finland, Iceland, Norway, and Sweden and administrative health care data from the United States and New South Wales, Australia. We described first trimester use of ASM combinations among pregnant people with epilepsy from 2000 to 2020. We compared the risk of MCM after first trimester exposure to ASM combinations vs valproate monotherapy and low-dose valproate plus lamotrigine or levetiracetam vs high-dose valproate (≥1,000 mg/d). We used log-binomial regression with propensity score weights to calculate adjusted risk ratios (aRRs) and 95% CIs for each dataset. Results were pooled using fixed-effects meta-analysis. Among 50,905 pregnancies in people with epilepsy identified from 7.8 million total pregnancies, 788 used lamotrigine and levetiracetam, 291 used lamotrigine and topiramate, 208 used levetiracetam and topiramate, 80 used lamotrigine and zonisamide, and 91 used levetiracetam and zonisamide. After excluding pregnancies with use of other ASMs, known teratogens, or a child diagnosed with MCM of infectious or genetic cause, we compared 587 exposed to lamotrigine-levetiracetam duotherapy and 186 exposed to lamotrigine-topiramate duotherapy with 1959 exposed to valproate monotherapy. Pooled aRRs were 0.41 (95% CI 0.24-0.69) and 1.26 (0.71-2.23), respectively. Duotherapy combinations containing low-dose valproate were infrequent, and comparisons with high-dose valproate monotherapy were inconclusive but suggested a lower risk for combination therapy. Other combinations were too rare for comparative safety analyses. Lamotrigine-levetiracetam duotherapy in first trimester was associated with a 60% lower risk of MCM than valproate monotherapy, while lamotrigine-topiramate was not associated with a reduced risk. Duotherapy with lamotrigine and levetiracetam may be favored to treat epilepsy in people with childbearing potential compared with valproate regarding MCM, but whether this combination is as effective as valproate remains to be determined. This study provides Class II evidence that in people with epilepsy treated in the first trimester of pregnancy, the risk of major congenital malformations is lower with lamotrigine-levetiracetam duotherapy than with valproate alone, but similar with lamotrigine-topiramate.

Aims We studied the health consequences of quitting smoking before age 43 by time since quitting, number of years smoked and cigarettes smoked per day. The outcomes were all-cause, ischaemic heart disease and lung cancer mortality. Design Prospective study. Setting Norwegian counties. Participants Men and women aged 40–43 years who participated in a national cardiovascular screening programme and who were followed from 1985 to 2018. Measurements Self-reports from questionnaire on time since quitting smoking, years smoked and number of cigarettes per day, and measurements of height, weight and blood pressure, and a blood sample where serum was analysed for total serum cholesterol and triglycerides. Findings The all-cause mortality rate was 30% higher among quitters less than 1 year ago compared with never smokers (adjusted HR=1.30, 95% CI 1.18–1.43 in men and HR=1.31, 95% CI 1.16 to 1.50 in women). Quitters who had smoked longer than 20 years had 23% higher mortality in men (HR=1.23, 95% CI 1.14 to 1.34) and 32% higher mortality in women (HR=1.32, 95% CI 1.18 to 1.49). Past smoking of more than 20 cigarettes/day was associated with HR=1.14 (1.05–1.23) in men and HR=1.16 (1.01–1.32) in women. The HR for lung cancer was 6.77 (95% CI 4.86 to 9.45) for quitting men who had smoked for more than 20 years compared with never smokers. The corresponding figure for women was 5.75 (95% CI 4.08 to 8.09). Conclusions The mortality among quitters was close to that of never smokers, except for a higher mortality for lung cancer, which on the other hand was much lower than the lung cancer mortality in current smokers.

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.

Introduction: Inconsistent results have been reported on the association between folic acid use in pregnancy and risk of GDM. The aim of this study was to estimate the association between folic acid use and GDM in two population-based Nordic cohorts. Material and methods: Two cohort studies were conducted using data from the national population registers in Norway (2005–2018, n = 791,709) and Sweden (2006–2016, n = 1,112,817). Logistic regression was used to estimate the associations between GDM and self-reported folic acid use and prescribed folic acid use, compared to non-users, adjusting for covariates. To quantify how potential unmeasured confounders may affect the estimates, E-values were reported. An exposure misclassification bias analysis was also performed. Results: In Norwegian and Swedish cohorts, adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for maternal self-reported folic acid use were 1.10 (1.06–1.14) and 0.89 (0.85–0.93), with E-values of 1.43 (1.31) and 1.50 (1.36), respectively. For prescribed folic acid use, ORs were 1.33 (1.15–1.53) and 1.56 (1.41–1.74), with E-values of 1.99 (1.57) and 2.49 (2.17), in Norway and Sweden respectively. Conclusions: The slightly higher or lower odds for GDM in self-reported users of folic acid in Norway and Sweden respectively, are likely not of clinical relevance and recommendations for folic acid use in pregnancy should remain unchanged. The two Nordic cohorts showed different directions of the association between self-reported folic acid use and GDM, but based on bias analysis, exposure misclassification is an unlikely explanation since there may still be differences in prevalence of use and residual confounding. Prescribed folic acid is used by women with specific comorbidities and co-medications, which likely underlies the higher odds for GDM.

