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.

Comparative Risk of Major Congenital Malformations With Antiseizure Medication Combinations vs Valproate Monotherapy in Pregnancy.

BACKGROUND AND OBJECTIVES: 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. METHODS: 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. RESULTS: 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. DISCUSSION: 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. CLASSIFICATION OF EVIDENCE: 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.

Stroke and bleeding risk in atrial fibrillation with CHA2DS2-VASC risk score of one: the Norwegian AFNOR study.

BACKGROUND AND AIMS: The benefit of oral anticoagulant (OAC) therapy in atrial fibrillation (AF) and intermediate stroke risk is debated. In a nationwide Norwegian cohort with a non-sex CHA2DS2-VASc risk score of one, this study aimed to investigate (i) stroke and bleeding risk in AF patients with and without OAC treatment, and (ii) the risk of stroke in non-anticoagulated individuals with and without AF. METHODS: A total of 1 118 762 individuals including 34 460 AF patients were followed during 2011-18 until ischaemic stroke, intracranial haemorrhage, increased CHA2DS2-VASc score, or study end. One-year incidence rates (IRs) were calculated as events per 100 person-years (%/py). Cox regression models provided adjusted hazard ratios (aHRs [95% confidence intervals]). RESULTS: Among AF patients, the ischaemic stroke IR was 0.51%/py in OAC users and 1.05%/py in non-users (aHR 0.47 [0.37-0.59]). Intracranial haemorrhage IR was 0.28%/py in OAC users and 0.19%/py in non-users (aHR 1.23 [0.88-1.72]). Oral anticoagulant use was associated with an increased risk of major bleeding (aHR 1.37 [1.16-1.63]) but lower risk of the combined outcome of ischaemic stroke, major bleeding, and mortality (aHR 0.57 [0.51-0.63]). Non-anticoagulated individuals with AF had higher risk of ischaemic stroke compared to non-AF individuals with the same risk profile (aHR 2.47 [2.17-2.81]). CONCLUSIONS: In AF patients at intermediate risk of stroke, OAC use was associated with overall favourable clinical outcomes. Non-anticoagulated AF patients had higher risk of ischaemic stroke compared to the general population without AF with the same risk profile.

Smoking history and all-cause, ischaemic heart disease and lung cancer mortality: follow-up study of 358 551 men and women aged 40-43 years.

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.

Stroke After SARS-CoV-2 mRNA Vaccine: A Nationwide Registry Study.

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.

Associations between serum high-density lipoprotein cholesterol levels and cause-specific mortality in a general population of 345 000 men and women aged 20-79 years.

BACKGROUND: Benefits of elevated high-density lipoprotein cholesterol (HDL-C) levels are challenged by reports demonstrating U-shaped relations between HDL-C levels and all-cause mortality; the association with cause-specific mortality is less studied. METHODS: A total of 344 556 individuals (20-79 years, 52 % women) recruited from population-based health screening during 1985-2003 were followed until the end of 2018 for all-cause and cause-specific mortality by serum HDL-C level at inclusion of <30, 30-39, 40-49, 50-59, 60-69, 70-79, 80-89, 90-99 and >99 mg/dl (< 0.78, 0.78-1.01, 1.04-1.27, 1.30-1.53, 1.55-1.79, 1.81-2.04, 2.07-2.31, 2.33-2.56, >2.56 mmol/L). Hazard ratios (HRs) were adjusted for sex, age, calendar period, smoking, total cholesterol, triglycerides, systolic blood pressure, physical activity, educational length, body mass index and ill health. RESULTS: During a mean follow-up of 22 years, 69 505 individuals died. There were U-shaped associations between HDL-C levels and all-cause, cancer and non-cardiovascular disease/non-cancer mortality (non-CVD/non-cancer), whereas for CVD there was increased risk of death only at lower levels. With HDL-C stratum 50-59 mg/dl (1.30-1.53 mmol/L) as reference, HRs [95% confidence intervals (CIs)] for levels >99 mg/dl (>2.56 mmol/L) were 1.32 (1.21-1.43), 1.05 (0.89-1.24), 1.26 (1.09-1.46) and 1.68 (1.48-1.90) for all-cause, CVD, cancer and non-CVD/non-cancer mortality, respectively. For HDL-C levels <30 mg/dl (0.78 mmol/L), the corresponding HRs (95% CIs) were 1.30 (1.24-1.36), 1.55 (1.44-1.67), 1.14 (1.05-1.23) and 1.19 (1.10-1.29). The mortality from alcoholic liver disease, cancers of mouth-oesophagus-liver, chronic liver diseases, chronic obstructive pulmonary disease, accidents and diabetes increased distinctly with increasing HDL-C above the reference level. HDL-C levels lower than the reference level were mainly associated with increased mortality of ischaemic heart disease (IHD), other CVDs, stomach cancer and diabetes. CONCLUSIONS: Higher HDL-C levels were associated with increased mortality risk of several diseases which also have been associated with heavy drinking, and lower HDL-C levels were associated with increased mortality from IHD, other CVDs, gastric cancer and diabetes.

