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.

Using the waiting time distribution with random index dates to estimate prescription durations in the presence of seasonal stockpiling.

PURPOSE: A pervasive problem in registry-based pharmacoepidemiological studies is what exposure duration to assign to individual prescriptions. The parametric waiting time distribution (WTD) has been proposed as a method to estimate such durations. However, when prescription durations vary due to seasonal stockpiling, WTD estimates will vary with choice of index date. To counter this, we propose using random index dates. METHODS: Within a calendar period of a given length, δ, we randomly sample individual index dates. We include the last prescription redemption prior to the index date in the analysis. Only redemptions within distance δ of the index date are included. In a simulation study with varying types and degrees of stockpiling at the end of the year, we investigated bias and precision of the reverse WTD with fixed and random index dates, respectively. In addition, we applied the new method to estimate durations of Norwegian warfarin prescriptions in 2014. RESULTS: In simulation settings with stockpiling, the reverse WTD with random index dates had low relative biases (-0.65% to 6.64%) and high coverage probabilities (92.0% to 95.3%), although when stockpiling was pronounced, coverage probabilities decreased (2.7% to 85.8%). Using a fixed index date was inferior. The estimated duration of warfarin prescriptions in Norway using random index dates was 131 (130; 132) days. CONCLUSIONS: In the presence of seasonal stockpiling, the WTD with random index dates provides estimates of prescription durations, which are more stable, less biased and with better coverage when compared to using a fixed index date.

Risk thresholds for alcohol consumption: combined analysis of individual-participant data for 599 912 current drinkers in 83 prospective studies.

BACKGROUND: Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease. METHODS: We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose-response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th-95th percentile 1·04-13·5]) from 71 011 participants from 37 studies. FINDINGS: In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1·14, 95% CI, 1·10-1·17), coronary disease excluding myocardial infarction (1·06, 1·00-1·11), heart failure (1·09, 1·03-1·15), fatal hypertensive disease (1·24, 1·15-1·33); and fatal aortic aneurysm (1·15, 1·03-1·28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0·94, 0·91-0·97). In comparison to those who reported drinking >0-≤100 g per week, those who reported drinking >100-≤200 g per week, >200-≤350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1-2 years, or 4-5 years, respectively. INTERPRETATION: In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines. FUNDING: UK Medical Research Council, British Heart Foundation, National Institute for Health Research, European Union Framework 7, and European Research Council.

Educational inequalities in midlife risk factors for non-communicable diseases in two Norwegian counties 1974-2002.

Background: The absolute educational differences in the mortality of Norwegian women and men increased during 1960-2000 and thereafter levelled off in men, but continued to widen in women. Which of the risk factors for non-communicable diseases (NCDs) might explain these trends? Aim: The aim of this study was to investigate trends in gender-specific, absolute educational differences in established risk factors during 1974-2002. Methods: We used cross-sectional data from 40-45-year-old women and men who participated in one of three health surveys in two counties, from the years 1974-1978, 1985-1988 and 2001-2002. To account for increasing educational attainment through the period we used a regression-based index of inequality (Slope Index of Inequality) to assess the educational gradients over time. Results: From 1974 to 2002, the mean levels of serum total cholesterol and blood pressure decreased and body mass index (BMI) increased in all subgroups by education in both sexes. In men, the educational gradient tended to diminish toward the null for serum total cholesterol and narrowed for systolic blood pressure, but increased for BMI. In women, the educational gradient increased to the double for smoking and increased for triglycerides. Conclusions: In two Norwegian counties, the NCD risk factors showed dynamic patterns during 1974-2002. For blood pressure and serum total cholesterol, the levels showed consistent beneficial changes in all educational subgroups, with a narrowing tendency for educational gradients in men. In women, the educational gradient for smoking increased markedly. Knowledge on midlife trends in the educational gradients of risk factors may help to explain recent and future NCD mortality.

Ethnic inequalities in acute myocardial infarction and stroke rates in Norway 1994-2009: a nationwide cohort study (CVDNOR).

BACKGROUND: Immigrants to Norway from South Asia and Former Yugoslavia have high levels of cardiovascular disease (CVD) risk factors. Yet, the incidence of CVD among immigrants in Norway has never been studied. Our aim was to study the burden of acute myocardial infarction (AMI) and stroke among ethnic groups in Norway. METHODS: We studied the whole Norwegian population (n = 2,637,057) aged 35-64 years during 1994-2009. The Cardiovascular Disease in Norway (CVDNOR) project provided information about all AMI and stroke hospital stays for this period, as well as deaths outside hospital through linkage to the Cause of Death Registry. The direct standardization method was used to estimate age standardized AMI and stroke event rates for immigrants and ethnic Norwegians. Rate ratios (RR) with ethnic Norwegians as reference were calculated using Poisson regression. RESULTS: The highest risk of AMI was seen in South Asians (men RR = 2.27; 95 % CI 2.08-2.49; women RR = 2.10; 95 % CI 1.76-2.51) while the lowest was seen in East Asians (RR = 0.38 in both men (95 % CI 0.25-0.58) and women (95 % CI 0.18-0.79)). Immigrants from Former Yugoslavia and Central Asia also had increased risk of AMI compared to ethnic Norwegians. South Asians had increased risk of stroke (men RR = 1.26; 95 % CI 1.10-1.44; women RR = 1.58; 95 % CI 1.32-1.90), as did men from Former Yugoslavia, Sub-Saharan Africa and women from Southeast Asia. CONCLUSIONS: Preventive measures should be aimed at reducing the excess numbers of CVD among immigrants from South Asia and Former Yugoslavia.