Background: The effect of oral anticoagulants (OAC) on prevention of stroke must be carefully balanced against the potential risk of bleeding in patients with atrial fibrillation (AF). The net benefit of OAC in AF patients at intermediate risk of stroke remains unclear. Aim: We aimed to determine whether the rates of ischemic and haemorrhagic stroke differ between users and non-users of OAC in a nationwide cohort of AF patients at intermediate risk of stroke. Method: We investigated the association between initiation of OAC treatment and rates of ischemic and haemorrhagic stroke in a cohort of Norwegian patients with non-valvular AF aged ≥18 years with one non-sex CHA2DS2-VASc risk factor registered from 2011 to 2018, linking data from the Norwegian Population Registry, Patient Registry, Prescription Database and Cause of Death Registry. Individuals using OAC at baseline were excluded. Each individual had at least a three years look-back period for identification of their first non-sex CHA2DS2-VASc risk factor, after which they entered the study cohort and were followed until occurrence of stroke, death, emigration, higher CHA2DS2-VASc score or end of follow-up on December 31, 2018. Individuals were defined as exposed to OAC from the first redeemed prescription of OAC with a reimbursement code for AF and throughout follow-up. Rates of ischemic and haemorrhagic stroke were calculated as the number of stroke cases per 100 person-years, with 95% confidence intervals (CI). Results: During 2011–2018, a total of 61,631 individuals with AF and intermediate risk of stroke were included (mean age 63,8±7,6 years (SD); 37% women), of whom 75% initiated OAC treatment. In total, 1709 ischemic strokes (405 cases in OAC users and 1304 in non-users) were registered during 214,738 person-years, and 378 haemorrhagic strokes (251 cases in OAC users and 127 in non-users) during 213,487 person-years. The rate of ischemic stroke was 0.39 (95% CI, 0.35–0.43) and 1.19 (95% CI, 1.12–1.25) per 100 person-years in OAC users and non-users, respectively. The haemorrhagic stroke rate was 0.24 (95% CI, 0.21–0-27) and 0.12 (95% CI, 0.10–0.14) per 100 person-years in OAC users and non-users, respectively. Both ischemic and haemorrhagic stroke rates were highest among those over 65 years of age (Figure 1). Conclusion: In a nationwide cohort of Norwegian AF patients at intermediate risk of stroke, three out of four initiated treatment with OAC. Use of OAC was associated with a considerably lower rate of ischemic stroke compared to non-OAC use. Although haemorrhagic stroke rates were increased in the OAC-users vs. non-users, the hemorrhagic stroke rates were generally low. Funding Acknowledgement: Type of funding sources: Public hospital(s). Main funding source(s): Vestre Viken Health Trust Figure 1. Rates of ischemic and haemorrhagic stroke per 100 person-years in AF-patients at intermediate risk of stroke (CHA2DS2-VASc score 1 in men, score 2 in women) by OAC use during 2011 to 2018. Age corresponds to age at attainment of the first non-sex CHA2DS2-VASc risk factor.

Background Experimental animal studies suggest a novel role for the folate receptor 1 in β-cell differentiation in the pancreas, with potential implications for glycemic control. Objective We tested the hypothesis of a protective association between prenatal folic acid use and neonatal diabetes or hyperglycemia and type 1 diabetes in an observational cohort study using data from the national population health registers in Norway. Method All singleton pregnancies resulting in livebirths from 2005-2018 were identified. Prenatal exposure to folic acid was determined based on maternal report at antenatal care in early pregnancy. Diagnoses of neonatal diabetes, hyperglycemia, and type 1 diabetes for the children were identified. Associations were estimated with logistic regression or Cox proportional hazard model and included crude and adjusted estimates. Results Amongst 781,567 children, 69% had prenatal exposure to folic acid, 264 were diagnosed with neonatal diabetes or hyperglycemia, and 1390 with type 1 diabetes. Compared to children with no prenatal exposure to folic acid, children with prenatal exposure to folic acid had similar odds of having a neonatal diabetes or hyperglycemia diagnosis (adjusted odds ratio 0.95, 95% confidence interval (CI) 0.72, 1.25) and similar risk of being diagnosed with type 1 diabetes (adjusted hazard ratio 1.05, 95%CI 0.93, 1.18). Conclusion No association between prenatal folic acid exposure and neonatal diabetes/hyperglycemia or type 1 diabetes was found. These findings do not rule out a translational effect of the experimental results and future studies with longer follow-up and more precise information on the window of prenatal exposure are needed.

Alcohol consumption has been linked to colorectal cancer (CRC) and also to the high-density lipoprotein cholesterol level (HDL-C). HDL-C has been associated with the incidence of CRC. The aim of this study was to investigate the association between self-reported alcohol consumption, HDL-C and incidence of CRC, separately for the two sites. Altogether, 250,010 participants in Norwegian surveys have been followed-up for an average of 18 years with respect to a first-time outcome of colon or rectal cancer. During follow-up, 3023 and 1439 colon and rectal cancers were registered. For men, the HR per 1 drink per day was 1.05 with 95% confidence interval (0.98–1.12) for colon and 1.08 (1.02–1.15) for rectal cancer. The corresponding figures for women were 1.03 (0.97–1.10) and 1.05 (1.00–1.10). There was a positive association between alcohol consumption and HDL-C. HDL-C was inversely associated with colon cancer in men (0.74 (0.62–0.89) per 1 mmol/l) and positively associated with rectal cancer, although not statistically significant (1.15 (0.92–1.44). A robust regression that assigned weights to each observation and exclusion of weights ≤ 0.1 increased the HRs per 1 drink per day and decreased the HR per 1 mmol/l for colon cancer. The associations with rectal cancer remained unchanged. Our results support a positive association between alcohol consumption and colon and rectal cancer, most pronounced for rectal cancer. Considering the positive relation between alcohol consumption and HDL-C, the inverse association between HDL-C and colon cancer in men remains unsettled.