Association of In Utero Antipsychotic Medication Exposure With Risk of Congenital Malformations in Nordic Countries and the US.

Importance: Psychiatric disorders are common among female individuals of reproductive age. While antipsychotic medication use is increasing, the safety of such medications in pregnancy is an area with large evidence gaps. Objective: To evaluate the risk of first-trimester antipsychotic exposure with respect to congenital malformations, focusing on individual drugs and specific malformation subtypes. Design, Setting, and Participants: This cohort study used data from nationwide health registers from the 5 Nordic countries and the US and spanned 1996 to 2018. The Nordic cohort included all pregnancies resulting in singleton live-born infants, and the US cohort consisted of publicly insured mothers linked to their live-born infants nested in the nationwide Medicaid Analytic eXtract. Data were analyzed from November 2020 to April 2022. Exposures: One or more first-trimester dispensing of any atypical, any typical, and individual antipsychotic drugs. Main Outcomes and Measures: Any major congenital malformation and specific malformation subtypes previously suggested to be associated with antipsychotic exposure in utero: cardiovascular malformations, oral clefts, neural tube defects, hip dysplasia, limb reduction defects, anorectal atresia/stenosis, gastroschisis, hydrocephalus, other specific brain anomalies, and esophageal disorders. Propensity score stratification was used to control for potential confounders. Pooled adjusted estimates were calculated using indirect standardization. Results: A total of 6 455 324 unexposed mothers (mean maternal age range across countries: 24-31 years), 21 751 mothers exposed to atypical antipsychotic drugs (mean age range, 26-31 years), and 6371 mothers exposed to typical antipsychotic drugs (mean age range, 27-32 years) were included in the study cohort. Prevalence of any major malformation was 2.7% (95% CI, 2.7%-2.8%) in unexposed infants, 4.3% (95% CI, 4.1%-4.6%) in infants with atypical antipsychotic drug exposure, and 3.1% (95% CI, 2.7%-3.5%) in infants with typical antipsychotic drug exposure in utero. Among the most prevalent exposure-outcome combinations, adjusted relative risks (aRR) were generally close to the null. One exception was olanzapine exposure and oral cleft (aRR, 2.1 [95% CI, 1.1-4.3]); however, estimates varied across sensitivity analyses. Among moderately prevalent combinations, increased risks were observed for gastroschisis and other specific brain anomalies after atypical antipsychotic exposure (aRR, 1.5 [95% CI, 0.8-2.6] and 1.9 [95% CI, 1.1-3.0]) and for cardiac malformations after chlorprothixene exposure (aRR, 1.6 [95% CI, 1.0-2.7]). While the association direction was consistent across sensitivity analyses, confidence intervals were wide, prohibiting firm conclusions. Conclusions and Relevance: In this study, considering the evidence from primary and sensitivity analyses and inevitable statistical noise for very rare exposure-outcome combinations, in utero antipsychotic exposure generally was not meaningfully associated with an increased risk of malformations. The observed increased risks of oral clefts associated with olanzapine, gastroschisis, and other specific brain anomalies with atypical antipsychotics and cardiac malformations with chlorprothixene requires confirmation as evidence continues to accumulate.