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.

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.

Choice of generic antihypertensive drugs for the primary prevention of cardiovascular disease--a cost-effectiveness analysis.

BACKGROUND: Hypertension is one of the leading causes of cardiovascular disease (CVD). A range of antihypertensive drugs exists, and their prices vary widely mainly due to patent rights. The objective of this study was to explore the cost-effectiveness of different generic antihypertensive drugs as first, second and third choice for primary prevention of cardiovascular disease. METHODS: We used the Norwegian Cardiovascular Disease model (NorCaD) to simulate the cardiovascular life of patients from hypertension without symptoms until they were all dead or 100 years old. The risk of CVD events and costs were based on recent Norwegian sources. RESULTS: In single-drug treatment, all antihypertensives are cost-effective compared to no drug treatment. In the base-case analysis, the first, second and third choice of antihypertensive were calcium channel blocker, thiazide and angiotensin-converting enzyme inhibitor. However the sensitivity and scenario analyses indicated considerable uncertainty in that angiotensin receptor blockers as well as, angiotensin-converting enzyme inhibitors, beta blockers and thiazides could be the most cost-effective antihypertensive drugs. CONCLUSIONS: Generic antihypertensives are cost-effective in a wide range of risk groups. There is considerable uncertainty, however, regarding which drug is the most cost-effective.

Anticipated longevity among lay people screened for cardiovascular risk factors: a cross-sectional questionnaire study.

BACKGROUND: In terms of mental health and quality of life previous studies have largely failed to show long-term effects of cardiovascular risk information. Such information may still have an impact of a more subtle nature. We aimed to explore the potential impact of cardiovascular risk information on lay people's anticipations of their own longevity. METHODS: In 2002 11,284 Norwegians were invited to take part in a health survey. Participants (n = 6,845) received comprehensive written information about their personal risk factors for cardiovascular disease. About six months later we selected 752 high risk and 996 low risk individuals for a cross-sectional survey. Participants were mailed a questionnaire and informed about the life expectancy for women and men in Norway. Subsequently they were asked whether they expected to live longer, shorter than or approximately as long as the mean figures. RESULTS: The response rate was 75% (n = 1,314). Whereas 210 respondents (16%) expected to live shorter than the mean, 198 (15%) expected to live longer. In a multivariate regression model high risk of cardiovascular disease (CVD) was associated with lower anticipated longevity (odds ratio 2.4, 95% confidence interval 1.7-3.3). Other predictors of low anticipation were use of lipid lowering drugs and a family history of heart attack before the age of 60. Higher age, male sex, better education and good self-reported health were associated with high anticipations. CONCLUSIONS: A CVD risk label was only moderately associated with lay people's anticipated longevity. The majority expected to live as long as the mean, regardless of risk status.

[Risk factors for myocardial infarction, stroke and diabetes in Norway]. / Risikofaktorer for hjerteinfarkt, hjerneslag og diabetes i Norge.

BACKGROUND: Frequency of and mortality from coronary heart disease (CHD) have decreased,but type 2 diabetes is on the rise. Risk factors measured in health surveys 2000-2003 are presented and compared with recommended or ideal levels. MATERIAL AND METHODS: In five counties, all inhabitants aged 30, 40, 45, 60 or 75 years were invited to participate in the survey (participation rate 29-75%). RESULTS: In the age group 30-60 years, about 30% were daily smokers, 50% exercised < 3 hours per week, and 75-90% had total serum cholesterol > or = 5 mmol/L. By age 60 years 40-50% had elevated blood pressure and 23% were obese (body mass index (BMI) > or =30 kg/m2 ). Different measures of obesity, general and abdominal, produced somewhat different results. In younger men, BMI and waist circumference gave a higher obesity prevalence than waist-hip ratio. In contrast, for women aged 60 and 75 years BMI gave the lowest prevalence. INTERPRETATION: The burden of risk factors in the population is relatively high, and a further increase of overweight and diabetes may stem the decline of CHD. Establishment of a health monitoring system including risk factors is an important element of health promotion.

Can traditional risk factors explain the higher risk of cardiovascular disease in South Asians compared to Europeans in Norway and New Zealand? Two cohort studies.