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.

Short-term safety of COVID-19 mRNA vaccines with respect to all-cause mortality in the older population in Norway.

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 theNorwegian 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.

Many refugees are at a high risk of cardiovascular disease. / Mange flyktninger har høy risiko for hjerte- og karsykdom.

The risk of cardiovascular disease varies considerably in different parts of the world, including within Europe. Norwegian doctors need to be aware of this when they see patients from other countries, such as refugees from Ukraine.

Association between folic acid use during pregnancy and gestational diabetes mellitus: Two population-based Nordic cohort studies.

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.

SARS-CoV-2 Vaccination and Myocarditis in a Nordic Cohort Study of 23 Million Residents.

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 23 122 522 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 23 122 522 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 100 000 vaccinees after the second dose of BNT162b2 and 18.39 (9.05-27.72) events per 100 000 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 100 000 vaccinees after BNT162b2, and between 9 and 28 excess events per 100 000 vaccinees after mRNA-1273. This risk should be balanced against the benefits of protecting against severe COVID-19 disease.

Alcohol consumption and incidence of pancreatic cancer.

Purpose: The association between alcohol consumption and pancreatic cancer is unsettled. Methods: Altogether 243,169 men and women 20-79 years, without cancer at baseline, were followed with respect to pancreatic cancer by linkage to the Cancer Registry of Norway and the Norwegian Cause of Death Registry. They participated in a cardiovascular survey where information on alcohol consumption, smoking habits, anthropometric measures, and some biological variables were recorded. During 20 years of follow-up, 991 incident pancreatic cancers were registered. We estimated the hazard ratios with the Cox proportional hazards model, and graphed spline curves between glass-units/d of alcohol and hazard ratio of incident pancreatic cancer. Results: The multivariable adjusted hazard per 1 glass-unit/d was 1.08 (95% confidence interval 1.02-1.15) for men and 1.04 (0.97-1.13) for women. The association between alcohol consumption and incident pancreatic cancer was present in ex- and current smokers, but the association could be ascribed to smoking habits. The multivariable adjusted spline curves increased with increasing glass-units/d and with confidence bands not encompassing 1.0 above one glass-unit/day. Conclusion: Our findings of an association between higher level of alcohol consumption and incident pancreatic cancer, could be attributed to confounding by smoking habits.

Investigating the association between prenatal exposure to folic acid and risk of neonatal diabetes/hyperglycemia and type 1 diabetes: A Norwegian register-based study.

BACKGROUND: Experimental animal studies suggest a novel role for the folate receptor 1 in ß-cell differentiation in the pancreas, with potential implications for glycemic control. 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. METHODS: All singleton pregnancies resulting in live births from 2005 to 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: Among 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). CONCLUSIONS: 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.

Using multiple random index dates with the reverse waiting time distribution improves precision of estimated prescription durations.

PURPOSE: To improve the precision of prescription duration estimates when using the reverse waiting time distribution (rWTD). METHODS: For each patient we uniformly sampled multiple random index dates within a sampling window of length δ . For each index date, we identified the last preceding prescription redemption, if any, within distance δ . Based on all pairs of last prescription and index date, we estimated prescription durations using the rWTD with robust variance estimation. In simulation studies with increasing misspecification we investigated bias, root mean square error (RMSE) and coverage probability of the rWTD using multiple index dates (1, 5, 10, and 20). We applied the method to Danish data on warfarin prescriptions from 2013 to 2014 stratifying by and adjusting for sex and age. RESULTS: In simulation scenarios without misspecification, the relative bias was negligible (-0.04% to 0.01%) and nominal coverage probabilities almost retained (93.8%-95.4%). RMSE decreased with the number of random index dates (e.g., from 1.3 with 1 index date to 0.6 days with 5). With misspecification, the relative bias was higher irrespective of the number of index dates. Precision increased with the number of index dates, and hence coverage probabilities decreased. When estimating durations of warfarin prescriptions in Denmark, precision increased with number of index dates, in particular in strata with few patients (e.g., men 90+ years: width of 95% confidence interval was 16.2 days with 5 index dates versus 35.4 with 1). CONCLUSIONS: Increasing the number of random index dates used with the rWTD improved precision without affecting bias.