OBJECTIVES: The objective was to prospectively examine potential differences in the risk of first cardiovascular disease (CVD) events between South Asians and Europeans living in Norway and New Zealand, and to investigate whether traditional risk factors could explain any differences. METHODS: We included participants (30-74 years) without prior CVD in a Norwegian (n=16 606) and a New Zealand (n=129 449) cohort. Ethnicity and cardiovascular risk factor information was linked with hospital registry data and cause of death registries to identify subsequent CVD events. We used Cox proportional hazards regression to investigate the relationship between risk factors and subsequent CVD for South Asians and Europeans, and to calculate age-adjusted HRs for CVD in South Asians versus Europeans in the two cohorts separately. We sequentially added the major CVD risk factors (blood pressure, lipids, diabetes and smoking) to study their explanatory role in observed ethnic CVD risk differences. RESULTS: South Asians had higher total cholesterol (TC)/high-density lipoprotein (HDL) ratio and more diabetes at baseline than Europeans, but lower blood pressure and smoking levels. South Asians had increased age-adjusted risk of CVD compared with Europeans (87%-92% higher in the Norwegian cohort and 42%-75% higher in the New Zealand cohort) and remained with significantly increased risk after adjusting for all major CVD risk factors. Adjusted HRs for South Asians versus Europeans in the Norwegian cohort were 1.57 (95% CI 1.19 to 2.07) in men and 1.76 (95% CI 1.09 to 2.82) in women. Corresponding figures for the New Zealand cohort were 1.64 (95% CI 1.43 to 1.88) in men and 1.39 (95% CI 1.11 to 1.73) in women. CONCLUSION: Differences in TC/HDL ratio and diabetes appear to explain some of the excess risk of CVD in South Asians compared with Europeans. Preventing dyslipidaemia and diabetes in South Asians may therefore help reduce their excess risk of CVD.

Body mass index and mortality: the influence of physical activity and smoking.

PURPOSE: To study the association between body mass index (BMI) and mortality, and to evaluate the effect of physical activity during leisure time and smoking on this association in a general male population. METHODS: During 1974-1978, all men aged 35-49 yr living in three Norwegian counties were invited to a cardiovascular screening, and 87.1% attended and had their weight and height measured. Men with recognized cardiovascular diseases, diabetes mellitus, or cancer at screening were excluded. The cohort (N = 22,304) was followed for an average of 16.3 yr with respect to total and cause-specific mortality. RESULTS: During follow-up, 1909 men died. We found a J-shaped association between BMI and total mortality, and the form of association was similar for death from cardiovascular diseases. Although not statistically significant, a J-shaped association was also suggested in never-smokers. Irrespective of BMI level, ex- and never-smokers had lower mortality than current smokers. Obese smoking men had a relative risk of dying of 2.01 (95% CI: 1.29-3.11) compared with obese never-smokers, and a relative risk of 4.55 (95% CI: 3.34-6.20) compared with normal weight never-smokers (BMI 22-24.9 kg x m(-2)). Within each category of physical activity during leisure time, obese men had a similar increased relative risk of death compared with normal-weight individuals. However, the U- to J-shaped association between BMI and mortality seemed to disappear by increasing level of physical activity, but this finding was not significant. CONCLUSION: This study suggests a J-shaped association between BMI and total mortality, also when stratified on smoking habits and physical activity. The suggested linear trend in the most physical active men needs to be reassessed.

Ethnic differences in risk factors and total risk of cardiovascular disease based on the Norwegian CONOR study.

BACKGROUND: Risk of cardiovascular disease varies between ethnic groups and the aim of this study was to investigate differences in cardiovascular risk factors, and total cardiovascular risk between ethnic groups in Norway. DESIGN: Cross-sectional study using data from the Cohort of Norway (CONOR). METHODS: A sample of 62,145 participants, 40-65 years of age, originating from 11 geographical regions, were included in our study. Self-reported variables, blood samples and physical measurements were used to estimate age- and time-adjusted mean values of cardiovascular risk factors for different ethnic groups. The 10-year risks of cardiovascular mortality and cardiovascular events were calculated using the Framingham and NORRISK risk models. RESULTS: We observed differences between ethnic groups for cardiovascular risk factors and both Framingham and NORRISK risk scores. NORRISK showed significant differences by ethnicity in women only. Immigrants from the Indian subcontinent had the lowest high-density lipoprotein (HDL) levels, the highest levels of blood glucose, triglycerides, total cholesterol/HDL ratio, waist hip ratio and diabetes prevalence. Immigrants from the former Yugoslavia had the highest Framingham scores, high blood pressure, high total cholesterol/HDL ratio, overweight measures and smoking. Low cardiovascular risk was observed among East Asian immigrants. CONCLUSION: The previously reported excess cardiovascular risk among immigrants from the Indian subcontinent was supported in this study. We also showed that immigrants from the former Yugoslavian countries had a higher total 10-year risk of cardiovascular events than other ethnic groups. This study adds information about ethnic groups in Norway which needs to be addressed in further research and targeted prevention strategies.

[Screening of 40-year-olds--400,000 men and women attended]. / 40-åringsundersøkelsene--400,000 menn og kvinner har møtt opp.

Over the period 1984-99, 400,000 Norwegian men and women aged 40-42 attended cardiovascular screenings carried out by the national health screening service. The data are available for research on application to the Norwegian Institute of Public Health. Details on the data and applications procedures are given in this article.