Change in cardiovascular risk assessment tool and updated Norwegian guidelines for cardiovascular disease in primary prevention increase the population proportion at risk: the Tromsø Study 2015-2016.

AIMS: To compare the population proportion at high risk of cardiovascular disease (CVD) using the Norwegian NORRISK 1 that predicts 10-year risk of CVD mortality and the Norwegian national guidelines from 2009, with the updated NORRISK 2 that predicts 10-year risk of both fatal and non-fatal risk of CVD and the Norwegian national guidelines from 2017. METHODS: We included participants from the Norwegian population-based Tromsø Study (2015-2016) aged 40-69 years without a history of CVD (n=16 566). The total proportion eligible for intervention was identified by NORRISK 1 and the 2009 guidelines (serum total cholesterol ≥8 mmol/L, systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥100 mm Hg) and NORRISK 2 and the 2017 guidelines (serum total cholesterol ≥7 mmol/L, low density lipoprotein (LDL) cholesterol ≥5 mmol/L, systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥100 mm Hg). RESULTS: The total proportion at high risk as defined by a risk score was 12.0% using NORRISK 1 and 9.8% using NORRISK 2. When including single risk factors specified by the guidelines, the total proportion eligible for intervention was 15.5% using NORRISK 1 and the 2009 guidelines and 18.9% using NORRISK 2 and the 2017 guidelines. The lowered threshold for total cholesterol and specified cut-off for LDL cholesterol stand for a large proportion of the increase in population at risk. CONCLUSION: The population proportion eligible for intervention increased by 3.4 percentage points from 2009 to 2017 using the revised NORRISK 2 score and guidelines.

Occupational physical activity and longevity in working men and women in Norway: a prospective cohort study.

BACKGROUND: Studies suggest that high occupational physical activity increases mortality risk. However, it is unclear whether this association is causal or can be explained by a complex network of socioeconomic and behavioural factors. We aimed to examine the association between occupational physical activity and longevity, taking a complex network of confounding variables into account. METHODS: In this prospective cohort study, we linked data from Norwegian population-based health examination surveys, covering all parts of Norway with data from the National Population and Housing Censuses and the Norwegian Cause of Death Registry. 437 378 participants (aged 18-65 years; 48·7% men) self-reported occupational physical activity (mutually exclusive groups: sedentary, walking, walking and lifting, and heavy labour) and were followed up from study entry (between February, 1974, and November, 2002) to death or end of follow-up on Dec 31, 2018, whichever came first. We estimated differences in survival time (death from all causes, cardiovascular disease, and cancer) between occupational physical activity categories using flexible parametric survival models adjusted for confounding factors. FINDINGS: During a median of 28 years (IQR 25-31) from study entry to the end of follow-up, 74 203 (17·0%) of the participants died (all-cause mortality), of which 20 111 (27·1%) of the deaths were due to cardiovascular disease and 29 886 (40·3%) were due to cancer. Crude modelling indicated shorter mean survival times among men in physically active occupations than in those with sedentary occupations. However, this finding was reversed following adjustment for confounding factors (birth cohort, education, income, ethnicity, prevalent cardiovascular disease, smoking, leisure-time physical activity, body-mass index), with estimates suggesting that men in occupations characterised by walking, walking and lifting, and heavy labour had life expectancies equivalent to 0·4 (95% CI -0·1 to 1·0), 0·8 (0·3 to 1·3), and 1·7 (1·2 to 2·3) years longer, respectively, than men in the sedentary referent category. Results for mortality from cardiovascular disease and cancer showed a similar pattern. No clear differences in survival times were observed between occupational physical activity groups in women. INTERPRETATION: Our results suggest that moderate to high occupational physical activity contributes to longevity in men. However, occupational physical activity does not seem to affect longevity in women. These results might inform future physical activity guidelines for public health. FUNDING: The Norwegian Research Council (grant number 249932/F20).

Alcohol Consumption, HDL-Cholesterol and Incidence of Colon and Rectal Cancer: A Prospective Cohort Study Including 250,010 Participants.

AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Validation of the cardiovascular risk model NORRISK 2 in South Asians and people with diabetes.

OBJECTIVES: To evaluate the predictive ability of the previously published NORRISK 2 cardiovascular risk model in Norwegian-born and immigrants born in South Asia living in Norway, and to add information about diabetes and ethnicity in an updated model for South Asians and diabetics (NORRISK 2-SADia). Design. We included participants (30-74 years) born in Norway (n = 13,885) or South Asia (n = 1942) from health surveys conducted in Oslo 2000-2003. Cardiovascular disease (CVD) risk factor information including self-reported diabetes was linked with information on subsequent acute myocardial infarction (AMI) and acute cerebral stroke in hospital and mortality registry data throughout 2014 from the nationwide CVDNOR project. We developed an updated model using Cox regression with diabetes and South Asian ethnicity as additional predictors. We assessed model performance by Harrell's C and calibration plots. Results. The NORRISK 2 model underestimated the risk in South Asians in all quintiles of predicted risk. The mean predicted 13-year risk by the NORRISK 2 model was 3.9% (95% CI 3.7-4.2) versus observed 7.3% (95% CI 5.9-9.1) in South Asian men and 1.1% (95% CI 1.0-1.2) versus 2.7% (95% CI 1.7-4.2) observed risk in South Asian women. The mean predictions from the NORRISK 2-SADia model were 7.2% (95% CI 6.7-7.6) in South Asian men and 2.7% (95% CI 2.4-3.0) in South Asian women. Conclusions. The NORRISK 2-SADia model improved predictions of CVD substantially in South Asians, whose risks were underestimated by the NORRISK 2 model. The NORRISK 2-SADia model may facilitate more intense preventive measures in this high-risk population.

Cannabis Use during Pregnancy and Risk of Adverse Birth Outcomes: A Longitudinal Cohort Study.

BACKGROUND: With recent changes in legislation regulating recreational and medical cannabis use around the globe, increased use in pregnancy is to be expected. OBJECTIVES: To investigate the association between cannabis use during pregnancy and birth outcomes. METHOD: Data from the Norwegian Mother and Child Cohort Study (MoBa), a prospective pregnancy cohort, were used. Participants were recruited from all over Norway between 1999 and 2008: 9,312 women with 10,373 pregnancies who reported use of cannabis before or in pregnancy. Women reported on their illegal drug use before pregnancy and at pregnancy weeks 17/18 and 30 and at 6 months postpartum. Linear regression was used to estimate crude and adjusted effects of prenatal cannabis exposure on birth outcomes. RESULTS: In 10,101 pregnancies, women had used cannabis before pregnancy but not during pregnancy. In 272 pregnancies, women had used cannabis during pregnancy, and among these, in 63 pregnancies, women had used cannabis in at least 2 periods. In adjusted analyses for potential confounders, only cannabis use during at least 2 periods of pregnancy showed statistically significant effects on birth weight. The effect was observed in the complete cohort (B = -228 g, 95% CI = -354 to -102, p < 0.001) and for the subgroup where information about the child's father was available (B = -225 g, 95% CI = -387 to -63, p = 0.01). Our results may indicate that prolonged use causes more harm, whereas short-term use did not indicate adverse effects on birth outcomes. CONCLUSIONS: There was a statistically significant and clinically relevant association between the use of cannabis during pregnancy and reduced birth weight. Clinicians should screen not only for cannabis use but also for the length and intensity of use as part of a comprehensive substance use screening.